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Statins raise the risks for increased glucose levels and the development of type 2 diabetes among people who don’t have it at baseline, but those risks are outweighed by the cardiovascular benefit, new data suggested.

The findings come from an analysis of individual participant data from a total of 23 randomized trials of statin therapy involving 154,664 individuals. In people without diabetes at baseline, statin therapy produces a dose-dependent increase in the risk for diabetes diagnosis, particularly among those whose glycemia marker levels are already at the diagnostic threshold.

Statins also tend to raise glucose levels in people who already have diabetes, but “the diabetes-related risks arising from the small changes in glycemia resulting from statin therapy are greatly outweighed by the benefits of statins on major vascular events when the direct clinical consequences of these outcomes are taken into consideration,” wrote the authors of the Cholesterol Treatment Trialists’ (CTT) Collaboration in their paper, published online in The Lancet Diabetes & Endocrinology.

Moreover, they say, “since the effect of statin therapy on measures of glycemia within an individual is small, there is likely to be little clinical benefit in measuring glucose concentrations and A1c values routinely after starting statin therapy with the aim of making comparisons to values taken before the initiation of a statin. However, people should continue to be screened for diabetes and associated risk factors and have their glycemic control monitored in accordance with current clinical guidelines.”

The CTT is co-led by Christina Reith, MBChB, PhD, and David Preiss, PhD, FRCPath, MRCP, both of the Nuffield Department of Population Health, University of Oxford, England.

In an accompanying editorial, Hertzel C. Gerstein, MD, and Marie Pigeyre, MD, PhD, both of McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada, noted that the decreased absolute annual incidence of life-threatening cardiovascular outcomes with statins in people at high risk for type 2 diabetes “clearly exceeds the 0.1%-1.3% per year increased absolute incidence of type 2 diabetes.”

Dr. Gerstein and Dr. Pigeyre also said “these findings emphasize the importance of holistic care. As people at risk for cardiovascular outcomes are also at risk for type 2 diabetes, any prescription of a statin should be accompanied by promoting proven strategies to prevent or delay diabetes, such as modest weight reduction and increased physical activity. Finally, these findings emphasize the importance of always being alert for harmful adverse effects, even with the most beneficial and successful preventive therapies.”
 

Statins Raise Diabetes Risk, Glucose Levels Slightly

The meta-analysis of trials in the CTT Collaboration included individual participant data from 19 double-blind randomized, controlled trials with a median follow-up of 4.3 years comparing statins with placebo in a total of 123,940 participants, including 18% who had known type 2 diabetes at randomization. Also analyzed were another four double-blind trials of lower- vs higher-intensity statins involving a total of 30,724 participants followed for a median of 4.9 years, with 15% having diabetes at baseline.

In the 19 trials of low- or moderate-intensity statins vs placebo, statins resulted in a significant 10% increase in new-onset diabetes compared with placebo (rate ratio, 1.10), while high-intensity statins raised the risk by an also significant 36% (1.36). This translated to a mean absolute excess of 0.12% per year of treatment.

Compared with less intensive statin therapy, more intensive statin therapy resulted in a significant 10% proportional increase in new-onset diabetes (1.10), giving an absolute annual excess of 0.22%.

In the statin vs placebo trials, differences in A1c values from placebo were 0.06 percentage points higher for low- or moderate-intensity statins and 0.08 points greater for high-intensity statins.

Nearly two thirds (62%) of the excess cases of new-onset diabetes occurred among participants in the highest quarter of the baseline glycemia distribution for both low-intensity or moderate-intensity and high-intensity statin therapy.

And among participants who already had diabetes at baseline, there was a significant 10% relative increase in worsening glycemia (defined by adverse glycemic event, A1c increase of ≥ 0.5 percentage points, or medication escalation) with low- or moderate-intensity statins compared with placebo and a 24% relative increase in the high-intensity trials.

The Nuffield Department of Population Health has an explicit policy of not accepting any personal honoraria payments directly or indirectly from the pharmaceutical and food industries. It seeks reimbursement to the University of Oxford for the costs of travel and accommodation to participate in scientific meetings. Dr. Reith reported receiving funding to the University of Oxford from the UK National Institute for Health and Care Research Health Technology Assessment Programme and holding unpaid roles on the Clinical Data Interchange Standards Consortium as a board member and WHO as a scientific advisor. Dr. Preiss reported receiving funding to his research institution (but no personal funding) from Novartis for the ORION 4 trial of inclisiran, Novo Nordisk for the ASCEND PLUS trial of semaglutide, and Boehringer Ingelheim and Eli Lilly for the EMPA-KIDNEY trial and being a committee member for a National Institute for Health and Care Excellence guideline.

Dr. Gerstein holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. He reported research grants from Eli Lilly, AstraZeneca, Novo Nordisk, Hanmi, and Merck; continuing medical education grants to McMaster University from Eli Lilly, Abbott, Sanofi, Novo Nordisk, and Boehringer Ingelheim; honoraria for speaking from AstraZeneca, Eli Lilly, Novo Nordisk, DKSH, Zuellig Pharma, Sanofi, and Jiangsu Hanson; and consulting fees from Abbott, Eli Lilly, Novo Nordisk, Pfizer, Carbon Brand, Sanofi, Kowa, and Hanmi. Pigeyre had no disclosures.
 

A version of this article appeared on Medscape.com.

Statins raise the risks for increased glucose levels and the development of type 2 diabetes among people who don’t have it at baseline, but those risks are outweighed by the cardiovascular benefit, new data suggested.

The findings come from an analysis of individual participant data from a total of 23 randomized trials of statin therapy involving 154,664 individuals. In people without diabetes at baseline, statin therapy produces a dose-dependent increase in the risk for diabetes diagnosis, particularly among those whose glycemia marker levels are already at the diagnostic threshold.

Statins also tend to raise glucose levels in people who already have diabetes, but “the diabetes-related risks arising from the small changes in glycemia resulting from statin therapy are greatly outweighed by the benefits of statins on major vascular events when the direct clinical consequences of these outcomes are taken into consideration,” wrote the authors of the Cholesterol Treatment Trialists’ (CTT) Collaboration in their paper, published online in The Lancet Diabetes & Endocrinology.

Moreover, they say, “since the effect of statin therapy on measures of glycemia within an individual is small, there is likely to be little clinical benefit in measuring glucose concentrations and A1c values routinely after starting statin therapy with the aim of making comparisons to values taken before the initiation of a statin. However, people should continue to be screened for diabetes and associated risk factors and have their glycemic control monitored in accordance with current clinical guidelines.”

The CTT is co-led by Christina Reith, MBChB, PhD, and David Preiss, PhD, FRCPath, MRCP, both of the Nuffield Department of Population Health, University of Oxford, England.

In an accompanying editorial, Hertzel C. Gerstein, MD, and Marie Pigeyre, MD, PhD, both of McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada, noted that the decreased absolute annual incidence of life-threatening cardiovascular outcomes with statins in people at high risk for type 2 diabetes “clearly exceeds the 0.1%-1.3% per year increased absolute incidence of type 2 diabetes.”

Dr. Gerstein and Dr. Pigeyre also said “these findings emphasize the importance of holistic care. As people at risk for cardiovascular outcomes are also at risk for type 2 diabetes, any prescription of a statin should be accompanied by promoting proven strategies to prevent or delay diabetes, such as modest weight reduction and increased physical activity. Finally, these findings emphasize the importance of always being alert for harmful adverse effects, even with the most beneficial and successful preventive therapies.”
 

Statins Raise Diabetes Risk, Glucose Levels Slightly

The meta-analysis of trials in the CTT Collaboration included individual participant data from 19 double-blind randomized, controlled trials with a median follow-up of 4.3 years comparing statins with placebo in a total of 123,940 participants, including 18% who had known type 2 diabetes at randomization. Also analyzed were another four double-blind trials of lower- vs higher-intensity statins involving a total of 30,724 participants followed for a median of 4.9 years, with 15% having diabetes at baseline.

In the 19 trials of low- or moderate-intensity statins vs placebo, statins resulted in a significant 10% increase in new-onset diabetes compared with placebo (rate ratio, 1.10), while high-intensity statins raised the risk by an also significant 36% (1.36). This translated to a mean absolute excess of 0.12% per year of treatment.

Compared with less intensive statin therapy, more intensive statin therapy resulted in a significant 10% proportional increase in new-onset diabetes (1.10), giving an absolute annual excess of 0.22%.

In the statin vs placebo trials, differences in A1c values from placebo were 0.06 percentage points higher for low- or moderate-intensity statins and 0.08 points greater for high-intensity statins.

Nearly two thirds (62%) of the excess cases of new-onset diabetes occurred among participants in the highest quarter of the baseline glycemia distribution for both low-intensity or moderate-intensity and high-intensity statin therapy.

And among participants who already had diabetes at baseline, there was a significant 10% relative increase in worsening glycemia (defined by adverse glycemic event, A1c increase of ≥ 0.5 percentage points, or medication escalation) with low- or moderate-intensity statins compared with placebo and a 24% relative increase in the high-intensity trials.

The Nuffield Department of Population Health has an explicit policy of not accepting any personal honoraria payments directly or indirectly from the pharmaceutical and food industries. It seeks reimbursement to the University of Oxford for the costs of travel and accommodation to participate in scientific meetings. Dr. Reith reported receiving funding to the University of Oxford from the UK National Institute for Health and Care Research Health Technology Assessment Programme and holding unpaid roles on the Clinical Data Interchange Standards Consortium as a board member and WHO as a scientific advisor. Dr. Preiss reported receiving funding to his research institution (but no personal funding) from Novartis for the ORION 4 trial of inclisiran, Novo Nordisk for the ASCEND PLUS trial of semaglutide, and Boehringer Ingelheim and Eli Lilly for the EMPA-KIDNEY trial and being a committee member for a National Institute for Health and Care Excellence guideline.

Dr. Gerstein holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. He reported research grants from Eli Lilly, AstraZeneca, Novo Nordisk, Hanmi, and Merck; continuing medical education grants to McMaster University from Eli Lilly, Abbott, Sanofi, Novo Nordisk, and Boehringer Ingelheim; honoraria for speaking from AstraZeneca, Eli Lilly, Novo Nordisk, DKSH, Zuellig Pharma, Sanofi, and Jiangsu Hanson; and consulting fees from Abbott, Eli Lilly, Novo Nordisk, Pfizer, Carbon Brand, Sanofi, Kowa, and Hanmi. Pigeyre had no disclosures.
 

A version of this article appeared on Medscape.com.

Statins raise the risks for increased glucose levels and the development of type 2 diabetes among people who don’t have it at baseline, but those risks are outweighed by the cardiovascular benefit, new data suggested.

The findings come from an analysis of individual participant data from a total of 23 randomized trials of statin therapy involving 154,664 individuals. In people without diabetes at baseline, statin therapy produces a dose-dependent increase in the risk for diabetes diagnosis, particularly among those whose glycemia marker levels are already at the diagnostic threshold.

Statins also tend to raise glucose levels in people who already have diabetes, but “the diabetes-related risks arising from the small changes in glycemia resulting from statin therapy are greatly outweighed by the benefits of statins on major vascular events when the direct clinical consequences of these outcomes are taken into consideration,” wrote the authors of the Cholesterol Treatment Trialists’ (CTT) Collaboration in their paper, published online in The Lancet Diabetes & Endocrinology.

Moreover, they say, “since the effect of statin therapy on measures of glycemia within an individual is small, there is likely to be little clinical benefit in measuring glucose concentrations and A1c values routinely after starting statin therapy with the aim of making comparisons to values taken before the initiation of a statin. However, people should continue to be screened for diabetes and associated risk factors and have their glycemic control monitored in accordance with current clinical guidelines.”

The CTT is co-led by Christina Reith, MBChB, PhD, and David Preiss, PhD, FRCPath, MRCP, both of the Nuffield Department of Population Health, University of Oxford, England.

In an accompanying editorial, Hertzel C. Gerstein, MD, and Marie Pigeyre, MD, PhD, both of McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada, noted that the decreased absolute annual incidence of life-threatening cardiovascular outcomes with statins in people at high risk for type 2 diabetes “clearly exceeds the 0.1%-1.3% per year increased absolute incidence of type 2 diabetes.”

Dr. Gerstein and Dr. Pigeyre also said “these findings emphasize the importance of holistic care. As people at risk for cardiovascular outcomes are also at risk for type 2 diabetes, any prescription of a statin should be accompanied by promoting proven strategies to prevent or delay diabetes, such as modest weight reduction and increased physical activity. Finally, these findings emphasize the importance of always being alert for harmful adverse effects, even with the most beneficial and successful preventive therapies.”
 

Statins Raise Diabetes Risk, Glucose Levels Slightly

The meta-analysis of trials in the CTT Collaboration included individual participant data from 19 double-blind randomized, controlled trials with a median follow-up of 4.3 years comparing statins with placebo in a total of 123,940 participants, including 18% who had known type 2 diabetes at randomization. Also analyzed were another four double-blind trials of lower- vs higher-intensity statins involving a total of 30,724 participants followed for a median of 4.9 years, with 15% having diabetes at baseline.

In the 19 trials of low- or moderate-intensity statins vs placebo, statins resulted in a significant 10% increase in new-onset diabetes compared with placebo (rate ratio, 1.10), while high-intensity statins raised the risk by an also significant 36% (1.36). This translated to a mean absolute excess of 0.12% per year of treatment.

Compared with less intensive statin therapy, more intensive statin therapy resulted in a significant 10% proportional increase in new-onset diabetes (1.10), giving an absolute annual excess of 0.22%.

In the statin vs placebo trials, differences in A1c values from placebo were 0.06 percentage points higher for low- or moderate-intensity statins and 0.08 points greater for high-intensity statins.

Nearly two thirds (62%) of the excess cases of new-onset diabetes occurred among participants in the highest quarter of the baseline glycemia distribution for both low-intensity or moderate-intensity and high-intensity statin therapy.

And among participants who already had diabetes at baseline, there was a significant 10% relative increase in worsening glycemia (defined by adverse glycemic event, A1c increase of ≥ 0.5 percentage points, or medication escalation) with low- or moderate-intensity statins compared with placebo and a 24% relative increase in the high-intensity trials.

The Nuffield Department of Population Health has an explicit policy of not accepting any personal honoraria payments directly or indirectly from the pharmaceutical and food industries. It seeks reimbursement to the University of Oxford for the costs of travel and accommodation to participate in scientific meetings. Dr. Reith reported receiving funding to the University of Oxford from the UK National Institute for Health and Care Research Health Technology Assessment Programme and holding unpaid roles on the Clinical Data Interchange Standards Consortium as a board member and WHO as a scientific advisor. Dr. Preiss reported receiving funding to his research institution (but no personal funding) from Novartis for the ORION 4 trial of inclisiran, Novo Nordisk for the ASCEND PLUS trial of semaglutide, and Boehringer Ingelheim and Eli Lilly for the EMPA-KIDNEY trial and being a committee member for a National Institute for Health and Care Excellence guideline.

Dr. Gerstein holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. He reported research grants from Eli Lilly, AstraZeneca, Novo Nordisk, Hanmi, and Merck; continuing medical education grants to McMaster University from Eli Lilly, Abbott, Sanofi, Novo Nordisk, and Boehringer Ingelheim; honoraria for speaking from AstraZeneca, Eli Lilly, Novo Nordisk, DKSH, Zuellig Pharma, Sanofi, and Jiangsu Hanson; and consulting fees from Abbott, Eli Lilly, Novo Nordisk, Pfizer, Carbon Brand, Sanofi, Kowa, and Hanmi. Pigeyre had no disclosures.
 

A version of this article appeared on Medscape.com.

ATLANTA — A novel antisense therapy called olezarsen reduced triglycerides (TGs) by approximately 50% with either of the two study doses relative to placebo and did so with a low relative risk for adverse events, new data from a phase 2b trial showed.

“The reduction in triglycerides was greater than that currently possible with any available therapy,” reported Brian A. Bergmark, MD, an interventional cardiologist at Brigham and Women’s Hospital, Boston.

The drug also produced meaningful improvements in multiple other lipid subfractions associated with increased cardiovascular (CV) risk, including ApoC-III, very low–density lipoprotein (VLDL) cholesterol, ApoB, and non-LDL cholesterol. High-density lipoprotein (HDL) cholesterol levels were significantly raised.

The results were presented on April 7 as a late breaker at the American College of Cardiology (ACC) Scientific Session 2024 and published online simultaneously in The New England Journal of Medicine.
 

No Major Subgroup Failed to Respond

The effect was seen across all the key subgroups evaluated, including women and patients with diabetes, obesity, and severe as well as moderate elevations in TGs at baseline, Dr. Bergmark reported.

Olezarsen is a N-acetylgalactosamine–conjugated antisense oligonucleotide targeting APOC3 RNA. The results of this randomized trial, called BRIDGE-TIMI 73a, are consistent with other evidence that inhibiting expression of ApoC-III lowers the levels of TGs and other lipid subfractions to a degree that would predict clinical benefit.

