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Liver transplants for CRC metastases: Coming into its own?
Liver transplant is an effective therapy for patients with primary liver cancer, and outcomes after transplantation are often superior to surgical resection. But the pool of potential patients is increasing, as transplantation is now emerging as an attractive option for select patients with nonresectable colorectal cancer (CRC) liver metastases, as well as those with intrahepatic cholangiocarcinoma (CCA).
Transplant is here to stay
To date, the only curative or potentially curative therapy for patients with CRC liver metastases and intrahepatic CCA has been the combination of systemic therapies and R0 resection, said Gonzalo Sapisochin Cantis, MD, associate professor, department of surgery, University of Toronto.
The new idea is that, for patients with unresectable disease, total hepatectomy followed by a liver transplant may be a promising strategy. “This is a very hot topic in transplant oncology,” he said.
Liver transplantation is already established as the best treatment option for patients with primary hepatocellular carcinoma, which has become the main indication for liver transplantation at many centers.
For patients with CRC metastases and intrahepatic CCA, liver transplantation may help cure some patients by extending the conventional margins of surgical oncology, he suggested. “This is basically going to work in patients who have exclusive liver-restricted disease and not in those with metastatic disease. The efficacy is going to be seen by objective and sustained response to some sort of neoadjuvant therapy.”
However, Dr. Sapisochin emphasized liver transplantation is not an option for every patient. “We’re going to have to have clear inclusion and exclusion criteria that need to be defined a priori.”
Intrahepatic CCA has historically been considered a contraindication for liver transplantation. Surgical resection is the preferred first-line treatment and the only one that is potentially curative, he explained. However, most patients are not candidates for surgery, and even if they do have a resection, many of these patients will experience a recurrence, usually in the liver.
There are some studies that support transplantation in this patient population, including one by Dr. Sapisochin and colleagues. That study looked at patients who were transplanted under the assumption that they had hepatocellular carcinoma but were found to actually have intrahepatic CCA. The recurrence rate at 5 years was 18%, and 5-year survival was 65%.
“We were able to show that those patients with small tumors actually can do very well after transplant, with survivals over 70%-80%, which in this population is a very good outcome,” he said.
Transplant for CRC metastases
Unresectable liver metastases from colorectal cancer can also be challenging to treat, he said. Surgical resection is the only potential cure with a combination of systemic chemotherapy, but only a minority of patients are candidates for surgery.
Data supporting transplantation for CRC metastases have been emerging. One trial was conducted by researchers in Norway, who developed the Oslo score for risk stratification. “Those with risk factors had worse outcomes, and obviously, having a large tumor diameter, a high CEA (carcinoembryonic antigen), progressing on chemotherapy, or a short interval between the primary resection and the transplant were risk factors for recurrence,” Dr. Sapisochin said.
The 10-year survival among patients with a low Oslo score was 50%. “We’re talking about patients who had no resection possibility and received a transplant after systemic chemotherapy, and they had a 10-year survival of 50%,” he emphasized.
However, Dr. Sapisochin acknowledged the biggest problem transplant surgeons face is that there are not enough donor organs.
One solution is living donor liver transplantation. “Given that this is an unlimited source, you can utilize this as extended criteria and it adds another graft to the system,” he explained.
“We have a protocol for living donor liver transplantations for patients with colorectal liver metastasis,” Dr. Sapisochin said. “We’ve done seven cases so far with pretty good outcomes. One patient, unfortunately, passed away 39 months after transplant with lung metastases, but the rest are alive with no recurrence.”*
More available organs?
R. Mark Ghobrial, MD, PhD, director of the J.C. Walter Jr. Transplant Center at Houston Methodist Hospital, said that, 5 years ago, he was very cautious about liver transplantation for intrahepatic CCA.
He pointed out that, although transplantation for hepatocellular cancer was being done in the 1990s, the results were so poor that a moratorium was placed on the practice. “But now liver transplantation has become the definitive therapy for hepatocellular cancer, and intrahepatic cholangiocarcinoma is going the same way,” he said.
Dr. Ghobrial reiterated that one of the issues in transplantation for oncology patients is the limited supply of available organs, but he believes the landscape for liver transplantation has changed, resulting in more available organs. One factor is that hepatitis C has become curable with the advent of new therapies, and hence, the need for transplantation for patients with this disease has plummeted.