In this study, 154 patients at 24 sites in North America were randomized in a 1:1 ratio to 50 or 80 mg olezarsen. Those in each of these cohorts were then randomized in a 3:1 ratio to active therapy or placebo. All therapies were administered by subcutaneous injection once per month.

Patients were eligible for the trial if they had moderate hypertriglyceridemia, defined as a level of 150-499 mg/dL, and elevated CV risk or if they had severe hypertriglyceridemia (≥ 500 mg/dL) with or without other evidence of elevated CV risk. The primary endpoint was a change in TGs at 6 months. Complete follow-up was available in about 97% of patients regardless of treatment assignment.

With a slight numerical advantage for the higher dose, the TG reductions were 49.1% for the 50-mg dose and 53.1% for the 80-mg dose relative to no significant change in the placebo group (P < .001 for both olezarsen doses). The reductions in ApoC-III, an upstream driver of TG production and a CV risk factor, were 64.2% and 73.2% relative to placebo (both P < .001), respectively, Dr. Bergmark reported.

In those with moderate hypertriglyceridemia, normal TG levels, defined as < 150 mg/dL, were reached at 6 months in 85.7% and 93.3% in the 40-mg and 80-mg dose groups, respectively. Relative to these reductions, normalization was seen in only 11.8% of placebo patients (P < .001).
 

TG Lowering Might Not Be Best Endpoint

The primary endpoint in this trial was a change in TGs, but this target was questioned by an invited ACC discussant, Daniel Soffer, MD, who is both an adjunct professor assistant professor of medicine at Penn Medicine, Philadelphia, and current president of the National Lipid Association.

Dr. Soffer noted that highly elevated TGs are a major risk factor for acute pancreatitis, so this predicts a clinical benefit for this purpose, but he thought the other lipid subfractions are far more important for the goal of reducing atherosclerotic cardiovascular disease (ASCVD).

Indeed, he said categorically that it is not TGs that drive ASCVD risk and therefore not what is the real importance of these data. Rather, “it is the non-HDL cholesterol and ApoB lowering” that will drive the likely benefits from this therapy in CV disease.

In addition to the TG reductions, olezarsen did, in fact, produce significant reductions in many of the lipid subfractions associated with increased CV risk. While slightly more favorable in most cases with the higher dose of olezarsen, even the lower dose reduced Apo C-III from baseline by 64.2% (P < .001), VLDL by 46.2% (P < .001), remnant cholesterol by 46.6% (P < .001), ApoB by 18.2% (P < .001), and non-HDL cholesterol by 25.4% (P < .001). HDL cholesterol was increased by 39.6% (P < .001).

These favorable effects on TG and other lipid subfractions were achieved with a safety profile that was reassuring, Dr. Bergmark said. Serious adverse events leading to discontinuation occurred in 0%, 1.7%, and 1.8% of the placebo, lower-dose, and higher-dose arms, respectively. These rates did not differ significantly.
 

Increased Liver Enzymes Is Common

Liver enzymes were significantly elevated (P < .001) for both doses of olezarsen vs placebo, but liver enzymes > 3× the upper limit of normal did not reach significance on either dose of olezarsen relative to placebo. Low platelet counts and reductions in kidney function were observed in a minority of patients but were generally manageable, according to Dr. Bergmark. There was no impact on hemoglobin A1c levels.

Further evaluation of change in hepatic function is planned in the ongoing extension studies.

Characterizing these results as “exciting,” Neha J. Pagidipati, MD, a member of the Duke Clinical Research Institute and an assistant professor at the Duke School of Medicine, Durham, North Carolina, said that identifying a drug effective for hypertriglyceridemia is likely to be a major advance. While elevated TGs are “one of the toughest” lipid abnormalities to manage, “there is not much out there to offer for treatment.”

She, like Dr. Soffer, was encouraged by the favorable effects on multiple lipid abnormalities associated with increased CV risk, but she said the ultimate clinical utility of this or other agents that lower TGs for ASCVD requires a study showing a change in CV events.

Dr. Bergmark reported financial relationships with 15 pharmaceutical companies, including Ionis, which provided funding for the BRIDGE-TIMI 73a trial. Soffer had financial relationships with Akcea, Amgen, Amryt, AstraZeneca, Ionis, Novartis, Regeneron, and Verve. Dr. Pagidipati had financial relationships with more than 10 pharmaceutical companies but was not involved in the design of management of the BRIDGE-TIMI 73a trial.

A version of this article first appeared on Medscape.com.

ATLANTA — A novel antisense therapy called olezarsen reduced triglycerides (TGs) by approximately 50% with either of the two study doses relative to placebo and did so with a low relative risk for adverse events, new data from a phase 2b trial showed.

“The reduction in triglycerides was greater than that currently possible with any available therapy,” reported Brian A. Bergmark, MD, an interventional cardiologist at Brigham and Women’s Hospital, Boston.

The drug also produced meaningful improvements in multiple other lipid subfractions associated with increased cardiovascular (CV) risk, including ApoC-III, very low–density lipoprotein (VLDL) cholesterol, ApoB, and non-LDL cholesterol. High-density lipoprotein (HDL) cholesterol levels were significantly raised.

The results were presented on April 7 as a late breaker at the American College of Cardiology (ACC) Scientific Session 2024 and published online simultaneously in The New England Journal of Medicine.
 

No Major Subgroup Failed to Respond

The effect was seen across all the key subgroups evaluated, including women and patients with diabetes, obesity, and severe as well as moderate elevations in TGs at baseline, Dr. Bergmark reported.

Olezarsen is a N-acetylgalactosamine–conjugated antisense oligonucleotide targeting APOC3 RNA. The results of this randomized trial, called BRIDGE-TIMI 73a, are consistent with other evidence that inhibiting expression of ApoC-III lowers the levels of TGs and other lipid subfractions to a degree that would predict clinical benefit.

In this study, 154 patients at 24 sites in North America were randomized in a 1:1 ratio to 50 or 80 mg olezarsen. Those in each of these cohorts were then randomized in a 3:1 ratio to active therapy or placebo. All therapies were administered by subcutaneous injection once per month.

Patients were eligible for the trial if they had moderate hypertriglyceridemia, defined as a level of 150-499 mg/dL, and elevated CV risk or if they had severe hypertriglyceridemia (≥ 500 mg/dL) with or without other evidence of elevated CV risk. The primary endpoint was a change in TGs at 6 months. Complete follow-up was available in about 97% of patients regardless of treatment assignment.

With a slight numerical advantage for the higher dose, the TG reductions were 49.1% for the 50-mg dose and 53.1% for the 80-mg dose relative to no significant change in the placebo group (P < .001 for both olezarsen doses). The reductions in ApoC-III, an upstream driver of TG production and a CV risk factor, were 64.2% and 73.2% relative to placebo (both P < .001), respectively, Dr. Bergmark reported.

In those with moderate hypertriglyceridemia, normal TG levels, defined as < 150 mg/dL, were reached at 6 months in 85.7% and 93.3% in the 40-mg and 80-mg dose groups, respectively. Relative to these reductions, normalization was seen in only 11.8% of placebo patients (P < .001).
 

TG Lowering Might Not Be Best Endpoint

The primary endpoint in this trial was a change in TGs, but this target was questioned by an invited ACC discussant, Daniel Soffer, MD, who is both an adjunct professor assistant professor of medicine at Penn Medicine, Philadelphia, and current president of the National Lipid Association.

Dr. Soffer noted that highly elevated TGs are a major risk factor for acute pancreatitis, so this predicts a clinical benefit for this purpose, but he thought the other lipid subfractions are far more important for the goal of reducing atherosclerotic cardiovascular disease (ASCVD).

Indeed, he said categorically that it is not TGs that drive ASCVD risk and therefore not what is the real importance of these data. Rather, “it is the non-HDL cholesterol and ApoB lowering” that will drive the likely benefits from this therapy in CV disease.

In addition to the TG reductions, olezarsen did, in fact, produce significant reductions in many of the lipid subfractions associated with increased CV risk. While slightly more favorable in most cases with the higher dose of olezarsen, even the lower dose reduced Apo C-III from baseline by 64.2% (P < .001), VLDL by 46.2% (P < .001), remnant cholesterol by 46.6% (P < .001), ApoB by 18.2% (P < .001), and non-HDL cholesterol by 25.4% (P < .001). HDL cholesterol was increased by 39.6% (P < .001).

These favorable effects on TG and other lipid subfractions were achieved with a safety profile that was reassuring, Dr. Bergmark said. Serious adverse events leading to discontinuation occurred in 0%, 1.7%, and 1.8% of the placebo, lower-dose, and higher-dose arms, respectively. These rates did not differ significantly.
 

Increased Liver Enzymes Is Common

Liver enzymes were significantly elevated (P < .001) for both doses of olezarsen vs placebo, but liver enzymes > 3× the upper limit of normal did not reach significance on either dose of olezarsen relative to placebo. Low platelet counts and reductions in kidney function were observed in a minority of patients but were generally manageable, according to Dr. Bergmark. There was no impact on hemoglobin A1c levels.

Further evaluation of change in hepatic function is planned in the ongoing extension studies.

Characterizing these results as “exciting,” Neha J. Pagidipati, MD, a member of the Duke Clinical Research Institute and an assistant professor at the Duke School of Medicine, Durham, North Carolina, said that identifying a drug effective for hypertriglyceridemia is likely to be a major advance. While elevated TGs are “one of the toughest” lipid abnormalities to manage, “there is not much out there to offer for treatment.”

She, like Dr. Soffer, was encouraged by the favorable effects on multiple lipid abnormalities associated with increased CV risk, but she said the ultimate clinical utility of this or other agents that lower TGs for ASCVD requires a study showing a change in CV events.

Dr. Bergmark reported financial relationships with 15 pharmaceutical companies, including Ionis, which provided funding for the BRIDGE-TIMI 73a trial. Soffer had financial relationships with Akcea, Amgen, Amryt, AstraZeneca, Ionis, Novartis, Regeneron, and Verve. Dr. Pagidipati had financial relationships with more than 10 pharmaceutical companies but was not involved in the design of management of the BRIDGE-TIMI 73a trial.

A version of this article first appeared on Medscape.com.

ATLANTA — A novel antisense therapy called olezarsen reduced triglycerides (TGs) by approximately 50% with either of the two study doses relative to placebo and did so with a low relative risk for adverse events, new data from a phase 2b trial showed.

“The reduction in triglycerides was greater than that currently possible with any available therapy,” reported Brian A. Bergmark, MD, an interventional cardiologist at Brigham and Women’s Hospital, Boston.

The drug also produced meaningful improvements in multiple other lipid subfractions associated with increased cardiovascular (CV) risk, including ApoC-III, very low–density lipoprotein (VLDL) cholesterol, ApoB, and non-LDL cholesterol. High-density lipoprotein (HDL) cholesterol levels were significantly raised.

The results were presented on April 7 as a late breaker at the American College of Cardiology (ACC) Scientific Session 2024 and published online simultaneously in The New England Journal of Medicine.
 

No Major Subgroup Failed to Respond

The effect was seen across all the key subgroups evaluated, including women and patients with diabetes, obesity, and severe as well as moderate elevations in TGs at baseline, Dr. Bergmark reported.

Olezarsen is a N-acetylgalactosamine–conjugated antisense oligonucleotide targeting APOC3 RNA. The results of this randomized trial, called BRIDGE-TIMI 73a, are consistent with other evidence that inhibiting expression of ApoC-III lowers the levels of TGs and other lipid subfractions to a degree that would predict clinical benefit.

In this study, 154 patients at 24 sites in North America were randomized in a 1:1 ratio to 50 or 80 mg olezarsen. Those in each of these cohorts were then randomized in a 3:1 ratio to active therapy or placebo. All therapies were administered by subcutaneous injection once per month.

Patients were eligible for the trial if they had moderate hypertriglyceridemia, defined as a level of 150-499 mg/dL, and elevated CV risk or if they had severe hypertriglyceridemia (≥ 500 mg/dL) with or without other evidence of elevated CV risk. The primary endpoint was a change in TGs at 6 months. Complete follow-up was available in about 97% of patients regardless of treatment assignment.

With a slight numerical advantage for the higher dose, the TG reductions were 49.1% for the 50-mg dose and 53.1% for the 80-mg dose relative to no significant change in the placebo group (P < .001 for both olezarsen doses). The reductions in ApoC-III, an upstream driver of TG production and a CV risk factor, were 64.2% and 73.2% relative to placebo (both P < .001), respectively, Dr. Bergmark reported.

In those with moderate hypertriglyceridemia, normal TG levels, defined as < 150 mg/dL, were reached at 6 months in 85.7% and 93.3% in the 40-mg and 80-mg dose groups, respectively. Relative to these reductions, normalization was seen in only 11.8% of placebo patients (P < .001).
 

TG Lowering Might Not Be Best Endpoint

The primary endpoint in this trial was a change in TGs, but this target was questioned by an invited ACC discussant, Daniel Soffer, MD, who is both an adjunct professor assistant professor of medicine at Penn Medicine, Philadelphia, and current president of the National Lipid Association.

Dr. Soffer noted that highly elevated TGs are a major risk factor for acute pancreatitis, so this predicts a clinical benefit for this purpose, but he thought the other lipid subfractions are far more important for the goal of reducing atherosclerotic cardiovascular disease (ASCVD).

Indeed, he said categorically that it is not TGs that drive ASCVD risk and therefore not what is the real importance of these data. Rather, “it is the non-HDL cholesterol and ApoB lowering” that will drive the likely benefits from this therapy in CV disease.

In addition to the TG reductions, olezarsen did, in fact, produce significant reductions in many of the lipid subfractions associated with increased CV risk. While slightly more favorable in most cases with the higher dose of olezarsen, even the lower dose reduced Apo C-III from baseline by 64.2% (P < .001), VLDL by 46.2% (P < .001), remnant cholesterol by 46.6% (P < .001), ApoB by 18.2% (P < .001), and non-HDL cholesterol by 25.4% (P < .001). HDL cholesterol was increased by 39.6% (P < .001).

These favorable effects on TG and other lipid subfractions were achieved with a safety profile that was reassuring, Dr. Bergmark said. Serious adverse events leading to discontinuation occurred in 0%, 1.7%, and 1.8% of the placebo, lower-dose, and higher-dose arms, respectively. These rates did not differ significantly.
 

Increased Liver Enzymes Is Common

Liver enzymes were significantly elevated (P < .001) for both doses of olezarsen vs placebo, but liver enzymes > 3× the upper limit of normal did not reach significance on either dose of olezarsen relative to placebo. Low platelet counts and reductions in kidney function were observed in a minority of patients but were generally manageable, according to Dr. Bergmark. There was no impact on hemoglobin A1c levels.

Further evaluation of change in hepatic function is planned in the ongoing extension studies.

Characterizing these results as “exciting,” Neha J. Pagidipati, MD, a member of the Duke Clinical Research Institute and an assistant professor at the Duke School of Medicine, Durham, North Carolina, said that identifying a drug effective for hypertriglyceridemia is likely to be a major advance. While elevated TGs are “one of the toughest” lipid abnormalities to manage, “there is not much out there to offer for treatment.”

She, like Dr. Soffer, was encouraged by the favorable effects on multiple lipid abnormalities associated with increased CV risk, but she said the ultimate clinical utility of this or other agents that lower TGs for ASCVD requires a study showing a change in CV events.

Dr. Bergmark reported financial relationships with 15 pharmaceutical companies, including Ionis, which provided funding for the BRIDGE-TIMI 73a trial. Soffer had financial relationships with Akcea, Amgen, Amryt, AstraZeneca, Ionis, Novartis, Regeneron, and Verve. Dr. Pagidipati had financial relationships with more than 10 pharmaceutical companies but was not involved in the design of management of the BRIDGE-TIMI 73a trial.

A version of this article first appeared on Medscape.com.

TOPLINE:

Monthly cycles of a fasting-mimicking diet (FMD) may slow metabolic and immune system aging and reduce the risk for metabolic disease.

METHODOLOGY:

• In two clinical trials, monthly 5-day cycles of an FMD (a proprietary line of plant-based, low-calorie, and low-protein food products) showed lower body weight, body fat, and blood pressure at 3 months.
• Researchers assessed secondary outcomes for the impact of the diet on risk factors for metabolic syndrome and biomarkers associated with aging and age-related diseases.
• This study looked at data from nearly half of the original 184 participants (aged 18-70 years) from the two clinical trials who went through three to four monthly cycles, adhering to 5 days of an FMD in either a crossover design compared with a normal diet or an intervention group compared with people following a Mediterranean diet.
• Abdominal fat and hepatic fat were measured using an MRI in a subset of representative participants. The study also assessed metabolic blood markers and lipids and lymphoid-to-myeloid ratios (for immune aging).
• Biological age estimation was calculated from seven clinical chemistry measures, and life expectancy and mortality risk estimates and a simulation of continued FMD cycles were based on the National Health and Nutrition Examination Survey.

TAKEAWAY:

• In 15 volunteers measured by MRI, the body mass index (P = .0002), total body fat (P = .002), subcutaneous adipose tissue (P = .008), visceral adipose tissue (P = .002), and hepatic fat fraction (P = .049) reduced after the third FMD cycle, with a 50% reduction in liver fat for the five people with hepatic steatosis.
• In 11 participants with prediabetes, insulin resistance (measured by homeostatic model assessment) reduced from 1.473 to 1.209 (P = .046), while A1c levels dropped from 5.8 to 5.43 (P = .032) after the third FMD cycle.

• The lymphoid-to-myeloid ratio improved (P = .005) in all study participants receiving three FMD cycles, indicating an immune aging reversal.
• The estimated median biological age of the 86 participants who completed three FMD cycles in both trials decreased by nearly 2.5 years, independent of weight loss.

IN PRACTICE:

“Together our findings indicate that the FMD is a feasible periodic dietary intervention that reduces disease risk factors and biological age,” the authors wrote.

SOURCE:

The study, led by Sebastian Brandhorst, PhD, Leonard Davis School of Gerontology, University of Southern California (USC), Los Angeles, and Morgan E. Levine, PhD, Department of Pathology, Yale School of Medicine, New Haven, Connecticut, was published in Nature Communications.

LIMITATIONS:

The study estimated the effects of monthly FMD cycles based on results from two clinical trials and included a small subset of trial volunteers. By study measures, the cohort was healthier and biologically younger than average people of similar chronological age. Of the 86 participants, 24 who underwent FMD cycles exhibited increased biological age. The simulation did not consider compliance, dropout, mortality, or the bias that may arise owing to enthusiastic volunteers. Estimated risk reductions assume an effect of change in biological age, which hasn’t been proven. Projections from extending the effects of FMD to a lifelong intervention may require cautious interpretation.

DISCLOSURES:

The study was supported by the USC Edna Jones chair fund and funds from NIH/NIA and the Yale PEPPER Center. The experimental diet was provided by L-Nutra Inc. Some authors declared an equity interest in L-Nutra, with one author’s equity to be assigned to the nonprofit foundation Create Cures. Others disclosed no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Monthly cycles of a fasting-mimicking diet (FMD) may slow metabolic and immune system aging and reduce the risk for metabolic disease.

METHODOLOGY:

• In two clinical trials, monthly 5-day cycles of an FMD (a proprietary line of plant-based, low-calorie, and low-protein food products) showed lower body weight, body fat, and blood pressure at 3 months.
• Researchers assessed secondary outcomes for the impact of the diet on risk factors for metabolic syndrome and biomarkers associated with aging and age-related diseases.
• This study looked at data from nearly half of the original 184 participants (aged 18-70 years) from the two clinical trials who went through three to four monthly cycles, adhering to 5 days of an FMD in either a crossover design compared with a normal diet or an intervention group compared with people following a Mediterranean diet.
• Abdominal fat and hepatic fat were measured using an MRI in a subset of representative participants. The study also assessed metabolic blood markers and lipids and lymphoid-to-myeloid ratios (for immune aging).
• Biological age estimation was calculated from seven clinical chemistry measures, and life expectancy and mortality risk estimates and a simulation of continued FMD cycles were based on the National Health and Nutrition Examination Survey.

TAKEAWAY:

• In 15 volunteers measured by MRI, the body mass index (P = .0002), total body fat (P = .002), subcutaneous adipose tissue (P = .008), visceral adipose tissue (P = .002), and hepatic fat fraction (P = .049) reduced after the third FMD cycle, with a 50% reduction in liver fat for the five people with hepatic steatosis.
• In 11 participants with prediabetes, insulin resistance (measured by homeostatic model assessment) reduced from 1.473 to 1.209 (P = .046), while A1c levels dropped from 5.8 to 5.43 (P = .032) after the third FMD cycle.

• The lymphoid-to-myeloid ratio improved (P = .005) in all study participants receiving three FMD cycles, indicating an immune aging reversal.
• The estimated median biological age of the 86 participants who completed three FMD cycles in both trials decreased by nearly 2.5 years, independent of weight loss.

IN PRACTICE:

“Together our findings indicate that the FMD is a feasible periodic dietary intervention that reduces disease risk factors and biological age,” the authors wrote.

SOURCE:

The study, led by Sebastian Brandhorst, PhD, Leonard Davis School of Gerontology, University of Southern California (USC), Los Angeles, and Morgan E. Levine, PhD, Department of Pathology, Yale School of Medicine, New Haven, Connecticut, was published in Nature Communications.

LIMITATIONS:

The study estimated the effects of monthly FMD cycles based on results from two clinical trials and included a small subset of trial volunteers. By study measures, the cohort was healthier and biologically younger than average people of similar chronological age. Of the 86 participants, 24 who underwent FMD cycles exhibited increased biological age. The simulation did not consider compliance, dropout, mortality, or the bias that may arise owing to enthusiastic volunteers. Estimated risk reductions assume an effect of change in biological age, which hasn’t been proven. Projections from extending the effects of FMD to a lifelong intervention may require cautious interpretation.

DISCLOSURES:

The study was supported by the USC Edna Jones chair fund and funds from NIH/NIA and the Yale PEPPER Center. The experimental diet was provided by L-Nutra Inc. Some authors declared an equity interest in L-Nutra, with one author’s equity to be assigned to the nonprofit foundation Create Cures. Others disclosed no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Monthly cycles of a fasting-mimicking diet (FMD) may slow metabolic and immune system aging and reduce the risk for metabolic disease.

METHODOLOGY:

• In two clinical trials, monthly 5-day cycles of an FMD (a proprietary line of plant-based, low-calorie, and low-protein food products) showed lower body weight, body fat, and blood pressure at 3 months.
• Researchers assessed secondary outcomes for the impact of the diet on risk factors for metabolic syndrome and biomarkers associated with aging and age-related diseases.
• This study looked at data from nearly half of the original 184 participants (aged 18-70 years) from the two clinical trials who went through three to four monthly cycles, adhering to 5 days of an FMD in either a crossover design compared with a normal diet or an intervention group compared with people following a Mediterranean diet.
• Abdominal fat and hepatic fat were measured using an MRI in a subset of representative participants. The study also assessed metabolic blood markers and lipids and lymphoid-to-myeloid ratios (for immune aging).
• Biological age estimation was calculated from seven clinical chemistry measures, and life expectancy and mortality risk estimates and a simulation of continued FMD cycles were based on the National Health and Nutrition Examination Survey.

TAKEAWAY:

• In 15 volunteers measured by MRI, the body mass index (P = .0002), total body fat (P = .002), subcutaneous adipose tissue (P = .008), visceral adipose tissue (P = .002), and hepatic fat fraction (P = .049) reduced after the third FMD cycle, with a 50% reduction in liver fat for the five people with hepatic steatosis.
• In 11 participants with prediabetes, insulin resistance (measured by homeostatic model assessment) reduced from 1.473 to 1.209 (P = .046), while A1c levels dropped from 5.8 to 5.43 (P = .032) after the third FMD cycle.

• The lymphoid-to-myeloid ratio improved (P = .005) in all study participants receiving three FMD cycles, indicating an immune aging reversal.
• The estimated median biological age of the 86 participants who completed three FMD cycles in both trials decreased by nearly 2.5 years, independent of weight loss.

IN PRACTICE:

“Together our findings indicate that the FMD is a feasible periodic dietary intervention that reduces disease risk factors and biological age,” the authors wrote.

SOURCE:

The study, led by Sebastian Brandhorst, PhD, Leonard Davis School of Gerontology, University of Southern California (USC), Los Angeles, and Morgan E. Levine, PhD, Department of Pathology, Yale School of Medicine, New Haven, Connecticut, was published in Nature Communications.

LIMITATIONS:

The study estimated the effects of monthly FMD cycles based on results from two clinical trials and included a small subset of trial volunteers. By study measures, the cohort was healthier and biologically younger than average people of similar chronological age. Of the 86 participants, 24 who underwent FMD cycles exhibited increased biological age. The simulation did not consider compliance, dropout, mortality, or the bias that may arise owing to enthusiastic volunteers. Estimated risk reductions assume an effect of change in biological age, which hasn’t been proven. Projections from extending the effects of FMD to a lifelong intervention may require cautious interpretation.

DISCLOSURES:

The study was supported by the USC Edna Jones chair fund and funds from NIH/NIA and the Yale PEPPER Center. The experimental diet was provided by L-Nutra Inc. Some authors declared an equity interest in L-Nutra, with one author’s equity to be assigned to the nonprofit foundation Create Cures. Others disclosed no conflicts of interest.
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Fewer than half of the cancer drugs approved under the US Food and Drug Administration’s (FDA’s) accelerated approval pathway between 2013 and 2017 have been shown to improve overall survival or quality of life, despite being on the US market for more than 5 years, according to a new study. 

Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response. 

Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.

The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.

In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.

To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits. 

Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.

Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results. 

The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff. 

However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials. 

In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”

There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit. 

The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious. 

In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial. 

“There have been some promising steps,” Dr. Cliff said, but much work needs to be done. 

Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.” 

But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.

Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.” 

Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.” 

As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together. 

The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures. 
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Fewer than half of the cancer drugs approved under the US Food and Drug Administration’s (FDA’s) accelerated approval pathway between 2013 and 2017 have been shown to improve overall survival or quality of life, despite being on the US market for more than 5 years, according to a new study. 

Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response. 

Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.

The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.

In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.

To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits. 

Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.

Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results. 

The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff. 

However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials. 

In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”

There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit. 

The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious. 

In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial. 

“There have been some promising steps,” Dr. Cliff said, but much work needs to be done. 

Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.” 

But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.

Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.” 

Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.” 

As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together. 

The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures. 
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Fewer than half of the cancer drugs approved under the US Food and Drug Administration’s (FDA’s) accelerated approval pathway between 2013 and 2017 have been shown to improve overall survival or quality of life, despite being on the US market for more than 5 years, according to a new study. 

Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response. 

Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.

The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.

In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.

To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits. 

Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.

Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results. 

The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff. 

However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials. 

In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”

There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit. 

The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious. 

In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial. 

“There have been some promising steps,” Dr. Cliff said, but much work needs to be done. 

Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.” 

But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.

Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.” 

Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.” 

As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together. 

The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures. 
 

A version of this article appeared on Medscape.com.

SAN DIEGO — First-line treatment with a combination of cadonilimab, a PD-1/CTLA-4 bispecific immune checkpoint inhibitor, and standard chemotherapy provides a survival advantage over placebo plus chemotherapy in patients with locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma,, according to a new study.

Jiafu Ji, MD, PhD, presented this and other findings of the randomized, double-blind, placebo-controlled phase 3 COMPASSION-15 trial at the annual meeting of the American Association for Cancer Research (AACR).

“The consistent survival benefits across all prespecified PD-L1 expression cutoffs, particularly in patients with low PD-L1 expression, have significant implications for clinical practice by expanding treatment options, improving outcomes for patients with PD-L1–low tumors, influencing guidelines, and stimulating further research in advanced G/GEJ adenocarcinoma treatment,” said Dr. Ji, a principal investigator of this trial, in an interview.

Unmet Need

The incidence of gastric cancer is particularly high in China, but as Dr. Ji discussed in his talk, the treatment options for patients with advanced disease remain limited. Although the Food and Drug Administration (FDA) has approved the combination of PD-L1 inhibitors with chemotherapy for the first-line treatment of advanced gastric cancer, not all patients respond to the treatment, explained Dr. Ji, who is a professor of gastrointestinal surgery and president of Peking University Cancer Hospital and Beijing Institute for Cancer Research in China.

He added that the combination of PD-L1 inhibitors and chemotherapy has not yet been approved for the treatment of advanced gastric cancer in China, leaving chemotherapy as the only treatment option for Chinese patients.

Study Design

To evaluate the efficacy and safety of first-line cadonilimab plus standard chemotherapy in patients with advanced or metastatic gastric cancer, the authors of the COMPASSION-15 trial enrolled 610 patients with unresectable, locally advanced, or metastatic G/GEJ adenocarcinoma who had not received any prior treatments. PD-L1 expression status was not used to exclude patients from the trial.

In a press conference held at AACR 2024, Dr. Ji explained the study rationale, design, and endpoints. He said that patients with tumors without PD-L1 expression typically show little to no benefit from anti–PD-1/PD-L1 inhibitors, and their treatment options are limited to chemotherapy.

“Testing the efficacy of this bispecific antibody in this patient population could provide an alternative treatment approach for them,” he added.

Patients were randomized 1:1 to receive either cadonilimab (10 mg/kg every 3 weeks) plus chemotherapy or placebo plus chemotherapy. The primary endpoint of the study was overall survival (OS) in the intent-to-treat (ITT) population, and secondary efficacy endpoints included OS, progression-free survival (PFS), and objective response rate (ORR) in the ITT population, as well as in patients stratified by PD-L1 expression.

Cadonilimab Plus Standard Chemotherapy Improves OS

Interim analysis, conducted with a median follow-up of 18.69 months, showed a significant improvement in OS for the cadonilimab plus chemotherapy group compared with the chemotherapy-alone group, according to data presented at the press conference. The median OS was 15.0 months in the cadonilimab group versus 10.8 months in the placebo group, representing a 38% reduction in the risk of death (hazard ratio [HR], 0.62; 95% CI, 0.50-0.78, P < .001).

Yelena Y. Janjigian, MD, who not involved in COMPASSION-15, provided critique of the study, during another session at the meeting, in which she discussed the CheckMate 649 trial. She noted that, although the median OS of 15 months in the COMPASSION-15 study was slightly higher than the OS in the CheckMate 649 trial (approximately 14 months), comparing the results of two studies is challenging.

“In the COMPASSION-15 trial, chemotherapy was stopped after [4.5 months], and only 50% of patients received chemotherapy with subsequent treatment — this is not standard and may limit the comparison with other immunotherapy trials,” explained Dr. Janjigian, who is a gastrointestinal oncologist and was a principal investigator in the phase 3 CheckMate 649 immunotherapy trial for advanced gastric cancer.

Importantly, survival benefit with cadonilimab plus chemotherapy was observed across all prespecified PD-L1 expression levels, including in patients with low PD-L1 expression (PD-L1 combined positive score [CPS] less than 5%). In the low PD-L1 expression group (CPS less than 5%), the median OS was 14.8 months in the cadonilimab group compared with 11.8 months in the placebo group (HR, 0.70; 95% CI, 0.51-0.95; P = .011).

“These positive survival outcomes when cadonilimab was combined with chemotherapy may be attributed to synergistic mechanisms of action, enhanced immune responses, modulation of the tumor microenvironment, and careful patient selection based on biomarker assessments,” noted Dr. Ji, during an interview. “Targeting multiple pathways using bispecific antibodies provides potential synergistic effects, enhancing anti-tumor activity and improving treatment outcomes.”

Cadonilimab Plus Standard Chemotherapy Reduces the Risk of Tumor Progression

In addition to prolonging OS, cadonilimab plus chemotherapy also provided superior PFS and ORR compared to placebo plus chemotherapy.

The median PFS was 7.0 months in the cadonilimab plus chemotherapy group, versus 5.3 months in the chemotherapy-only group (HR, 0.53; 95% CI, 0.44-0.65, P < .001), and the ORR was 65.2% versus 48.9%, respectively. Furthermore, the duration of response was longer with cadonilimab plus chemotherapy than with placebo plus chemotherapy (8.8 versus 4.4 months, respectively).

Toxicities Associated With Cadonilimab Plus Standard Chemotherapy Are Manageable

The safety profile of the cadonilimab plus chemotherapy regimen was manageable, with grade 3 or higher treatment-related adverse events occurring in 71.8% of patients in the cadonilimab group and 60.5% of patients in the placebo group. No new safety signals were observed.

During an interview, Dr. Ji said that the most common adverse events were endocrine toxicity, skin toxicity, and lung toxicity. “These adverse events were managed through close monitoring, symptom management, and appropriate interventions based on the severity and nature of the toxicity experienced by patients,” he explained. He added that this toxicity profile of cadonilimab is similar to the toxicity profiles of approved PD-1 and CTLA-4 inhibitors.

Implications — A New Treatment Paradigm for Advanced Gastric Cancer?

According to Dr. Ji, the interim results from the cadonilimab study suggest that this novel PD-1/CTLA-4 bispecific antibody, in combination with chemotherapy, could become a new standard first-line treatment option for patients with advanced G/GEJ adenocarcinoma, offering a significant survival advantage over chemotherapy alone, regardless of PD-L1 status.

“The ability of cadonilimab to improve survival outcomes, regardless of PD-L1 status, is a significant advancement, as we have struggled to find effective treatments for patients with low PD-L1 expression in this setting,” he said, during the interview.