“I’ve done about maybe 800 transplants in the last 5 years. I’ve only transplanted two patients with hepatitis C,” he said. “Now we are doing more transplants for alcoholic liver disease and cancer.”
Improvements in technology are also allowing for more livers to become useable, he pointed out. One example is normothermic machine perfusion, which has entered the clinical arena in the last decade. The technique has shown promising results in improving the quality of marginal organs and increasing the pool of liver grafts.
Another factor that has increased the number of livers available for transplantation is the move to accept organs from circulatory death donors, as well as donations after brain death. “Our transplantation was about 4% of donors after cardiac death, but today this has gone up to almost 16% or 20% of the livers,” Dr. Ghobrial said. “In some centers this has gone up to about 50%.
“Liver transplantation for intrahepatic cholangiocarcinoma and colorectal cancer metastases has come of age for selected patients,” he said.
More caution needed
However, another expert urged some caution, warning that live donation carries risk. Yuman Fong, MD, a surgical oncologist with City of Hope National Medical Center, Duarte, Calif., said that around “1 in 600 live donors die from donation. That is a healthy person dying. This is not a small issue.”
He pointed out that if the criteria for transplant is greatly liberalized, the 5-year survival will not be as high as demonstrated in clinical trials.
Writing about the issue in a recent editorial, Dr. Fong pointed out that cadaveric livers for transplant remain a finite resource and that more than 1,000 patients still die every year on the waiting list for a transplant.
A more reasonable approach would be to advocate for this type of program in regions of the world where cadaveric livers are more plentiful or centers with established living donor transplant programs.
“For us to develop this resource and safeguard patients, family organ donors, and resources, we need to develop what are the best inclusion criteria,” Dr. Fong said. “We have to optimize use of all cadaveric organs and determine if we are willing to transplant borderline organs.”
Ethics of transplanting
Ethicist Arthur L. Caplan, PhD, the Drs. William F. and Virginia Connolly Mitty Professor of Bioethics at New York University, said this is an interesting development in the field of liver transplantation. “There have been attempts in the past, and many did not end well, such as with Steve Jobs. But transplantation is always pushing to expand eligibility, and there has also been much success with that.”
However, Dr. Caplan emphasized the new data are innovative and experimental, which may control how many centers will be able to perform liver transplants in these cancer patient populations. “It has to be data driven as we are dealing with an exceedingly scarce source,” he said. “We know that people can do well, but it adds more stress to the supply of organs, and some patients may not do as well.”
He also emphasized that live donation is not a panacea. “Liver donation from a live donor is not the same as live donation for a kidney. It is much riskier and not that common. So not quite the same.”
The bottom line is that livers for transplantation are a scarce resource and transplant may work well in some cancer patients but not others, he emphasized. “Morally, we want to save lives, but not by adding in people who may not do well. If programs try to stretch the criteria, some may try transplants with more marginal organs.”
Dr. Sapisochin has disclosed relationships with Bayer, Roche, Novartis, Integra, AstraZeneca, Chiesi, Evidera, and Stryker. Dr. Ghobrial reported no relevant financial relationships. Dr. Fong has reported being a scientific consultant for Medtronic and Johnson & Johnson and receiving royalties from Merck and Imugene. Dr. Caplan writes a regular column on ethics for Medscape.
A version of this article first appeared on Medscape.com.
Correction, 4/28/23 - An earlier version of this article misstated when the patient passed away.
Liver transplant is an effective therapy for patients with primary liver cancer, and outcomes after transplantation are often superior to surgical resection. But the pool of potential patients is increasing, as transplantation is now emerging as an attractive option for select patients with nonresectable colorectal cancer (CRC) liver metastases, as well as those with intrahepatic cholangiocarcinoma (CCA).
Transplant is here to stay
To date, the only curative or potentially curative therapy for patients with CRC liver metastases and intrahepatic CCA has been the combination of systemic therapies and R0 resection, said Gonzalo Sapisochin Cantis, MD, associate professor, department of surgery, University of Toronto.
The new idea is that, for patients with unresectable disease, total hepatectomy followed by a liver transplant may be a promising strategy. “This is a very hot topic in transplant oncology,” he said.
Liver transplantation is already established as the best treatment option for patients with primary hepatocellular carcinoma, which has become the main indication for liver transplantation at many centers.
For patients with CRC metastases and intrahepatic CCA, liver transplantation may help cure some patients by extending the conventional margins of surgical oncology, he suggested. “This is basically going to work in patients who have exclusive liver-restricted disease and not in those with metastatic disease. The efficacy is going to be seen by objective and sustained response to some sort of neoadjuvant therapy.”
However, Dr. Sapisochin emphasized liver transplantation is not an option for every patient. “We’re going to have to have clear inclusion and exclusion criteria that need to be defined a priori.”
Intrahepatic CCA has historically been considered a contraindication for liver transplantation. Surgical resection is the preferred first-line treatment and the only one that is potentially curative, he explained. However, most patients are not candidates for surgery, and even if they do have a resection, many of these patients will experience a recurrence, usually in the liver.
There are some studies that support transplantation in this patient population, including one by Dr. Sapisochin and colleagues. That study looked at patients who were transplanted under the assumption that they had hepatocellular carcinoma but were found to actually have intrahepatic CCA. The recurrence rate at 5 years was 18%, and 5-year survival was 65%.
“We were able to show that those patients with small tumors actually can do very well after transplant, with survivals over 70%-80%, which in this population is a very good outcome,” he said.
Transplant for CRC metastases
Unresectable liver metastases from colorectal cancer can also be challenging to treat, he said. Surgical resection is the only potential cure with a combination of systemic chemotherapy, but only a minority of patients are candidates for surgery.
Data supporting transplantation for CRC metastases have been emerging. One trial was conducted by researchers in Norway, who developed the Oslo score for risk stratification. “Those with risk factors had worse outcomes, and obviously, having a large tumor diameter, a high CEA (carcinoembryonic antigen), progressing on chemotherapy, or a short interval between the primary resection and the transplant were risk factors for recurrence,” Dr. Sapisochin said.
The 10-year survival among patients with a low Oslo score was 50%. “We’re talking about patients who had no resection possibility and received a transplant after systemic chemotherapy, and they had a 10-year survival of 50%,” he emphasized.
However, Dr. Sapisochin acknowledged the biggest problem transplant surgeons face is that there are not enough donor organs.
One solution is living donor liver transplantation. “Given that this is an unlimited source, you can utilize this as extended criteria and it adds another graft to the system,” he explained.
“We have a protocol for living donor liver transplantations for patients with colorectal liver metastasis,” Dr. Sapisochin said. “We’ve done seven cases so far with pretty good outcomes. One patient, unfortunately, passed away 39 months after transplant with lung metastases, but the rest are alive with no recurrence.”*
More available organs?
R. Mark Ghobrial, MD, PhD, director of the J.C. Walter Jr. Transplant Center at Houston Methodist Hospital, said that, 5 years ago, he was very cautious about liver transplantation for intrahepatic CCA.
He pointed out that, although transplantation for hepatocellular cancer was being done in the 1990s, the results were so poor that a moratorium was placed on the practice. “But now liver transplantation has become the definitive therapy for hepatocellular cancer, and intrahepatic cholangiocarcinoma is going the same way,” he said.
Dr. Ghobrial reiterated that one of the issues in transplantation for oncology patients is the limited supply of available organs, but he believes the landscape for liver transplantation has changed, resulting in more available organs. One factor is that hepatitis C has become curable with the advent of new therapies, and hence, the need for transplantation for patients with this disease has plummeted.
“I’ve done about maybe 800 transplants in the last 5 years. I’ve only transplanted two patients with hepatitis C,” he said. “Now we are doing more transplants for alcoholic liver disease and cancer.”
Improvements in technology are also allowing for more livers to become useable, he pointed out. One example is normothermic machine perfusion, which has entered the clinical arena in the last decade. The technique has shown promising results in improving the quality of marginal organs and increasing the pool of liver grafts.
Another factor that has increased the number of livers available for transplantation is the move to accept organs from circulatory death donors, as well as donations after brain death. “Our transplantation was about 4% of donors after cardiac death, but today this has gone up to almost 16% or 20% of the livers,” Dr. Ghobrial said. “In some centers this has gone up to about 50%.
“Liver transplantation for intrahepatic cholangiocarcinoma and colorectal cancer metastases has come of age for selected patients,” he said.