Despite these promising findings, Dr. Janjigian highlighted that patient stratification in the COMPASSION-15 study is currently lacking. She explained that biomarkers such as MSI status, T-reg signatures, and HER-2 are important to consider according to data from the CheckMate 649 trial.

“Hazard ratios for patients with T-reg–high tumors were almost 0.6, independent of inflammatory status. These data suggest that we can maybe even cure some patients with PD-1/CTLA-4 inhibitors,” she noted.

She added that knowing the status of MSI and HER-2 is clinically important as it can inform clinicians whether they can avoid chemotherapy or add trastuzumab.

“Despite the suboptimal comparator arm, the study is very important and offers a rationale for dual PD-1/CTLA-4 blockade,” Dr. Janjigian concluded.

COMPASSION-15 was funded by Akeso Biopharma, Inc. Dr. Ji reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients. Dr. Janjigian lists relationships with AbbVie, AmerisourceBergen Drug Corporation, Arcus Biosciences, Ask-Gene Pharma, Inc., Astellas Pharma, AstraZeneca, Basilea Pharmaceutica Ltd., Bayer, Bristol Myers, Squibb, Eli Lilly and Company, GlaxoSmithKline, Merck, Pfizer, and many other companies, as well as the U.S. Department of Defense, National Cancer Institute, and others.

SAN DIEGO — First-line treatment with a combination of cadonilimab, a PD-1/CTLA-4 bispecific immune checkpoint inhibitor, and standard chemotherapy provides a survival advantage over placebo plus chemotherapy in patients with locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma,, according to a new study.

Jiafu Ji, MD, PhD, presented this and other findings of the randomized, double-blind, placebo-controlled phase 3 COMPASSION-15 trial at the annual meeting of the American Association for Cancer Research (AACR).

“The consistent survival benefits across all prespecified PD-L1 expression cutoffs, particularly in patients with low PD-L1 expression, have significant implications for clinical practice by expanding treatment options, improving outcomes for patients with PD-L1–low tumors, influencing guidelines, and stimulating further research in advanced G/GEJ adenocarcinoma treatment,” said Dr. Ji, a principal investigator of this trial, in an interview.

Unmet Need

The incidence of gastric cancer is particularly high in China, but as Dr. Ji discussed in his talk, the treatment options for patients with advanced disease remain limited. Although the Food and Drug Administration (FDA) has approved the combination of PD-L1 inhibitors with chemotherapy for the first-line treatment of advanced gastric cancer, not all patients respond to the treatment, explained Dr. Ji, who is a professor of gastrointestinal surgery and president of Peking University Cancer Hospital and Beijing Institute for Cancer Research in China.

He added that the combination of PD-L1 inhibitors and chemotherapy has not yet been approved for the treatment of advanced gastric cancer in China, leaving chemotherapy as the only treatment option for Chinese patients.

Study Design

To evaluate the efficacy and safety of first-line cadonilimab plus standard chemotherapy in patients with advanced or metastatic gastric cancer, the authors of the COMPASSION-15 trial enrolled 610 patients with unresectable, locally advanced, or metastatic G/GEJ adenocarcinoma who had not received any prior treatments. PD-L1 expression status was not used to exclude patients from the trial.

In a press conference held at AACR 2024, Dr. Ji explained the study rationale, design, and endpoints. He said that patients with tumors without PD-L1 expression typically show little to no benefit from anti–PD-1/PD-L1 inhibitors, and their treatment options are limited to chemotherapy.

“Testing the efficacy of this bispecific antibody in this patient population could provide an alternative treatment approach for them,” he added.

Patients were randomized 1:1 to receive either cadonilimab (10 mg/kg every 3 weeks) plus chemotherapy or placebo plus chemotherapy. The primary endpoint of the study was overall survival (OS) in the intent-to-treat (ITT) population, and secondary efficacy endpoints included OS, progression-free survival (PFS), and objective response rate (ORR) in the ITT population, as well as in patients stratified by PD-L1 expression.

Cadonilimab Plus Standard Chemotherapy Improves OS

Interim analysis, conducted with a median follow-up of 18.69 months, showed a significant improvement in OS for the cadonilimab plus chemotherapy group compared with the chemotherapy-alone group, according to data presented at the press conference. The median OS was 15.0 months in the cadonilimab group versus 10.8 months in the placebo group, representing a 38% reduction in the risk of death (hazard ratio [HR], 0.62; 95% CI, 0.50-0.78, P < .001).

Yelena Y. Janjigian, MD, who not involved in COMPASSION-15, provided critique of the study, during another session at the meeting, in which she discussed the CheckMate 649 trial. She noted that, although the median OS of 15 months in the COMPASSION-15 study was slightly higher than the OS in the CheckMate 649 trial (approximately 14 months), comparing the results of two studies is challenging.

“In the COMPASSION-15 trial, chemotherapy was stopped after [4.5 months], and only 50% of patients received chemotherapy with subsequent treatment — this is not standard and may limit the comparison with other immunotherapy trials,” explained Dr. Janjigian, who is a gastrointestinal oncologist and was a principal investigator in the phase 3 CheckMate 649 immunotherapy trial for advanced gastric cancer.

Importantly, survival benefit with cadonilimab plus chemotherapy was observed across all prespecified PD-L1 expression levels, including in patients with low PD-L1 expression (PD-L1 combined positive score [CPS] less than 5%). In the low PD-L1 expression group (CPS less than 5%), the median OS was 14.8 months in the cadonilimab group compared with 11.8 months in the placebo group (HR, 0.70; 95% CI, 0.51-0.95; P = .011).

“These positive survival outcomes when cadonilimab was combined with chemotherapy may be attributed to synergistic mechanisms of action, enhanced immune responses, modulation of the tumor microenvironment, and careful patient selection based on biomarker assessments,” noted Dr. Ji, during an interview. “Targeting multiple pathways using bispecific antibodies provides potential synergistic effects, enhancing anti-tumor activity and improving treatment outcomes.”

Cadonilimab Plus Standard Chemotherapy Reduces the Risk of Tumor Progression

In addition to prolonging OS, cadonilimab plus chemotherapy also provided superior PFS and ORR compared to placebo plus chemotherapy.

The median PFS was 7.0 months in the cadonilimab plus chemotherapy group, versus 5.3 months in the chemotherapy-only group (HR, 0.53; 95% CI, 0.44-0.65, P < .001), and the ORR was 65.2% versus 48.9%, respectively. Furthermore, the duration of response was longer with cadonilimab plus chemotherapy than with placebo plus chemotherapy (8.8 versus 4.4 months, respectively).

Toxicities Associated With Cadonilimab Plus Standard Chemotherapy Are Manageable

The safety profile of the cadonilimab plus chemotherapy regimen was manageable, with grade 3 or higher treatment-related adverse events occurring in 71.8% of patients in the cadonilimab group and 60.5% of patients in the placebo group. No new safety signals were observed.

During an interview, Dr. Ji said that the most common adverse events were endocrine toxicity, skin toxicity, and lung toxicity. “These adverse events were managed through close monitoring, symptom management, and appropriate interventions based on the severity and nature of the toxicity experienced by patients,” he explained. He added that this toxicity profile of cadonilimab is similar to the toxicity profiles of approved PD-1 and CTLA-4 inhibitors.

Implications — A New Treatment Paradigm for Advanced Gastric Cancer?

According to Dr. Ji, the interim results from the cadonilimab study suggest that this novel PD-1/CTLA-4 bispecific antibody, in combination with chemotherapy, could become a new standard first-line treatment option for patients with advanced G/GEJ adenocarcinoma, offering a significant survival advantage over chemotherapy alone, regardless of PD-L1 status.

“The ability of cadonilimab to improve survival outcomes, regardless of PD-L1 status, is a significant advancement, as we have struggled to find effective treatments for patients with low PD-L1 expression in this setting,” he said, during the interview.

Despite these promising findings, Dr. Janjigian highlighted that patient stratification in the COMPASSION-15 study is currently lacking. She explained that biomarkers such as MSI status, T-reg signatures, and HER-2 are important to consider according to data from the CheckMate 649 trial.

“Hazard ratios for patients with T-reg–high tumors were almost 0.6, independent of inflammatory status. These data suggest that we can maybe even cure some patients with PD-1/CTLA-4 inhibitors,” she noted.

She added that knowing the status of MSI and HER-2 is clinically important as it can inform clinicians whether they can avoid chemotherapy or add trastuzumab.

“Despite the suboptimal comparator arm, the study is very important and offers a rationale for dual PD-1/CTLA-4 blockade,” Dr. Janjigian concluded.

COMPASSION-15 was funded by Akeso Biopharma, Inc. Dr. Ji reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients. Dr. Janjigian lists relationships with AbbVie, AmerisourceBergen Drug Corporation, Arcus Biosciences, Ask-Gene Pharma, Inc., Astellas Pharma, AstraZeneca, Basilea Pharmaceutica Ltd., Bayer, Bristol Myers, Squibb, Eli Lilly and Company, GlaxoSmithKline, Merck, Pfizer, and many other companies, as well as the U.S. Department of Defense, National Cancer Institute, and others.

SAN DIEGO — First-line treatment with a combination of cadonilimab, a PD-1/CTLA-4 bispecific immune checkpoint inhibitor, and standard chemotherapy provides a survival advantage over placebo plus chemotherapy in patients with locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma,, according to a new study.

Jiafu Ji, MD, PhD, presented this and other findings of the randomized, double-blind, placebo-controlled phase 3 COMPASSION-15 trial at the annual meeting of the American Association for Cancer Research (AACR).

“The consistent survival benefits across all prespecified PD-L1 expression cutoffs, particularly in patients with low PD-L1 expression, have significant implications for clinical practice by expanding treatment options, improving outcomes for patients with PD-L1–low tumors, influencing guidelines, and stimulating further research in advanced G/GEJ adenocarcinoma treatment,” said Dr. Ji, a principal investigator of this trial, in an interview.

Unmet Need

The incidence of gastric cancer is particularly high in China, but as Dr. Ji discussed in his talk, the treatment options for patients with advanced disease remain limited. Although the Food and Drug Administration (FDA) has approved the combination of PD-L1 inhibitors with chemotherapy for the first-line treatment of advanced gastric cancer, not all patients respond to the treatment, explained Dr. Ji, who is a professor of gastrointestinal surgery and president of Peking University Cancer Hospital and Beijing Institute for Cancer Research in China.

He added that the combination of PD-L1 inhibitors and chemotherapy has not yet been approved for the treatment of advanced gastric cancer in China, leaving chemotherapy as the only treatment option for Chinese patients.

Study Design

To evaluate the efficacy and safety of first-line cadonilimab plus standard chemotherapy in patients with advanced or metastatic gastric cancer, the authors of the COMPASSION-15 trial enrolled 610 patients with unresectable, locally advanced, or metastatic G/GEJ adenocarcinoma who had not received any prior treatments. PD-L1 expression status was not used to exclude patients from the trial.

In a press conference held at AACR 2024, Dr. Ji explained the study rationale, design, and endpoints. He said that patients with tumors without PD-L1 expression typically show little to no benefit from anti–PD-1/PD-L1 inhibitors, and their treatment options are limited to chemotherapy.

“Testing the efficacy of this bispecific antibody in this patient population could provide an alternative treatment approach for them,” he added.

Patients were randomized 1:1 to receive either cadonilimab (10 mg/kg every 3 weeks) plus chemotherapy or placebo plus chemotherapy. The primary endpoint of the study was overall survival (OS) in the intent-to-treat (ITT) population, and secondary efficacy endpoints included OS, progression-free survival (PFS), and objective response rate (ORR) in the ITT population, as well as in patients stratified by PD-L1 expression.

Cadonilimab Plus Standard Chemotherapy Improves OS

Interim analysis, conducted with a median follow-up of 18.69 months, showed a significant improvement in OS for the cadonilimab plus chemotherapy group compared with the chemotherapy-alone group, according to data presented at the press conference. The median OS was 15.0 months in the cadonilimab group versus 10.8 months in the placebo group, representing a 38% reduction in the risk of death (hazard ratio [HR], 0.62; 95% CI, 0.50-0.78, P < .001).

Yelena Y. Janjigian, MD, who not involved in COMPASSION-15, provided critique of the study, during another session at the meeting, in which she discussed the CheckMate 649 trial. She noted that, although the median OS of 15 months in the COMPASSION-15 study was slightly higher than the OS in the CheckMate 649 trial (approximately 14 months), comparing the results of two studies is challenging.

“In the COMPASSION-15 trial, chemotherapy was stopped after [4.5 months], and only 50% of patients received chemotherapy with subsequent treatment — this is not standard and may limit the comparison with other immunotherapy trials,” explained Dr. Janjigian, who is a gastrointestinal oncologist and was a principal investigator in the phase 3 CheckMate 649 immunotherapy trial for advanced gastric cancer.

Importantly, survival benefit with cadonilimab plus chemotherapy was observed across all prespecified PD-L1 expression levels, including in patients with low PD-L1 expression (PD-L1 combined positive score [CPS] less than 5%). In the low PD-L1 expression group (CPS less than 5%), the median OS was 14.8 months in the cadonilimab group compared with 11.8 months in the placebo group (HR, 0.70; 95% CI, 0.51-0.95; P = .011).

“These positive survival outcomes when cadonilimab was combined with chemotherapy may be attributed to synergistic mechanisms of action, enhanced immune responses, modulation of the tumor microenvironment, and careful patient selection based on biomarker assessments,” noted Dr. Ji, during an interview. “Targeting multiple pathways using bispecific antibodies provides potential synergistic effects, enhancing anti-tumor activity and improving treatment outcomes.”

Cadonilimab Plus Standard Chemotherapy Reduces the Risk of Tumor Progression

In addition to prolonging OS, cadonilimab plus chemotherapy also provided superior PFS and ORR compared to placebo plus chemotherapy.

The median PFS was 7.0 months in the cadonilimab plus chemotherapy group, versus 5.3 months in the chemotherapy-only group (HR, 0.53; 95% CI, 0.44-0.65, P < .001), and the ORR was 65.2% versus 48.9%, respectively. Furthermore, the duration of response was longer with cadonilimab plus chemotherapy than with placebo plus chemotherapy (8.8 versus 4.4 months, respectively).

Toxicities Associated With Cadonilimab Plus Standard Chemotherapy Are Manageable

The safety profile of the cadonilimab plus chemotherapy regimen was manageable, with grade 3 or higher treatment-related adverse events occurring in 71.8% of patients in the cadonilimab group and 60.5% of patients in the placebo group. No new safety signals were observed.

During an interview, Dr. Ji said that the most common adverse events were endocrine toxicity, skin toxicity, and lung toxicity. “These adverse events were managed through close monitoring, symptom management, and appropriate interventions based on the severity and nature of the toxicity experienced by patients,” he explained. He added that this toxicity profile of cadonilimab is similar to the toxicity profiles of approved PD-1 and CTLA-4 inhibitors.

Implications — A New Treatment Paradigm for Advanced Gastric Cancer?

According to Dr. Ji, the interim results from the cadonilimab study suggest that this novel PD-1/CTLA-4 bispecific antibody, in combination with chemotherapy, could become a new standard first-line treatment option for patients with advanced G/GEJ adenocarcinoma, offering a significant survival advantage over chemotherapy alone, regardless of PD-L1 status.

“The ability of cadonilimab to improve survival outcomes, regardless of PD-L1 status, is a significant advancement, as we have struggled to find effective treatments for patients with low PD-L1 expression in this setting,” he said, during the interview.

Despite these promising findings, Dr. Janjigian highlighted that patient stratification in the COMPASSION-15 study is currently lacking. She explained that biomarkers such as MSI status, T-reg signatures, and HER-2 are important to consider according to data from the CheckMate 649 trial.

“Hazard ratios for patients with T-reg–high tumors were almost 0.6, independent of inflammatory status. These data suggest that we can maybe even cure some patients with PD-1/CTLA-4 inhibitors,” she noted.

She added that knowing the status of MSI and HER-2 is clinically important as it can inform clinicians whether they can avoid chemotherapy or add trastuzumab.

“Despite the suboptimal comparator arm, the study is very important and offers a rationale for dual PD-1/CTLA-4 blockade,” Dr. Janjigian concluded.

COMPASSION-15 was funded by Akeso Biopharma, Inc. Dr. Ji reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients. Dr. Janjigian lists relationships with AbbVie, AmerisourceBergen Drug Corporation, Arcus Biosciences, Ask-Gene Pharma, Inc., Astellas Pharma, AstraZeneca, Basilea Pharmaceutica Ltd., Bayer, Bristol Myers, Squibb, Eli Lilly and Company, GlaxoSmithKline, Merck, Pfizer, and many other companies, as well as the U.S. Department of Defense, National Cancer Institute, and others.

A lightbulb moment hit as Lawrence David was chatting one day with an ecologist who studies the microbiomes and diets of large herbivores in the African savanna. David was envious. He’d been studying the human microbiome, and this ecologist had tons of animal statistics that were way more specific than what David had obtained from people.

“How on earth do you get all these dietary data?” David recalled asking. “Obviously, he didn’t ask the animals what they ate.”

All those specific statistics came from DNA sequencing of animal scat scooped up from the savanna. 

Indeed. 

Depending on when you read this, you may have the DNA of more than a dozen plant species, plus another three or four animal species, gurgling through your gut. That’s the straight poop taken straight from, well, poop.

David and colleagues are analyzing the DNA in human feces to better understand digestion and the links between diet and health, potentially paving the way to treatments for diet-linked diseases.

Diet, DNA, and Feces

Everything we eat (except vitamins, minerals, and salt) came from something that was living, and all living things have genomes. 

“A decent fraction of that DNA” goes undigested and is then excreted, said David, a PhD and associate professor of molecular genetics and microbiology at Duke University, Durham, North Carolina. 

“We are using DNA sequencing to reconstruct what people eat,” David said. “We try to see if there are patterns in what people eat and how we can measure them by DNA, or kind of genetic forensics.” Then they connect that data to health outcomes like obesity. 

A typical person’s excrement probably contains the DNA of 10-20 plant species and three or four types of animal DNA. “And that’s the average person. Some people may have more like 40 types at any given time,” David said. 

Studying DNA in human feces has potential applications in research and in clinical settings. For instance, it could help design personalized nutrition strategies for patients, something that’s already being tested. He hopes that DNA information will help “connect patterns in what people eat to their microbiomes.” 

One big advantage: Feces don’t lie. In reconstructing someone’s diet, people either forget what they ate, fudge the truth, or can’t be bothered to keep track. 

“Patients report the fruit they ate yesterday but not the M&Ms,” said Neil Stollman, MD, chief of the division of gastroenterology at Alta Bates Summit Medical Center in Oakland, California. 

Some people can’t write it all down because they’re too old or too young — the very people at highest risk of nutrition-associated disease, said David. 

Fetching and Figuring Out Feces

It’s a lot of work to collect and analyze fecal matter, for ethical, legal, and logistical reasons. “And then there’s sort of an ick factor to this kind of work,” David said. 

To get samples, people place a plastic collection cup under the toilet seat to catch the stool. The person then swabs or scoops some of that into a tube, seals the top, and either brings it in or mails it to the lab. 

In the lab, David said, “if the DNA is still inside the plant cells, we crack the cells open using a variety of methods. We use what’s called ‘a stomacher,’ which is like two big paddles, and we load the poop [which is in a plastic bag] into it and then squash it — mash it up. We also sometimes load small particles of what is basically glass into it and then shake really hard — it is another way you can physically break open the plant cells. This can also be done with chemicals. It’s like a chemistry lab,” he said, noting that this process takes about half a day to do.

There is much more bacterial DNA in stool than there is food DNA, and even a little human DNA and sometimes fungi, said David. “The concentration of bacteria in stool is amongst the highest concentrations of bacteria on the planet,” he said, but his lab focuses on the plant DNA they find. 

They use a molecular process called polymerase chain reaction (PCR) that amplifies and selectively copies DNA from plants. (The scientists who invented this “ingenious” process won a Nobel Prize, David noted.) Like a COVID PCR test, the process only matches up for certain kinds of DNA and can be designed to be more specific or less specific. In David’s lab, they shoot for a middle ground of specificity, where the PCR process is targeting chloroplasts in plants. 

Once they’ve detected all the different sequences of food species, they need to find the DNA code, a time-consuming step. His colleague Briana Petrone compiled a reference database of specific sequences of DNA that correspond to different species of plants. This work took more than a year, said David, noting that only a handful of other labs around the country are sequencing DNA in feces, most of them looking at it in animals, not humans. 

There are 200,000 to 300,000 species of edible plants estimated to be on the planet, he said. “I think historically, humans have eaten about 7000 of them. We’re kind of like a walking repository of all this genetic material.” 

What Scientists Learn from Fecal DNA

Tracking DNA in digested food can provide valuable data to researchers — information that could have a major impact on nutritional guidance for people with obesity and digestive diseases and other gastrointestinal and nutrition-related issues. 

David and Petrone’s 2023 study analyzing DNA in stool samples, published in the Proceedings of the National Academy of Sciences (PNAS), showed what — and roughly how much — people ate. 

They noticed that kids with obesity had a higher diversity of plants in them than kids without obesity. Sounds backward — wouldn’t a child who eats more plants be a healthier weight? “The more I dug into it, it turns out that foods that are more processed often tend to have more ingredients. So, a Big Mac and fries and a coffee have 19 different plant species,” said David. 

Going forward, he said, researchers may have to be “more specific about how we think about dietary diversity. Maybe not all plant species count toward health in the same way.” 

David’s work provides an innovative way to conduct nutrition research, said Jotham Suez, PhD, an assistant professor in the department of molecular microbiology and immunology at Johns Hopkins Bloomberg School of Public Health. 

“We need to have some means of tracking what people actually ate during a study, whether it’s an intervention where we provide them with the food or an observational study where we let people eat their habitual diet and track it themselves,” said Suez, who studies the gut microbiome. 

“Recall bias” makes food questionnaires and apps unreliable. And research suggests that some participants may underreport food intake, possibly because they don’t want to be judged or they misestimate how much they actually consumed. 

“There’s huge promise” with a tool like the one described in the PNAS study for making connections between diet and disease, Suez said. But access may be an issue for many researchers. He expects techniques to improve and costs to go down, but there will be challenges. “This method is also almost exclusively looking at plant DNA material, Suez added, “and our diets contain multiple components that are not plants.” 

And even if a person just eats an apple or a single cucumber, that food may be degraded somewhere else in the gut, and it may be digested differently in different people’s guts. “Metabolism, of course, can be different between people,” Suez said, so the amounts of data will vary. “In their study, the qualitative data is convincing. The quantitative is TBD [to be determined].” 

But he said it might be “a perfect tool” for scientists who want to study indigestible fiber, which is an important area of science, too. 

“I totally buy it as a potentially better way to do dietary analytics for disease associations,” said Stollman, an expert in fecal transplant and diverticulitis and a trustee of the American College of Gastroenterology. Stollman sees many patients with diverticular disease who could benefit. 

“One of the core questions in the diverticular world is, what causes diverticular disease, so we can ideally prevent it? For decades, the theory has been that a low fiber diet contributes to it,” said Stollman, but testing DNA in patients’ stools could help researchers explore the question in a new and potentially more nuanced and accurate way. Findings might allow scientists to learn, “Do people who eat X get polyps? Is this diet a risk factor for X, Y, or Z disease?” said Stollman. 

Future Clinical Applications

Brenda Davy, PhD, is a registered dietitian and professor in the Department of Human Nutrition, Foods, and Exercise at Virginia Tech. She conducts research investigating the role of diet in the prevention and treatment of obesity and related conditions such as type 2 diabetes. She also develops dietary assessment methods. More than a decade ago, she developed one of the first rapid assessment tools for quantifying beverage intake — the Beverage Intake Questionnaire — an assessment that is still used today. 

“Dietary assessment is necessary in both research and clinical settings,” Davy said. “If a physician diagnoses a patient with a certain condition, information about the patient’s usual dietary habits can help him or her prescribe dietary changes that may help treat that condition.” 

Biospecimens, like fecal and urine samples, can be a safe, accurate way to collect that data, she said. Samples can be obtained easily and noninvasively “in a wide variety of populations such as children or older adults” and in clinical settings. 

Davy and her team use David’s technology in their work — in particular, a tool called FoodSeq that applies DNA metabarcoding to human stool to collect information about food taxa consumed. Their two labs are now collaborating on a project investigating how ultraprocessed foods might impact type 2 diabetes risk and cardiovascular health. 

There are many directions David’s lab would like to take their research, possibly partnering with epidemiologists on global studies that would help them expand their DNA database and better understand how, for example, climate change may be affecting diet diversity and to learn more about diet across different populations.

A version of this article appeared on Medscape.com.

A lightbulb moment hit as Lawrence David was chatting one day with an ecologist who studies the microbiomes and diets of large herbivores in the African savanna. David was envious. He’d been studying the human microbiome, and this ecologist had tons of animal statistics that were way more specific than what David had obtained from people.

“How on earth do you get all these dietary data?” David recalled asking. “Obviously, he didn’t ask the animals what they ate.”

All those specific statistics came from DNA sequencing of animal scat scooped up from the savanna. 

Indeed. 

Depending on when you read this, you may have the DNA of more than a dozen plant species, plus another three or four animal species, gurgling through your gut. That’s the straight poop taken straight from, well, poop.

David and colleagues are analyzing the DNA in human feces to better understand digestion and the links between diet and health, potentially paving the way to treatments for diet-linked diseases.

Diet, DNA, and Feces

Everything we eat (except vitamins, minerals, and salt) came from something that was living, and all living things have genomes. 

“A decent fraction of that DNA” goes undigested and is then excreted, said David, a PhD and associate professor of molecular genetics and microbiology at Duke University, Durham, North Carolina. 

“We are using DNA sequencing to reconstruct what people eat,” David said. “We try to see if there are patterns in what people eat and how we can measure them by DNA, or kind of genetic forensics.” Then they connect that data to health outcomes like obesity. 

A typical person’s excrement probably contains the DNA of 10-20 plant species and three or four types of animal DNA. “And that’s the average person. Some people may have more like 40 types at any given time,” David said. 

Studying DNA in human feces has potential applications in research and in clinical settings. For instance, it could help design personalized nutrition strategies for patients, something that’s already being tested. He hopes that DNA information will help “connect patterns in what people eat to their microbiomes.” 

One big advantage: Feces don’t lie. In reconstructing someone’s diet, people either forget what they ate, fudge the truth, or can’t be bothered to keep track. 

“Patients report the fruit they ate yesterday but not the M&Ms,” said Neil Stollman, MD, chief of the division of gastroenterology at Alta Bates Summit Medical Center in Oakland, California. 

Some people can’t write it all down because they’re too old or too young — the very people at highest risk of nutrition-associated disease, said David. 

Fetching and Figuring Out Feces

It’s a lot of work to collect and analyze fecal matter, for ethical, legal, and logistical reasons. “And then there’s sort of an ick factor to this kind of work,” David said. 

To get samples, people place a plastic collection cup under the toilet seat to catch the stool. The person then swabs or scoops some of that into a tube, seals the top, and either brings it in or mails it to the lab. 

In the lab, David said, “if the DNA is still inside the plant cells, we crack the cells open using a variety of methods. We use what’s called ‘a stomacher,’ which is like two big paddles, and we load the poop [which is in a plastic bag] into it and then squash it — mash it up. We also sometimes load small particles of what is basically glass into it and then shake really hard — it is another way you can physically break open the plant cells. This can also be done with chemicals. It’s like a chemistry lab,” he said, noting that this process takes about half a day to do.

There is much more bacterial DNA in stool than there is food DNA, and even a little human DNA and sometimes fungi, said David. “The concentration of bacteria in stool is amongst the highest concentrations of bacteria on the planet,” he said, but his lab focuses on the plant DNA they find. 

They use a molecular process called polymerase chain reaction (PCR) that amplifies and selectively copies DNA from plants. (The scientists who invented this “ingenious” process won a Nobel Prize, David noted.) Like a COVID PCR test, the process only matches up for certain kinds of DNA and can be designed to be more specific or less specific. In David’s lab, they shoot for a middle ground of specificity, where the PCR process is targeting chloroplasts in plants. 

Once they’ve detected all the different sequences of food species, they need to find the DNA code, a time-consuming step. His colleague Briana Petrone compiled a reference database of specific sequences of DNA that correspond to different species of plants. This work took more than a year, said David, noting that only a handful of other labs around the country are sequencing DNA in feces, most of them looking at it in animals, not humans. 

There are 200,000 to 300,000 species of edible plants estimated to be on the planet, he said. “I think historically, humans have eaten about 7000 of them. We’re kind of like a walking repository of all this genetic material.” 

What Scientists Learn from Fecal DNA

Tracking DNA in digested food can provide valuable data to researchers — information that could have a major impact on nutritional guidance for people with obesity and digestive diseases and other gastrointestinal and nutrition-related issues. 

David and Petrone’s 2023 study analyzing DNA in stool samples, published in the Proceedings of the National Academy of Sciences (PNAS), showed what — and roughly how much — people ate. 

They noticed that kids with obesity had a higher diversity of plants in them than kids without obesity. Sounds backward — wouldn’t a child who eats more plants be a healthier weight? “The more I dug into it, it turns out that foods that are more processed often tend to have more ingredients. So, a Big Mac and fries and a coffee have 19 different plant species,” said David. 

Going forward, he said, researchers may have to be “more specific about how we think about dietary diversity. Maybe not all plant species count toward health in the same way.” 

David’s work provides an innovative way to conduct nutrition research, said Jotham Suez, PhD, an assistant professor in the department of molecular microbiology and immunology at Johns Hopkins Bloomberg School of Public Health. 

“We need to have some means of tracking what people actually ate during a study, whether it’s an intervention where we provide them with the food or an observational study where we let people eat their habitual diet and track it themselves,” said Suez, who studies the gut microbiome. 

“Recall bias” makes food questionnaires and apps unreliable. And research suggests that some participants may underreport food intake, possibly because they don’t want to be judged or they misestimate how much they actually consumed. 

“There’s huge promise” with a tool like the one described in the PNAS study for making connections between diet and disease, Suez said. But access may be an issue for many researchers. He expects techniques to improve and costs to go down, but there will be challenges. “This method is also almost exclusively looking at plant DNA material, Suez added, “and our diets contain multiple components that are not plants.” 

And even if a person just eats an apple or a single cucumber, that food may be degraded somewhere else in the gut, and it may be digested differently in different people’s guts. “Metabolism, of course, can be different between people,” Suez said, so the amounts of data will vary. “In their study, the qualitative data is convincing. The quantitative is TBD [to be determined].” 

But he said it might be “a perfect tool” for scientists who want to study indigestible fiber, which is an important area of science, too. 

“I totally buy it as a potentially better way to do dietary analytics for disease associations,” said Stollman, an expert in fecal transplant and diverticulitis and a trustee of the American College of Gastroenterology. Stollman sees many patients with diverticular disease who could benefit. 

“One of the core questions in the diverticular world is, what causes diverticular disease, so we can ideally prevent it? For decades, the theory has been that a low fiber diet contributes to it,” said Stollman, but testing DNA in patients’ stools could help researchers explore the question in a new and potentially more nuanced and accurate way. Findings might allow scientists to learn, “Do people who eat X get polyps? Is this diet a risk factor for X, Y, or Z disease?” said Stollman. 

Future Clinical Applications

Brenda Davy, PhD, is a registered dietitian and professor in the Department of Human Nutrition, Foods, and Exercise at Virginia Tech. She conducts research investigating the role of diet in the prevention and treatment of obesity and related conditions such as type 2 diabetes. She also develops dietary assessment methods. More than a decade ago, she developed one of the first rapid assessment tools for quantifying beverage intake — the Beverage Intake Questionnaire — an assessment that is still used today. 

“Dietary assessment is necessary in both research and clinical settings,” Davy said. “If a physician diagnoses a patient with a certain condition, information about the patient’s usual dietary habits can help him or her prescribe dietary changes that may help treat that condition.” 

Biospecimens, like fecal and urine samples, can be a safe, accurate way to collect that data, she said. Samples can be obtained easily and noninvasively “in a wide variety of populations such as children or older adults” and in clinical settings. 

Davy and her team use David’s technology in their work — in particular, a tool called FoodSeq that applies DNA metabarcoding to human stool to collect information about food taxa consumed. Their two labs are now collaborating on a project investigating how ultraprocessed foods might impact type 2 diabetes risk and cardiovascular health. 

There are many directions David’s lab would like to take their research, possibly partnering with epidemiologists on global studies that would help them expand their DNA database and better understand how, for example, climate change may be affecting diet diversity and to learn more about diet across different populations.

A version of this article appeared on Medscape.com.

A lightbulb moment hit as Lawrence David was chatting one day with an ecologist who studies the microbiomes and diets of large herbivores in the African savanna. David was envious. He’d been studying the human microbiome, and this ecologist had tons of animal statistics that were way more specific than what David had obtained from people.

“How on earth do you get all these dietary data?” David recalled asking. “Obviously, he didn’t ask the animals what they ate.”

All those specific statistics came from DNA sequencing of animal scat scooped up from the savanna. 

Indeed. 

Depending on when you read this, you may have the DNA of more than a dozen plant species, plus another three or four animal species, gurgling through your gut. That’s the straight poop taken straight from, well, poop.

David and colleagues are analyzing the DNA in human feces to better understand digestion and the links between diet and health, potentially paving the way to treatments for diet-linked diseases.

Diet, DNA, and Feces

Everything we eat (except vitamins, minerals, and salt) came from something that was living, and all living things have genomes. 

“A decent fraction of that DNA” goes undigested and is then excreted, said David, a PhD and associate professor of molecular genetics and microbiology at Duke University, Durham, North Carolina. 