More caution needed
However, another expert urged some caution, warning that live donation carries risk. Yuman Fong, MD, a surgical oncologist with City of Hope National Medical Center, Duarte, Calif., said that around “1 in 600 live donors die from donation. That is a healthy person dying. This is not a small issue.”
He pointed out that if the criteria for transplant is greatly liberalized, the 5-year survival will not be as high as demonstrated in clinical trials.
Writing about the issue in a recent editorial, Dr. Fong pointed out that cadaveric livers for transplant remain a finite resource and that more than 1,000 patients still die every year on the waiting list for a transplant.
A more reasonable approach would be to advocate for this type of program in regions of the world where cadaveric livers are more plentiful or centers with established living donor transplant programs.
“For us to develop this resource and safeguard patients, family organ donors, and resources, we need to develop what are the best inclusion criteria,” Dr. Fong said. “We have to optimize use of all cadaveric organs and determine if we are willing to transplant borderline organs.”
Ethics of transplanting
Ethicist Arthur L. Caplan, PhD, the Drs. William F. and Virginia Connolly Mitty Professor of Bioethics at New York University, said this is an interesting development in the field of liver transplantation. “There have been attempts in the past, and many did not end well, such as with Steve Jobs. But transplantation is always pushing to expand eligibility, and there has also been much success with that.”
However, Dr. Caplan emphasized the new data are innovative and experimental, which may control how many centers will be able to perform liver transplants in these cancer patient populations. “It has to be data driven as we are dealing with an exceedingly scarce source,” he said. “We know that people can do well, but it adds more stress to the supply of organs, and some patients may not do as well.”
He also emphasized that live donation is not a panacea. “Liver donation from a live donor is not the same as live donation for a kidney. It is much riskier and not that common. So not quite the same.”
The bottom line is that livers for transplantation are a scarce resource and transplant may work well in some cancer patients but not others, he emphasized. “Morally, we want to save lives, but not by adding in people who may not do well. If programs try to stretch the criteria, some may try transplants with more marginal organs.”
Dr. Sapisochin has disclosed relationships with Bayer, Roche, Novartis, Integra, AstraZeneca, Chiesi, Evidera, and Stryker. Dr. Ghobrial reported no relevant financial relationships. Dr. Fong has reported being a scientific consultant for Medtronic and Johnson & Johnson and receiving royalties from Merck and Imugene. Dr. Caplan writes a regular column on ethics for Medscape.
A version of this article first appeared on Medscape.com.
Correction, 4/28/23 - An earlier version of this article misstated when the patient passed away.
Liver transplant is an effective therapy for patients with primary liver cancer, and outcomes after transplantation are often superior to surgical resection. But the pool of potential patients is increasing, as transplantation is now emerging as an attractive option for select patients with nonresectable colorectal cancer (CRC) liver metastases, as well as those with intrahepatic cholangiocarcinoma (CCA).
Transplant is here to stay
To date, the only curative or potentially curative therapy for patients with CRC liver metastases and intrahepatic CCA has been the combination of systemic therapies and R0 resection, said Gonzalo Sapisochin Cantis, MD, associate professor, department of surgery, University of Toronto.
The new idea is that, for patients with unresectable disease, total hepatectomy followed by a liver transplant may be a promising strategy. “This is a very hot topic in transplant oncology,” he said.
Liver transplantation is already established as the best treatment option for patients with primary hepatocellular carcinoma, which has become the main indication for liver transplantation at many centers.
For patients with CRC metastases and intrahepatic CCA, liver transplantation may help cure some patients by extending the conventional margins of surgical oncology, he suggested. “This is basically going to work in patients who have exclusive liver-restricted disease and not in those with metastatic disease. The efficacy is going to be seen by objective and sustained response to some sort of neoadjuvant therapy.”
However, Dr. Sapisochin emphasized liver transplantation is not an option for every patient. “We’re going to have to have clear inclusion and exclusion criteria that need to be defined a priori.”
Intrahepatic CCA has historically been considered a contraindication for liver transplantation. Surgical resection is the preferred first-line treatment and the only one that is potentially curative, he explained. However, most patients are not candidates for surgery, and even if they do have a resection, many of these patients will experience a recurrence, usually in the liver.