“We are using DNA sequencing to reconstruct what people eat,” David said. “We try to see if there are patterns in what people eat and how we can measure them by DNA, or kind of genetic forensics.” Then they connect that data to health outcomes like obesity. 

A typical person’s excrement probably contains the DNA of 10-20 plant species and three or four types of animal DNA. “And that’s the average person. Some people may have more like 40 types at any given time,” David said. 

Studying DNA in human feces has potential applications in research and in clinical settings. For instance, it could help design personalized nutrition strategies for patients, something that’s already being tested. He hopes that DNA information will help “connect patterns in what people eat to their microbiomes.” 

One big advantage: Feces don’t lie. In reconstructing someone’s diet, people either forget what they ate, fudge the truth, or can’t be bothered to keep track. 

“Patients report the fruit they ate yesterday but not the M&Ms,” said Neil Stollman, MD, chief of the division of gastroenterology at Alta Bates Summit Medical Center in Oakland, California. 

Some people can’t write it all down because they’re too old or too young — the very people at highest risk of nutrition-associated disease, said David. 

Fetching and Figuring Out Feces

It’s a lot of work to collect and analyze fecal matter, for ethical, legal, and logistical reasons. “And then there’s sort of an ick factor to this kind of work,” David said. 

To get samples, people place a plastic collection cup under the toilet seat to catch the stool. The person then swabs or scoops some of that into a tube, seals the top, and either brings it in or mails it to the lab. 

In the lab, David said, “if the DNA is still inside the plant cells, we crack the cells open using a variety of methods. We use what’s called ‘a stomacher,’ which is like two big paddles, and we load the poop [which is in a plastic bag] into it and then squash it — mash it up. We also sometimes load small particles of what is basically glass into it and then shake really hard — it is another way you can physically break open the plant cells. This can also be done with chemicals. It’s like a chemistry lab,” he said, noting that this process takes about half a day to do.

There is much more bacterial DNA in stool than there is food DNA, and even a little human DNA and sometimes fungi, said David. “The concentration of bacteria in stool is amongst the highest concentrations of bacteria on the planet,” he said, but his lab focuses on the plant DNA they find. 

They use a molecular process called polymerase chain reaction (PCR) that amplifies and selectively copies DNA from plants. (The scientists who invented this “ingenious” process won a Nobel Prize, David noted.) Like a COVID PCR test, the process only matches up for certain kinds of DNA and can be designed to be more specific or less specific. In David’s lab, they shoot for a middle ground of specificity, where the PCR process is targeting chloroplasts in plants. 

Once they’ve detected all the different sequences of food species, they need to find the DNA code, a time-consuming step. His colleague Briana Petrone compiled a reference database of specific sequences of DNA that correspond to different species of plants. This work took more than a year, said David, noting that only a handful of other labs around the country are sequencing DNA in feces, most of them looking at it in animals, not humans. 

There are 200,000 to 300,000 species of edible plants estimated to be on the planet, he said. “I think historically, humans have eaten about 7000 of them. We’re kind of like a walking repository of all this genetic material.” 

What Scientists Learn from Fecal DNA

Tracking DNA in digested food can provide valuable data to researchers — information that could have a major impact on nutritional guidance for people with obesity and digestive diseases and other gastrointestinal and nutrition-related issues. 

David and Petrone’s 2023 study analyzing DNA in stool samples, published in the Proceedings of the National Academy of Sciences (PNAS), showed what — and roughly how much — people ate. 

They noticed that kids with obesity had a higher diversity of plants in them than kids without obesity. Sounds backward — wouldn’t a child who eats more plants be a healthier weight? “The more I dug into it, it turns out that foods that are more processed often tend to have more ingredients. So, a Big Mac and fries and a coffee have 19 different plant species,” said David. 

Going forward, he said, researchers may have to be “more specific about how we think about dietary diversity. Maybe not all plant species count toward health in the same way.” 

David’s work provides an innovative way to conduct nutrition research, said Jotham Suez, PhD, an assistant professor in the department of molecular microbiology and immunology at Johns Hopkins Bloomberg School of Public Health. 

“We need to have some means of tracking what people actually ate during a study, whether it’s an intervention where we provide them with the food or an observational study where we let people eat their habitual diet and track it themselves,” said Suez, who studies the gut microbiome. 

“Recall bias” makes food questionnaires and apps unreliable. And research suggests that some participants may underreport food intake, possibly because they don’t want to be judged or they misestimate how much they actually consumed. 

“There’s huge promise” with a tool like the one described in the PNAS study for making connections between diet and disease, Suez said. But access may be an issue for many researchers. He expects techniques to improve and costs to go down, but there will be challenges. “This method is also almost exclusively looking at plant DNA material, Suez added, “and our diets contain multiple components that are not plants.” 

And even if a person just eats an apple or a single cucumber, that food may be degraded somewhere else in the gut, and it may be digested differently in different people’s guts. “Metabolism, of course, can be different between people,” Suez said, so the amounts of data will vary. “In their study, the qualitative data is convincing. The quantitative is TBD [to be determined].” 

But he said it might be “a perfect tool” for scientists who want to study indigestible fiber, which is an important area of science, too. 

“I totally buy it as a potentially better way to do dietary analytics for disease associations,” said Stollman, an expert in fecal transplant and diverticulitis and a trustee of the American College of Gastroenterology. Stollman sees many patients with diverticular disease who could benefit. 

“One of the core questions in the diverticular world is, what causes diverticular disease, so we can ideally prevent it? For decades, the theory has been that a low fiber diet contributes to it,” said Stollman, but testing DNA in patients’ stools could help researchers explore the question in a new and potentially more nuanced and accurate way. Findings might allow scientists to learn, “Do people who eat X get polyps? Is this diet a risk factor for X, Y, or Z disease?” said Stollman. 

Future Clinical Applications

Brenda Davy, PhD, is a registered dietitian and professor in the Department of Human Nutrition, Foods, and Exercise at Virginia Tech. She conducts research investigating the role of diet in the prevention and treatment of obesity and related conditions such as type 2 diabetes. She also develops dietary assessment methods. More than a decade ago, she developed one of the first rapid assessment tools for quantifying beverage intake — the Beverage Intake Questionnaire — an assessment that is still used today. 

“Dietary assessment is necessary in both research and clinical settings,” Davy said. “If a physician diagnoses a patient with a certain condition, information about the patient’s usual dietary habits can help him or her prescribe dietary changes that may help treat that condition.” 

Biospecimens, like fecal and urine samples, can be a safe, accurate way to collect that data, she said. Samples can be obtained easily and noninvasively “in a wide variety of populations such as children or older adults” and in clinical settings. 

Davy and her team use David’s technology in their work — in particular, a tool called FoodSeq that applies DNA metabarcoding to human stool to collect information about food taxa consumed. Their two labs are now collaborating on a project investigating how ultraprocessed foods might impact type 2 diabetes risk and cardiovascular health. 

There are many directions David’s lab would like to take their research, possibly partnering with epidemiologists on global studies that would help them expand their DNA database and better understand how, for example, climate change may be affecting diet diversity and to learn more about diet across different populations.

A version of this article appeared on Medscape.com.

A newly developed quality performance measure that tracks completion of colorectal cancer (CRC) screening with a colonoscopy within 6 months of an abnormal stool-based screening test (SBT) in adults could help address high rates of incomplete CRC screening, the developers said.

As part of their work, the researchers conducted a retrospective study of 20,581 adults aged 50-75 years from 38 health systems that showed that fewer than half (48%) had a follow-up colonoscopy within 180 days of an initial abnormal SBT for CRC.

“The low follow-up rates to an abnormal SBT were initially surprising,” first author Elizabeth L. Ciemins, PhD, MPH, MA, Research and Analytics, American Medical Group Association (AMGA), Alexandria, Virginia, told this news organization.

“However, once we interviewed clinicians and learned that this was not a measure they were tracking, along with their own incorrect assumptions of a much higher follow-up rate, the low rates made sense. As is commonly said, ‘you can’t change what you don’t measure,’” she said.

The CRC screening completion measure the researchers propose “builds on and addresses an important shortcoming in an existing measure and will help ensure complete screening for CRC,” they noted in their JAMA Network Open paper.

The key elements of the follow-up measure are the date and result of a SBT and the date of the follow-up colonoscopy — if it occurred, Dr. Ciemins explained.

“Currently, health systems are not consistently tracking this measure, but they have the data elements to do so, especially if they are doing colonoscopies in-house,” she said.

Field testing showed that use of this new measure is “feasible, valid, and reliable,” the authors said. Dr. Ciemins believed this CRC screening completion measure could be widely implemented.

“Three AMGA member health systems feasibility tested the data elements and found that they could reliably abstract the required elements from electronic health records (EHRs),” she told this news organization.

The researchers are currently testing the measure among 20 AMGA member health systems, that are submitting quarterly data on a version of the specified measure.

“Advancing this measure as a quality performance measure could significantly increase the early detection of CRC, thereby improving health and ultimately saving lives,” the authors concluded in their paper.

The Right Direction, But Questions Remain

The coauthors of a linked commentary said this research highlights the “suboptimal” rates of a timely follow-up colonoscopy after positive SBT results. They applauded the authors for “focusing attention on a meaningful approach to measuring high-quality CRC screening and providing guidance for standardized measurement.”

However, several questions arise from this study, “including whether 6 months is the ideal interval for colonoscopy completion after a positive SBT result, where this measure fits in the context of existing CRC screening measures, and how to implement it in practice,” Jennifer K. Maratt, MD, with Indiana University School of Medicine, Indianapolis, and coauthors wrote.

“This measure alone does not address all the gaps in the screening process, nor does it address barriers to colonoscopy completion, but it points us in the right direction for measuring the success of screening programs,” Dr. Maratt and her colleagues added.

The study was supported by a grant from the AARP. The authors and editorial writers had no relevant disclosures.

A version of this article appeared on Medscape.com.

A newly developed quality performance measure that tracks completion of colorectal cancer (CRC) screening with a colonoscopy within 6 months of an abnormal stool-based screening test (SBT) in adults could help address high rates of incomplete CRC screening, the developers said.

As part of their work, the researchers conducted a retrospective study of 20,581 adults aged 50-75 years from 38 health systems that showed that fewer than half (48%) had a follow-up colonoscopy within 180 days of an initial abnormal SBT for CRC.

“The low follow-up rates to an abnormal SBT were initially surprising,” first author Elizabeth L. Ciemins, PhD, MPH, MA, Research and Analytics, American Medical Group Association (AMGA), Alexandria, Virginia, told this news organization.

“However, once we interviewed clinicians and learned that this was not a measure they were tracking, along with their own incorrect assumptions of a much higher follow-up rate, the low rates made sense. As is commonly said, ‘you can’t change what you don’t measure,’” she said.

The CRC screening completion measure the researchers propose “builds on and addresses an important shortcoming in an existing measure and will help ensure complete screening for CRC,” they noted in their JAMA Network Open paper.

The key elements of the follow-up measure are the date and result of a SBT and the date of the follow-up colonoscopy — if it occurred, Dr. Ciemins explained.

“Currently, health systems are not consistently tracking this measure, but they have the data elements to do so, especially if they are doing colonoscopies in-house,” she said.

Field testing showed that use of this new measure is “feasible, valid, and reliable,” the authors said. Dr. Ciemins believed this CRC screening completion measure could be widely implemented.

“Three AMGA member health systems feasibility tested the data elements and found that they could reliably abstract the required elements from electronic health records (EHRs),” she told this news organization.

The researchers are currently testing the measure among 20 AMGA member health systems, that are submitting quarterly data on a version of the specified measure.

“Advancing this measure as a quality performance measure could significantly increase the early detection of CRC, thereby improving health and ultimately saving lives,” the authors concluded in their paper.

The Right Direction, But Questions Remain

The coauthors of a linked commentary said this research highlights the “suboptimal” rates of a timely follow-up colonoscopy after positive SBT results. They applauded the authors for “focusing attention on a meaningful approach to measuring high-quality CRC screening and providing guidance for standardized measurement.”

However, several questions arise from this study, “including whether 6 months is the ideal interval for colonoscopy completion after a positive SBT result, where this measure fits in the context of existing CRC screening measures, and how to implement it in practice,” Jennifer K. Maratt, MD, with Indiana University School of Medicine, Indianapolis, and coauthors wrote.

“This measure alone does not address all the gaps in the screening process, nor does it address barriers to colonoscopy completion, but it points us in the right direction for measuring the success of screening programs,” Dr. Maratt and her colleagues added.

The study was supported by a grant from the AARP. The authors and editorial writers had no relevant disclosures.

A version of this article appeared on Medscape.com.

A newly developed quality performance measure that tracks completion of colorectal cancer (CRC) screening with a colonoscopy within 6 months of an abnormal stool-based screening test (SBT) in adults could help address high rates of incomplete CRC screening, the developers said.

As part of their work, the researchers conducted a retrospective study of 20,581 adults aged 50-75 years from 38 health systems that showed that fewer than half (48%) had a follow-up colonoscopy within 180 days of an initial abnormal SBT for CRC.

“The low follow-up rates to an abnormal SBT were initially surprising,” first author Elizabeth L. Ciemins, PhD, MPH, MA, Research and Analytics, American Medical Group Association (AMGA), Alexandria, Virginia, told this news organization.

“However, once we interviewed clinicians and learned that this was not a measure they were tracking, along with their own incorrect assumptions of a much higher follow-up rate, the low rates made sense. As is commonly said, ‘you can’t change what you don’t measure,’” she said.

The CRC screening completion measure the researchers propose “builds on and addresses an important shortcoming in an existing measure and will help ensure complete screening for CRC,” they noted in their JAMA Network Open paper.

The key elements of the follow-up measure are the date and result of a SBT and the date of the follow-up colonoscopy — if it occurred, Dr. Ciemins explained.

“Currently, health systems are not consistently tracking this measure, but they have the data elements to do so, especially if they are doing colonoscopies in-house,” she said.

Field testing showed that use of this new measure is “feasible, valid, and reliable,” the authors said. Dr. Ciemins believed this CRC screening completion measure could be widely implemented.

“Three AMGA member health systems feasibility tested the data elements and found that they could reliably abstract the required elements from electronic health records (EHRs),” she told this news organization.

The researchers are currently testing the measure among 20 AMGA member health systems, that are submitting quarterly data on a version of the specified measure.

“Advancing this measure as a quality performance measure could significantly increase the early detection of CRC, thereby improving health and ultimately saving lives,” the authors concluded in their paper.

The Right Direction, But Questions Remain

The coauthors of a linked commentary said this research highlights the “suboptimal” rates of a timely follow-up colonoscopy after positive SBT results. They applauded the authors for “focusing attention on a meaningful approach to measuring high-quality CRC screening and providing guidance for standardized measurement.”

However, several questions arise from this study, “including whether 6 months is the ideal interval for colonoscopy completion after a positive SBT result, where this measure fits in the context of existing CRC screening measures, and how to implement it in practice,” Jennifer K. Maratt, MD, with Indiana University School of Medicine, Indianapolis, and coauthors wrote.

“This measure alone does not address all the gaps in the screening process, nor does it address barriers to colonoscopy completion, but it points us in the right direction for measuring the success of screening programs,” Dr. Maratt and her colleagues added.

The study was supported by a grant from the AARP. The authors and editorial writers had no relevant disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Being positive for Helicobacter pylori is associated with a higher risk for colorectal cancer (CRC) incidence and CRC mortality, new data show; however, a 2-week course of antibiotics to eliminate the bacterial infection can reduce the risk of developing and dying from CRC.

METHODOLOGY:

• H pylori is a known cause of peptic ulcers and stomach cancer and has been classified as a group I carcinogen by the World Health Organization›s International Agency for Research on Cancer.
• Studies showed that H pylori increases the risk for gastric cancer and may increase the risk for CRC, but evidence supporting the CRC connection remains inconsistent.
• To investigate a possible H pylori-CRC link, investigators reviewed CRC incidence and mortality in a nationwide cohort of 812,736 veterans tested for H pylori at Veterans Health Administration facilities; of the 205,178 (25.2%) who tested positive for H pylori, 134,417 (34%) were treated.
• Patients were followed from their first H pylori test, and researchers tracked subsequent CRC diagnoses as well as CRC-related and non-CRC–related deaths.

TAKEAWAY:

• H pylori infection was associated with an 18% higher risk for CRC (adjusted hazard ratio [aHR], 1.18) and a 12% higher risk for CRC mortality (aHR, 1.12).
• Untreated patients had a 23% higher risk for CRC (aHR, 1.23) and a 40% higher risk for CRC mortality (aHR, 1.40) than treated individuals.
• Over the 15-year follow-up, receiving treatment for H pylori infection vs no treatment was associated with a lower risk of developing and dying from CRC (absolute risk reduction, 0.23%-0.35%). For context, among individuals receiving a screening colonoscopy, the invasive test was associated with a 0.84%-1.22% absolute risk reduction in CRC incidence and a 0.15-0.30% absolute risk reduction in CRC mortality.
• Excluding patients diagnosed with CRC within a year of H pylori testing did not change the associations in the study.

IN PRACTICE:

“We would like to highlight the potentially exciting clinical implications of these findings,” the authors of an accompanying editorial wrote. “Although the mechanistic connection between H pylori and colorectal cancer is not fully resolved,” the finding that eliminating H pylori “could reduce both gastric and colorectal cancers is incredibly potent and should be considered in clinical care for individuals at high risk for GI [gastrointestinal] cancers.”

SOURCE:

The work, led by Shailja C. Shah, MD, of the University of California San Diego, was published in the Journal of Clinical Oncology, alongside the accompanying editorial by Julia Butt, PhD, of the German Cancer Research Center, Heidelberg, Germany, and Meira Epplein, PhD, of Duke University in Durham, North Carolina.

LIMITATIONS:

The study was limited to US veterans, which means generalizability to other populations needed to be confirmed. There may have been differences in CRC risk factors between treated and untreated patients.

DISCLOSURES:

The work was funded by the Veterans Health Administration, the National Cancer Institute, and others. Investigators reported ties to numerous companies, including AstraZeneca, Novartis, Guardant Health, and Medscape Medical News, publisher of this article. The editorialists had no disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Being positive for Helicobacter pylori is associated with a higher risk for colorectal cancer (CRC) incidence and CRC mortality, new data show; however, a 2-week course of antibiotics to eliminate the bacterial infection can reduce the risk of developing and dying from CRC.

METHODOLOGY:

• H pylori is a known cause of peptic ulcers and stomach cancer and has been classified as a group I carcinogen by the World Health Organization›s International Agency for Research on Cancer.
• Studies showed that H pylori increases the risk for gastric cancer and may increase the risk for CRC, but evidence supporting the CRC connection remains inconsistent.
• To investigate a possible H pylori-CRC link, investigators reviewed CRC incidence and mortality in a nationwide cohort of 812,736 veterans tested for H pylori at Veterans Health Administration facilities; of the 205,178 (25.2%) who tested positive for H pylori, 134,417 (34%) were treated.
• Patients were followed from their first H pylori test, and researchers tracked subsequent CRC diagnoses as well as CRC-related and non-CRC–related deaths.

TAKEAWAY:

• H pylori infection was associated with an 18% higher risk for CRC (adjusted hazard ratio [aHR], 1.18) and a 12% higher risk for CRC mortality (aHR, 1.12).
• Untreated patients had a 23% higher risk for CRC (aHR, 1.23) and a 40% higher risk for CRC mortality (aHR, 1.40) than treated individuals.
• Over the 15-year follow-up, receiving treatment for H pylori infection vs no treatment was associated with a lower risk of developing and dying from CRC (absolute risk reduction, 0.23%-0.35%). For context, among individuals receiving a screening colonoscopy, the invasive test was associated with a 0.84%-1.22% absolute risk reduction in CRC incidence and a 0.15-0.30% absolute risk reduction in CRC mortality.
• Excluding patients diagnosed with CRC within a year of H pylori testing did not change the associations in the study.

IN PRACTICE:

“We would like to highlight the potentially exciting clinical implications of these findings,” the authors of an accompanying editorial wrote. “Although the mechanistic connection between H pylori and colorectal cancer is not fully resolved,” the finding that eliminating H pylori “could reduce both gastric and colorectal cancers is incredibly potent and should be considered in clinical care for individuals at high risk for GI [gastrointestinal] cancers.”

SOURCE:

The work, led by Shailja C. Shah, MD, of the University of California San Diego, was published in the Journal of Clinical Oncology, alongside the accompanying editorial by Julia Butt, PhD, of the German Cancer Research Center, Heidelberg, Germany, and Meira Epplein, PhD, of Duke University in Durham, North Carolina.

LIMITATIONS:

The study was limited to US veterans, which means generalizability to other populations needed to be confirmed. There may have been differences in CRC risk factors between treated and untreated patients.

DISCLOSURES:

The work was funded by the Veterans Health Administration, the National Cancer Institute, and others. Investigators reported ties to numerous companies, including AstraZeneca, Novartis, Guardant Health, and Medscape Medical News, publisher of this article. The editorialists had no disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Being positive for Helicobacter pylori is associated with a higher risk for colorectal cancer (CRC) incidence and CRC mortality, new data show; however, a 2-week course of antibiotics to eliminate the bacterial infection can reduce the risk of developing and dying from CRC.

METHODOLOGY:

• H pylori is a known cause of peptic ulcers and stomach cancer and has been classified as a group I carcinogen by the World Health Organization›s International Agency for Research on Cancer.
• Studies showed that H pylori increases the risk for gastric cancer and may increase the risk for CRC, but evidence supporting the CRC connection remains inconsistent.
• To investigate a possible H pylori-CRC link, investigators reviewed CRC incidence and mortality in a nationwide cohort of 812,736 veterans tested for H pylori at Veterans Health Administration facilities; of the 205,178 (25.2%) who tested positive for H pylori, 134,417 (34%) were treated.
• Patients were followed from their first H pylori test, and researchers tracked subsequent CRC diagnoses as well as CRC-related and non-CRC–related deaths.

TAKEAWAY:

• H pylori infection was associated with an 18% higher risk for CRC (adjusted hazard ratio [aHR], 1.18) and a 12% higher risk for CRC mortality (aHR, 1.12).
• Untreated patients had a 23% higher risk for CRC (aHR, 1.23) and a 40% higher risk for CRC mortality (aHR, 1.40) than treated individuals.
• Over the 15-year follow-up, receiving treatment for H pylori infection vs no treatment was associated with a lower risk of developing and dying from CRC (absolute risk reduction, 0.23%-0.35%). For context, among individuals receiving a screening colonoscopy, the invasive test was associated with a 0.84%-1.22% absolute risk reduction in CRC incidence and a 0.15-0.30% absolute risk reduction in CRC mortality.
• Excluding patients diagnosed with CRC within a year of H pylori testing did not change the associations in the study.

IN PRACTICE:

“We would like to highlight the potentially exciting clinical implications of these findings,” the authors of an accompanying editorial wrote. “Although the mechanistic connection between H pylori and colorectal cancer is not fully resolved,” the finding that eliminating H pylori “could reduce both gastric and colorectal cancers is incredibly potent and should be considered in clinical care for individuals at high risk for GI [gastrointestinal] cancers.”

SOURCE:

The work, led by Shailja C. Shah, MD, of the University of California San Diego, was published in the Journal of Clinical Oncology, alongside the accompanying editorial by Julia Butt, PhD, of the German Cancer Research Center, Heidelberg, Germany, and Meira Epplein, PhD, of Duke University in Durham, North Carolina.

LIMITATIONS:

The study was limited to US veterans, which means generalizability to other populations needed to be confirmed. There may have been differences in CRC risk factors between treated and untreated patients.

DISCLOSURES:

The work was funded by the Veterans Health Administration, the National Cancer Institute, and others. Investigators reported ties to numerous companies, including AstraZeneca, Novartis, Guardant Health, and Medscape Medical News, publisher of this article. The editorialists had no disclosures.

A version of this article appeared on Medscape.com.

Several new clinical trials in prostate cancer have started recruiting in recent months. Maybe one of your patients could benefit from enrolling?

Metastatic castration-sensitive prostate cancer 

Adults with this diagnosis may be interested in a randomized, double-blind, phase 3 study examining whether an experimental poly (ADP-ribose) polymerase (PARP) inhibitor called saruparib can further delay disease progression when added to a next-generation hormonal agent such as abiraterone (Zytiga), darolutamide (Nubeqa), or enzalutamide (Xtandi).

One group of participants will take daily oral doses of saruparib plus physician’s choice of a next-generation hormonal agent until disease progression or another reason for stopping therapy. The other group will add a placebo to a next-generation hormonal agent.

Sites in Rhode Island, Arkansas, California, Michigan, Australia, Canada, Japan, Taiwan, Thailand, the United Kingdom, and South Korea began seeking the trial’s 1800 participants in November 2023. Research centers in 31 other US states and 18 other countries are gearing up. The primary endpoint is radiographic progression-free survival. Overall survival and quality of life (QoL) are secondary endpoints. More details at clinicaltrials.gov.

This news organization asked Marc Garnick, MD, professor of medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, for his take on the trial. “The study is interesting since it is adding to the evaluations of continued intensification for first-line therapy and will help further elucidate the role of PARP inhibition regardless of homologous repair status,” Dr. Garnick said. “Plus, saruparib is supposedly more selective on PARP1, which in-and-of-itself is of potential benefit.”

Metastatic castration-resistant prostate cancer

People with this type of cancer who have progressed on a next-generation hormonal agent may be eligible for a randomized, open-label, phase 3 trial testing an investigational oral treatment called MK-5684 to see if it increases survival more effectively than switching to an alternative next-generation hormonal agent.

MK-5684 is designed to inhibit the CYP11A1 enzyme, thereby disrupting the androgen-receptor signaling pathway.

One group will take twice-daily tablets of MK-5684 plus hormone replacement therapy, oral dexamethasone, and oral fludrocortisone acetate (Florinef), with rescue hydrocortisone as needed. The other participants will take daily tablets of a next-generation hormonal agent: Either enzalutamide or abiraterone. Patients assigned to abiraterone will also be given prednisone tablets.

US-based sites in nine states and Puerto Rico started looking for the trial’s 1500 participants in December 2023 in partnership with study centers in Australia, Israel, South Korea, and Taiwan. The primary endpoints are radiographic progression-free survival and overall survival. QoL will not be tracked. More details at clinicaltrials.gov.

Metastatic castration-resistant prostate cancer

Patients in this situation who have progressed on taxane-based chemotherapy as well as a next-generation hormonal agent have the option to enroll in another phase 3 MK-5684 study.

Like the trial described above, all patients will remain on their respective therapy until disease progression. In this trial, one group will take twice-daily tablets of MK-5684 without hormone replacement therapy but the same mix of oral dexamethasone and fludrocortisone. Rescue hydrocortisone will also be available. The second group will be assigned either enzalutamide or abiraterone plus prednisone.

Sites in Puerto Rico, Colorado, Nevada, and Virginia, and five other countries outside the United States, opened their doors to the first of 1200 patients in December 2023. The primary endpoints are radiographic progression-free survival and overall survival, analyzed separately for patients with and without an androgen receptor ligand-binding domain mutation. QoL will not be measured. More details at clinicaltrials.gov.

High-risk prostate cancer

People with this diagnosis can join a randomized, open-label, phase 3 National Cancer Institute study to test whether stereotactic body radiation therapy (SBRT) is as effective as conventional external beam radiation therapy (EBRT) at preventing metastasis.

SBRT delivers radiation to tumors with higher precision than EBRT. The advantage of SBRT is the ability to deliver fewer doses over a shorter duration with less collateral damage to surrounding tissues.

In the trial, half of participants will undergo five treatments of SBRT over 2 weeks, while the other half will receive 20-45 treatments of EBRT over 4-9 weeks. Study sites in 14 US states began recruiting the trial’s 1209 participants in November 2023. Metastasis-free survival over 15 years is the primary endpoint, overall survival is a secondary endpoint, and QoL measures, apart from fatigue, will not be tracked. More details at clinicaltrials.gov.

Dr. Garnick viewed this study as “problematic because patient accrual ends in 2036 with a readout in 2041.” He added, “What its relevance will be at that time is unlikely to provide practice changes, since in that interval there will undoubtedly be multiple advances in place.”

Newly diagnosed favorable intermediate risk prostate cancer

People with this type of cancer are eligible for an open-label, phase 4 real-world study of a radioactive diagnostic agent called piflufolastat F 18 (Pylarify) that targets prostate-specific membrane antigen (PSMA)–positive lesions. Piflufolastat is designed to enhance detection of metastases during PSMA-targeted PET.

Participants will receive a single injection of piflufolastat followed 1-2 hours later by a single whole-body PET-CT or PET-MRI scan. A study site at the Hoag Cancer Center in Irvine, California, welcomed the first of the trial’s 274 participants in February 2024. Sites in Tower Urology, Los Angeles, and the Cleveland Clinic, Ohio, are gearing up. Detection rate is the primary endpoint. Overall survival and QoL are not measured. More details at clinicaltrials.gov

Stages I-IV prostate cancer without bone metastases. People 60 years or older with this type of prostate cancer who are just starting androgen deprivation therapy are eligible for a phase 3, placebo-controlled trial investigating whether high-dose vitamin D can prevent or reduce androgen-deprivation therapy-induced bone loss.

For 1 year, participants will take tablets of high-dose vitamin D or a placebo and then undergo dual x-ray absorptiometry. The Ochsner Medical Center in Jefferson, Louisiana, started recruiting 366 trial participants in December 2023. Reduction in bone mineral density loss in the hip and spine over 1 year is the primary objective. QoL is a secondary objective, and overall survival will not be measured. More details at clinicaltrials.gov

Dr. Garnick expressed some concerns with the trial design so far, including that “the dose of vitamin D is not delineated nor is the target vitamin D level.”

All trial information is from the National Institutes of Health’s National Library of Medicine (online at clinicaltrials.gov). Dr. Garnick did not report conflicts with any of the trials.
 

A version of this article appeared on Medscape.com.

Several new clinical trials in prostate cancer have started recruiting in recent months. Maybe one of your patients could benefit from enrolling?

Metastatic castration-sensitive prostate cancer 

Adults with this diagnosis may be interested in a randomized, double-blind, phase 3 study examining whether an experimental poly (ADP-ribose) polymerase (PARP) inhibitor called saruparib can further delay disease progression when added to a next-generation hormonal agent such as abiraterone (Zytiga), darolutamide (Nubeqa), or enzalutamide (Xtandi).

One group of participants will take daily oral doses of saruparib plus physician’s choice of a next-generation hormonal agent until disease progression or another reason for stopping therapy. The other group will add a placebo to a next-generation hormonal agent.

Sites in Rhode Island, Arkansas, California, Michigan, Australia, Canada, Japan, Taiwan, Thailand, the United Kingdom, and South Korea began seeking the trial’s 1800 participants in November 2023. Research centers in 31 other US states and 18 other countries are gearing up. The primary endpoint is radiographic progression-free survival. Overall survival and quality of life (QoL) are secondary endpoints. More details at clinicaltrials.gov.

This news organization asked Marc Garnick, MD, professor of medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, for his take on the trial. “The study is interesting since it is adding to the evaluations of continued intensification for first-line therapy and will help further elucidate the role of PARP inhibition regardless of homologous repair status,” Dr. Garnick said. “Plus, saruparib is supposedly more selective on PARP1, which in-and-of-itself is of potential benefit.”

Metastatic castration-resistant prostate cancer

People with this type of cancer who have progressed on a next-generation hormonal agent may be eligible for a randomized, open-label, phase 3 trial testing an investigational oral treatment called MK-5684 to see if it increases survival more effectively than switching to an alternative next-generation hormonal agent.

MK-5684 is designed to inhibit the CYP11A1 enzyme, thereby disrupting the androgen-receptor signaling pathway.

One group will take twice-daily tablets of MK-5684 plus hormone replacement therapy, oral dexamethasone, and oral fludrocortisone acetate (Florinef), with rescue hydrocortisone as needed. The other participants will take daily tablets of a next-generation hormonal agent: Either enzalutamide or abiraterone. Patients assigned to abiraterone will also be given prednisone tablets.

US-based sites in nine states and Puerto Rico started looking for the trial’s 1500 participants in December 2023 in partnership with study centers in Australia, Israel, South Korea, and Taiwan. The primary endpoints are radiographic progression-free survival and overall survival. QoL will not be tracked. More details at clinicaltrials.gov.

Metastatic castration-resistant prostate cancer

Patients in this situation who have progressed on taxane-based chemotherapy as well as a next-generation hormonal agent have the option to enroll in another phase 3 MK-5684 study.

Like the trial described above, all patients will remain on their respective therapy until disease progression. In this trial, one group will take twice-daily tablets of MK-5684 without hormone replacement therapy but the same mix of oral dexamethasone and fludrocortisone. Rescue hydrocortisone will also be available. The second group will be assigned either enzalutamide or abiraterone plus prednisone.

Sites in Puerto Rico, Colorado, Nevada, and Virginia, and five other countries outside the United States, opened their doors to the first of 1200 patients in December 2023. The primary endpoints are radiographic progression-free survival and overall survival, analyzed separately for patients with and without an androgen receptor ligand-binding domain mutation. QoL will not be measured. More details at clinicaltrials.gov.

High-risk prostate cancer

People with this diagnosis can join a randomized, open-label, phase 3 National Cancer Institute study to test whether stereotactic body radiation therapy (SBRT) is as effective as conventional external beam radiation therapy (EBRT) at preventing metastasis.

SBRT delivers radiation to tumors with higher precision than EBRT. The advantage of SBRT is the ability to deliver fewer doses over a shorter duration with less collateral damage to surrounding tissues.