There are some studies that support transplantation in this patient population, including one by Dr. Sapisochin and colleagues. That study looked at patients who were transplanted under the assumption that they had hepatocellular carcinoma but were found to actually have intrahepatic CCA. The recurrence rate at 5 years was 18%, and 5-year survival was 65%.
“We were able to show that those patients with small tumors actually can do very well after transplant, with survivals over 70%-80%, which in this population is a very good outcome,” he said.
Transplant for CRC metastases
Unresectable liver metastases from colorectal cancer can also be challenging to treat, he said. Surgical resection is the only potential cure with a combination of systemic chemotherapy, but only a minority of patients are candidates for surgery.
Data supporting transplantation for CRC metastases have been emerging. One trial was conducted by researchers in Norway, who developed the Oslo score for risk stratification. “Those with risk factors had worse outcomes, and obviously, having a large tumor diameter, a high CEA (carcinoembryonic antigen), progressing on chemotherapy, or a short interval between the primary resection and the transplant were risk factors for recurrence,” Dr. Sapisochin said.
The 10-year survival among patients with a low Oslo score was 50%. “We’re talking about patients who had no resection possibility and received a transplant after systemic chemotherapy, and they had a 10-year survival of 50%,” he emphasized.
However, Dr. Sapisochin acknowledged the biggest problem transplant surgeons face is that there are not enough donor organs.
One solution is living donor liver transplantation. “Given that this is an unlimited source, you can utilize this as extended criteria and it adds another graft to the system,” he explained.
“We have a protocol for living donor liver transplantations for patients with colorectal liver metastasis,” Dr. Sapisochin said. “We’ve done seven cases so far with pretty good outcomes. One patient, unfortunately, passed away 39 months after transplant with lung metastases, but the rest are alive with no recurrence.”*
More available organs?
R. Mark Ghobrial, MD, PhD, director of the J.C. Walter Jr. Transplant Center at Houston Methodist Hospital, said that, 5 years ago, he was very cautious about liver transplantation for intrahepatic CCA.
He pointed out that, although transplantation for hepatocellular cancer was being done in the 1990s, the results were so poor that a moratorium was placed on the practice. “But now liver transplantation has become the definitive therapy for hepatocellular cancer, and intrahepatic cholangiocarcinoma is going the same way,” he said.
Dr. Ghobrial reiterated that one of the issues in transplantation for oncology patients is the limited supply of available organs, but he believes the landscape for liver transplantation has changed, resulting in more available organs. One factor is that hepatitis C has become curable with the advent of new therapies, and hence, the need for transplantation for patients with this disease has plummeted.
“I’ve done about maybe 800 transplants in the last 5 years. I’ve only transplanted two patients with hepatitis C,” he said. “Now we are doing more transplants for alcoholic liver disease and cancer.”
Improvements in technology are also allowing for more livers to become useable, he pointed out. One example is normothermic machine perfusion, which has entered the clinical arena in the last decade. The technique has shown promising results in improving the quality of marginal organs and increasing the pool of liver grafts.
Another factor that has increased the number of livers available for transplantation is the move to accept organs from circulatory death donors, as well as donations after brain death. “Our transplantation was about 4% of donors after cardiac death, but today this has gone up to almost 16% or 20% of the livers,” Dr. Ghobrial said. “In some centers this has gone up to about 50%.
“Liver transplantation for intrahepatic cholangiocarcinoma and colorectal cancer metastases has come of age for selected patients,” he said.
More caution needed
However, another expert urged some caution, warning that live donation carries risk. Yuman Fong, MD, a surgical oncologist with City of Hope National Medical Center, Duarte, Calif., said that around “1 in 600 live donors die from donation. That is a healthy person dying. This is not a small issue.”
He pointed out that if the criteria for transplant is greatly liberalized, the 5-year survival will not be as high as demonstrated in clinical trials.
Writing about the issue in a recent editorial, Dr. Fong pointed out that cadaveric livers for transplant remain a finite resource and that more than 1,000 patients still die every year on the waiting list for a transplant.
A more reasonable approach would be to advocate for this type of program in regions of the world where cadaveric livers are more plentiful or centers with established living donor transplant programs.
“For us to develop this resource and safeguard patients, family organ donors, and resources, we need to develop what are the best inclusion criteria,” Dr. Fong said. “We have to optimize use of all cadaveric organs and determine if we are willing to transplant borderline organs.”
Ethics of transplanting
Ethicist Arthur L. Caplan, PhD, the Drs. William F. and Virginia Connolly Mitty Professor of Bioethics at New York University, said this is an interesting development in the field of liver transplantation. “There have been attempts in the past, and many did not end well, such as with Steve Jobs. But transplantation is always pushing to expand eligibility, and there has also been much success with that.”
However, Dr. Caplan emphasized the new data are innovative and experimental, which may control how many centers will be able to perform liver transplants in these cancer patient populations. “It has to be data driven as we are dealing with an exceedingly scarce source,” he said. “We know that people can do well, but it adds more stress to the supply of organs, and some patients may not do as well.”
He also emphasized that live donation is not a panacea. “Liver donation from a live donor is not the same as live donation for a kidney. It is much riskier and not that common. So not quite the same.”
The bottom line is that livers for transplantation are a scarce resource and transplant may work well in some cancer patients but not others, he emphasized. “Morally, we want to save lives, but not by adding in people who may not do well. If programs try to stretch the criteria, some may try transplants with more marginal organs.”
Dr. Sapisochin has disclosed relationships with Bayer, Roche, Novartis, Integra, AstraZeneca, Chiesi, Evidera, and Stryker. Dr. Ghobrial reported no relevant financial relationships. Dr. Fong has reported being a scientific consultant for Medtronic and Johnson & Johnson and receiving royalties from Merck and Imugene. Dr. Caplan writes a regular column on ethics for Medscape.
A version of this article first appeared on Medscape.com.
Correction, 4/28/23 - An earlier version of this article misstated when the patient passed away.
FROM ASCO GU 2023
Plant-based diet linked to better outcomes in prostate cancer
The findings, which were reported at the 2023 ASCO Genitourinary Cancers Symposium in February, are based on a study of 2,038 men (median age, 64 years) with prostate cancer at stage T1, T2, or T3a.
“Consuming a whole foods plant-based diet may be an option to decrease risk for recurrence and improve overall survivorship,” said Vivian N. Liu, a clinical research coordinator at the University of California, San Francisco, who presented the findings.
The patients were interviewed about their diets at about 31.5 months after diagnosis. The study group was broken down into four groups based on how much of their diet consisted of a plant-based diet. Men in the highest quintile group who consumed at least 2.4 servings daily of fruit, 4.2 servings of vegetables, 2.6 servings of dairy, and 1.2 servings of meat (not seafood), had a 52% lower risk of progression (hazard ratio, 0.48; 95% confidence interval, 0.36-0.65; P-trend < 0.001) and a 53% lower risk of recurrence (HR, 0.47; 95% CI, 0.32-0.68; P-trend < 0.001), which was statistically significant. This compares with men in the lowest quintile who consumed 0.8 servings a day of fruit, 2.1 servings of vegetables, 3.1 servings of dairy, and 1.4 servings of meat. The findings were adjusted for total caloric intake, race, and smoking status.
For men over 65 years old, researchers found that a plant-based diet was associated with lower risk of recurrence (HR, 0.41; 95% CI, 0.24-0.7; P-trend = 0.03). And for those who exercised daily – in this case walking at a fast pace more than 3 times a week – a plant-based diet had a 56% (HR, 0.33; 95% CI, 0.26-0.73) lower risk of progression in the highest quintile group and a 59% decrease in recurrence (HR, 0.41; 95% CI, 0.25-0.68).
A new analysis like this, Ms. Liu said, “could guide people to make better, more healthful choices across their whole diet rather than adding or removing select foods.”
The primary endpoint was progression including recurrence, secondary treatment, bone metastases, and death due to prostate cancer, and the secondary endpoint was recurrence (PSA > 0.2ng/mL at 2 consecutive follow-up visits or during secondary treatment). At 7.4 years follow-up, there were 204 cases of progression.
“Fruits and vegetables contain antioxidants and anti-inflammatory components as well as dietary fiber that improve glucose control and reduce inflammation,” Ms. Liu said. In contrast, she said, animal-based foods may increase insulin resistance and insulin levels and boost levels of insulin-like growth factor 1, which is associated with prostate cancer risk. More studies, especially randomized controlled trials, are needed to provide evidence whether healthful plant-based foods and prostate cancer progression are connected.