In the trial, half of participants will undergo five treatments of SBRT over 2 weeks, while the other half will receive 20-45 treatments of EBRT over 4-9 weeks. Study sites in 14 US states began recruiting the trial’s 1209 participants in November 2023. Metastasis-free survival over 15 years is the primary endpoint, overall survival is a secondary endpoint, and QoL measures, apart from fatigue, will not be tracked. More details at clinicaltrials.gov.

Dr. Garnick viewed this study as “problematic because patient accrual ends in 2036 with a readout in 2041.” He added, “What its relevance will be at that time is unlikely to provide practice changes, since in that interval there will undoubtedly be multiple advances in place.”

Newly diagnosed favorable intermediate risk prostate cancer

People with this type of cancer are eligible for an open-label, phase 4 real-world study of a radioactive diagnostic agent called piflufolastat F 18 (Pylarify) that targets prostate-specific membrane antigen (PSMA)–positive lesions. Piflufolastat is designed to enhance detection of metastases during PSMA-targeted PET.

Participants will receive a single injection of piflufolastat followed 1-2 hours later by a single whole-body PET-CT or PET-MRI scan. A study site at the Hoag Cancer Center in Irvine, California, welcomed the first of the trial’s 274 participants in February 2024. Sites in Tower Urology, Los Angeles, and the Cleveland Clinic, Ohio, are gearing up. Detection rate is the primary endpoint. Overall survival and QoL are not measured. More details at clinicaltrials.gov

Stages I-IV prostate cancer without bone metastases. People 60 years or older with this type of prostate cancer who are just starting androgen deprivation therapy are eligible for a phase 3, placebo-controlled trial investigating whether high-dose vitamin D can prevent or reduce androgen-deprivation therapy-induced bone loss.

For 1 year, participants will take tablets of high-dose vitamin D or a placebo and then undergo dual x-ray absorptiometry. The Ochsner Medical Center in Jefferson, Louisiana, started recruiting 366 trial participants in December 2023. Reduction in bone mineral density loss in the hip and spine over 1 year is the primary objective. QoL is a secondary objective, and overall survival will not be measured. More details at clinicaltrials.gov

Dr. Garnick expressed some concerns with the trial design so far, including that “the dose of vitamin D is not delineated nor is the target vitamin D level.”

All trial information is from the National Institutes of Health’s National Library of Medicine (online at clinicaltrials.gov). Dr. Garnick did not report conflicts with any of the trials.
 

A version of this article appeared on Medscape.com.

Several new clinical trials in prostate cancer have started recruiting in recent months. Maybe one of your patients could benefit from enrolling?

Metastatic castration-sensitive prostate cancer 

Adults with this diagnosis may be interested in a randomized, double-blind, phase 3 study examining whether an experimental poly (ADP-ribose) polymerase (PARP) inhibitor called saruparib can further delay disease progression when added to a next-generation hormonal agent such as abiraterone (Zytiga), darolutamide (Nubeqa), or enzalutamide (Xtandi).

One group of participants will take daily oral doses of saruparib plus physician’s choice of a next-generation hormonal agent until disease progression or another reason for stopping therapy. The other group will add a placebo to a next-generation hormonal agent.

Sites in Rhode Island, Arkansas, California, Michigan, Australia, Canada, Japan, Taiwan, Thailand, the United Kingdom, and South Korea began seeking the trial’s 1800 participants in November 2023. Research centers in 31 other US states and 18 other countries are gearing up. The primary endpoint is radiographic progression-free survival. Overall survival and quality of life (QoL) are secondary endpoints. More details at clinicaltrials.gov.

This news organization asked Marc Garnick, MD, professor of medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, for his take on the trial. “The study is interesting since it is adding to the evaluations of continued intensification for first-line therapy and will help further elucidate the role of PARP inhibition regardless of homologous repair status,” Dr. Garnick said. “Plus, saruparib is supposedly more selective on PARP1, which in-and-of-itself is of potential benefit.”

Metastatic castration-resistant prostate cancer

People with this type of cancer who have progressed on a next-generation hormonal agent may be eligible for a randomized, open-label, phase 3 trial testing an investigational oral treatment called MK-5684 to see if it increases survival more effectively than switching to an alternative next-generation hormonal agent.

MK-5684 is designed to inhibit the CYP11A1 enzyme, thereby disrupting the androgen-receptor signaling pathway.

One group will take twice-daily tablets of MK-5684 plus hormone replacement therapy, oral dexamethasone, and oral fludrocortisone acetate (Florinef), with rescue hydrocortisone as needed. The other participants will take daily tablets of a next-generation hormonal agent: Either enzalutamide or abiraterone. Patients assigned to abiraterone will also be given prednisone tablets.

US-based sites in nine states and Puerto Rico started looking for the trial’s 1500 participants in December 2023 in partnership with study centers in Australia, Israel, South Korea, and Taiwan. The primary endpoints are radiographic progression-free survival and overall survival. QoL will not be tracked. More details at clinicaltrials.gov.

Metastatic castration-resistant prostate cancer

Patients in this situation who have progressed on taxane-based chemotherapy as well as a next-generation hormonal agent have the option to enroll in another phase 3 MK-5684 study.

Like the trial described above, all patients will remain on their respective therapy until disease progression. In this trial, one group will take twice-daily tablets of MK-5684 without hormone replacement therapy but the same mix of oral dexamethasone and fludrocortisone. Rescue hydrocortisone will also be available. The second group will be assigned either enzalutamide or abiraterone plus prednisone.

Sites in Puerto Rico, Colorado, Nevada, and Virginia, and five other countries outside the United States, opened their doors to the first of 1200 patients in December 2023. The primary endpoints are radiographic progression-free survival and overall survival, analyzed separately for patients with and without an androgen receptor ligand-binding domain mutation. QoL will not be measured. More details at clinicaltrials.gov.

High-risk prostate cancer

People with this diagnosis can join a randomized, open-label, phase 3 National Cancer Institute study to test whether stereotactic body radiation therapy (SBRT) is as effective as conventional external beam radiation therapy (EBRT) at preventing metastasis.

SBRT delivers radiation to tumors with higher precision than EBRT. The advantage of SBRT is the ability to deliver fewer doses over a shorter duration with less collateral damage to surrounding tissues.

In the trial, half of participants will undergo five treatments of SBRT over 2 weeks, while the other half will receive 20-45 treatments of EBRT over 4-9 weeks. Study sites in 14 US states began recruiting the trial’s 1209 participants in November 2023. Metastasis-free survival over 15 years is the primary endpoint, overall survival is a secondary endpoint, and QoL measures, apart from fatigue, will not be tracked. More details at clinicaltrials.gov.

Dr. Garnick viewed this study as “problematic because patient accrual ends in 2036 with a readout in 2041.” He added, “What its relevance will be at that time is unlikely to provide practice changes, since in that interval there will undoubtedly be multiple advances in place.”

Newly diagnosed favorable intermediate risk prostate cancer

People with this type of cancer are eligible for an open-label, phase 4 real-world study of a radioactive diagnostic agent called piflufolastat F 18 (Pylarify) that targets prostate-specific membrane antigen (PSMA)–positive lesions. Piflufolastat is designed to enhance detection of metastases during PSMA-targeted PET.

Participants will receive a single injection of piflufolastat followed 1-2 hours later by a single whole-body PET-CT or PET-MRI scan. A study site at the Hoag Cancer Center in Irvine, California, welcomed the first of the trial’s 274 participants in February 2024. Sites in Tower Urology, Los Angeles, and the Cleveland Clinic, Ohio, are gearing up. Detection rate is the primary endpoint. Overall survival and QoL are not measured. More details at clinicaltrials.gov

Stages I-IV prostate cancer without bone metastases. People 60 years or older with this type of prostate cancer who are just starting androgen deprivation therapy are eligible for a phase 3, placebo-controlled trial investigating whether high-dose vitamin D can prevent or reduce androgen-deprivation therapy-induced bone loss.

For 1 year, participants will take tablets of high-dose vitamin D or a placebo and then undergo dual x-ray absorptiometry. The Ochsner Medical Center in Jefferson, Louisiana, started recruiting 366 trial participants in December 2023. Reduction in bone mineral density loss in the hip and spine over 1 year is the primary objective. QoL is a secondary objective, and overall survival will not be measured. More details at clinicaltrials.gov

Dr. Garnick expressed some concerns with the trial design so far, including that “the dose of vitamin D is not delineated nor is the target vitamin D level.”

All trial information is from the National Institutes of Health’s National Library of Medicine (online at clinicaltrials.gov). Dr. Garnick did not report conflicts with any of the trials.
 

A version of this article appeared on Medscape.com.

A San Antonio oncology practice and diagnostic reference laboratory have agreed to settle a federal lawsuit, which alleged the two entities had entered an unlawful kickback arrangement.

The US Department of Justice (DOJ) announced on April 2 that Oncology San Antonio, PA, and its physicians have agreed to pay $1.3 million, and CorePath Laboratories, PA, has agreed to pay nearly $2.75 million plus accrued interest in civil settlements with the United States and Texas for alleged violations of the False Claims Act.

According to the DOJ, the diagnostic reference laboratory, CorePath Laboratories, conducted in-office bone marrow biopsies at Oncology San Antonio practice locations and performed diagnostic testing on the samples. CorePath Laboratories agreed to pay $115 for each biopsy referred by Oncology San Antonio physicians, and these biopsy payments were allegedly paid to the private practices of three physicians at Oncology San Antonio. This arrangement allegedly began in August 2016.

The DOJ claimed that the payments for referring biopsies constituted illegal kickbacks under the Anti-Kickback Statute, which prohibits offering or receiving payments to encourage referrals of services covered by federal healthcare programs like Medicare and Medicaid.

“Violations of the Anti-Kickback Statute involving oncology services can waste scarce federal healthcare program funds and corrupt the medical decision-making process,” Special Agent in Charge Jason E. Meadows with the US Department of Health and Human Services Office of Inspector General said in a statement.

Oncology San Antonio told this news organization that the cost and distraction of prolonged litigation were the primary factors in its decision to settle. “The decision to settle was an extremely difficult one because Oncology San Antonio was confident that it would have prevailed in any action,” the practice said via email.

This civil settlement with Oncology San Antonio also resolved allegations that a physician affiliated with the practice, Jayasree Rao, MD, provided unnecessary tests, services, and treatments to patients covered by Medicare, TRICARE, and Texas Medicaid in the San Antonio Metro Area and billed these federal healthcare programs for the unnecessary services.

The DOJ identified Slavisa Gasic, MD, a physician formerly employed by Dr. Rao, as a whistleblower in the investigation. When asked for comment, Oncology San Antonio alleged Dr. Gasic was “disgruntled for not being promoted.”

According to Oncology San Antonio, the contract for bone marrow biopsies was negotiated and signed by a former nonphysician officer of the company without the input of Oncology San Antonio physicians. The contract permitted bone marrow biopsies at Oncology San Antonio clinics instead of requiring older adult and sick patients to go to a different facility for these services.

“Oncology San Antonio and Rao vehemently denied Gasic’s allegations as wholly unfounded,” the company told this news organization.

Dr. Rao retired in March and is no longer practicing. CorePath Laboratories, PA, did not respond to this news organization’s request for comment.

According to the DOJ press release, the “investigation and resolution of this matter illustrate the government’s emphasis on combating healthcare fraud.”
 

A version of this article appeared on Medscape.com.

A San Antonio oncology practice and diagnostic reference laboratory have agreed to settle a federal lawsuit, which alleged the two entities had entered an unlawful kickback arrangement.

The US Department of Justice (DOJ) announced on April 2 that Oncology San Antonio, PA, and its physicians have agreed to pay $1.3 million, and CorePath Laboratories, PA, has agreed to pay nearly $2.75 million plus accrued interest in civil settlements with the United States and Texas for alleged violations of the False Claims Act.

According to the DOJ, the diagnostic reference laboratory, CorePath Laboratories, conducted in-office bone marrow biopsies at Oncology San Antonio practice locations and performed diagnostic testing on the samples. CorePath Laboratories agreed to pay $115 for each biopsy referred by Oncology San Antonio physicians, and these biopsy payments were allegedly paid to the private practices of three physicians at Oncology San Antonio. This arrangement allegedly began in August 2016.

The DOJ claimed that the payments for referring biopsies constituted illegal kickbacks under the Anti-Kickback Statute, which prohibits offering or receiving payments to encourage referrals of services covered by federal healthcare programs like Medicare and Medicaid.

“Violations of the Anti-Kickback Statute involving oncology services can waste scarce federal healthcare program funds and corrupt the medical decision-making process,” Special Agent in Charge Jason E. Meadows with the US Department of Health and Human Services Office of Inspector General said in a statement.

Oncology San Antonio told this news organization that the cost and distraction of prolonged litigation were the primary factors in its decision to settle. “The decision to settle was an extremely difficult one because Oncology San Antonio was confident that it would have prevailed in any action,” the practice said via email.

This civil settlement with Oncology San Antonio also resolved allegations that a physician affiliated with the practice, Jayasree Rao, MD, provided unnecessary tests, services, and treatments to patients covered by Medicare, TRICARE, and Texas Medicaid in the San Antonio Metro Area and billed these federal healthcare programs for the unnecessary services.

The DOJ identified Slavisa Gasic, MD, a physician formerly employed by Dr. Rao, as a whistleblower in the investigation. When asked for comment, Oncology San Antonio alleged Dr. Gasic was “disgruntled for not being promoted.”

According to Oncology San Antonio, the contract for bone marrow biopsies was negotiated and signed by a former nonphysician officer of the company without the input of Oncology San Antonio physicians. The contract permitted bone marrow biopsies at Oncology San Antonio clinics instead of requiring older adult and sick patients to go to a different facility for these services.

“Oncology San Antonio and Rao vehemently denied Gasic’s allegations as wholly unfounded,” the company told this news organization.

Dr. Rao retired in March and is no longer practicing. CorePath Laboratories, PA, did not respond to this news organization’s request for comment.

According to the DOJ press release, the “investigation and resolution of this matter illustrate the government’s emphasis on combating healthcare fraud.”
 

A version of this article appeared on Medscape.com.

A San Antonio oncology practice and diagnostic reference laboratory have agreed to settle a federal lawsuit, which alleged the two entities had entered an unlawful kickback arrangement.

The US Department of Justice (DOJ) announced on April 2 that Oncology San Antonio, PA, and its physicians have agreed to pay $1.3 million, and CorePath Laboratories, PA, has agreed to pay nearly $2.75 million plus accrued interest in civil settlements with the United States and Texas for alleged violations of the False Claims Act.

According to the DOJ, the diagnostic reference laboratory, CorePath Laboratories, conducted in-office bone marrow biopsies at Oncology San Antonio practice locations and performed diagnostic testing on the samples. CorePath Laboratories agreed to pay $115 for each biopsy referred by Oncology San Antonio physicians, and these biopsy payments were allegedly paid to the private practices of three physicians at Oncology San Antonio. This arrangement allegedly began in August 2016.

The DOJ claimed that the payments for referring biopsies constituted illegal kickbacks under the Anti-Kickback Statute, which prohibits offering or receiving payments to encourage referrals of services covered by federal healthcare programs like Medicare and Medicaid.

“Violations of the Anti-Kickback Statute involving oncology services can waste scarce federal healthcare program funds and corrupt the medical decision-making process,” Special Agent in Charge Jason E. Meadows with the US Department of Health and Human Services Office of Inspector General said in a statement.

Oncology San Antonio told this news organization that the cost and distraction of prolonged litigation were the primary factors in its decision to settle. “The decision to settle was an extremely difficult one because Oncology San Antonio was confident that it would have prevailed in any action,” the practice said via email.

This civil settlement with Oncology San Antonio also resolved allegations that a physician affiliated with the practice, Jayasree Rao, MD, provided unnecessary tests, services, and treatments to patients covered by Medicare, TRICARE, and Texas Medicaid in the San Antonio Metro Area and billed these federal healthcare programs for the unnecessary services.

The DOJ identified Slavisa Gasic, MD, a physician formerly employed by Dr. Rao, as a whistleblower in the investigation. When asked for comment, Oncology San Antonio alleged Dr. Gasic was “disgruntled for not being promoted.”

According to Oncology San Antonio, the contract for bone marrow biopsies was negotiated and signed by a former nonphysician officer of the company without the input of Oncology San Antonio physicians. The contract permitted bone marrow biopsies at Oncology San Antonio clinics instead of requiring older adult and sick patients to go to a different facility for these services.

“Oncology San Antonio and Rao vehemently denied Gasic’s allegations as wholly unfounded,” the company told this news organization.

Dr. Rao retired in March and is no longer practicing. CorePath Laboratories, PA, did not respond to this news organization’s request for comment.

According to the DOJ press release, the “investigation and resolution of this matter illustrate the government’s emphasis on combating healthcare fraud.”
 

A version of this article appeared on Medscape.com.