NYU Langone Health urologist Natasha Gupta, MD, published a systematic review in 2022 on the impact of a plant-based diet on prostate cancer.* The review, which included 5 interventional studies and 11 observational studies, found that consuming a plant-based diet was associated with improvements in general health for men with prostate cancer. The observational studies found either a lower risk of prostate cancer or no significant difference.
“Patients often ask if there is anything that they can do to reduce the risk of recurrence, and it is great to be able to tell patients that a healthy lifestyle including plant-based foods and physical activity is helpful,” Dr. Gupta said.
The review’s coauthor, Stacy Loeb, MD, also of NYU Langone Health, said the new study was “a well-done observational study by experts in nutritional epidemiology from UCSF. It adds to a large body of evidence showing that plant-based diets improve health outcomes.”
“In the short-term, purchasing plant-based protein sources, such as beans and lentils, is less expensive than buying meat. Plant-based diets also reduce the risk of obesity, diabetes, and cardiovascular disease, which are associated with hundreds of thousands of dollars over a lifetime,” she said.
Limitations of the new study included the small number of non-White participants and self-reporting of diet. The study doesn’t examine the cost of various diets or the availability of plant-based foods like fresh produce, which can be limited in some neighborhoods.
Ms. Liu and colleagues plan to conduct a study that examines postdiagnostic plant-based diets in relation to prostate cancer–specific mortality. She and her team will also examine the plant-based dietary indices in relation to prostate cancer–specific quality of life at 2, 5, and 10 years from baseline.
The study authors, Dr. Loeb, and Dr. Gupta report no disclosures.
Correction, 3/17/23: An earlier version of this article misstated the name of NYU Langone Health.
The findings, which were reported at the 2023 ASCO Genitourinary Cancers Symposium in February, are based on a study of 2,038 men (median age, 64 years) with prostate cancer at stage T1, T2, or T3a.
“Consuming a whole foods plant-based diet may be an option to decrease risk for recurrence and improve overall survivorship,” said Vivian N. Liu, a clinical research coordinator at the University of California, San Francisco, who presented the findings.
The patients were interviewed about their diets at about 31.5 months after diagnosis. The study group was broken down into four groups based on how much of their diet consisted of a plant-based diet. Men in the highest quintile group who consumed at least 2.4 servings daily of fruit, 4.2 servings of vegetables, 2.6 servings of dairy, and 1.2 servings of meat (not seafood), had a 52% lower risk of progression (hazard ratio, 0.48; 95% confidence interval, 0.36-0.65; P-trend < 0.001) and a 53% lower risk of recurrence (HR, 0.47; 95% CI, 0.32-0.68; P-trend < 0.001), which was statistically significant. This compares with men in the lowest quintile who consumed 0.8 servings a day of fruit, 2.1 servings of vegetables, 3.1 servings of dairy, and 1.4 servings of meat. The findings were adjusted for total caloric intake, race, and smoking status.
For men over 65 years old, researchers found that a plant-based diet was associated with lower risk of recurrence (HR, 0.41; 95% CI, 0.24-0.7; P-trend = 0.03). And for those who exercised daily – in this case walking at a fast pace more than 3 times a week – a plant-based diet had a 56% (HR, 0.33; 95% CI, 0.26-0.73) lower risk of progression in the highest quintile group and a 59% decrease in recurrence (HR, 0.41; 95% CI, 0.25-0.68).
A new analysis like this, Ms. Liu said, “could guide people to make better, more healthful choices across their whole diet rather than adding or removing select foods.”
The primary endpoint was progression including recurrence, secondary treatment, bone metastases, and death due to prostate cancer, and the secondary endpoint was recurrence (PSA > 0.2ng/mL at 2 consecutive follow-up visits or during secondary treatment). At 7.4 years follow-up, there were 204 cases of progression.
“Fruits and vegetables contain antioxidants and anti-inflammatory components as well as dietary fiber that improve glucose control and reduce inflammation,” Ms. Liu said. In contrast, she said, animal-based foods may increase insulin resistance and insulin levels and boost levels of insulin-like growth factor 1, which is associated with prostate cancer risk. More studies, especially randomized controlled trials, are needed to provide evidence whether healthful plant-based foods and prostate cancer progression are connected.
NYU Langone Health urologist Natasha Gupta, MD, published a systematic review in 2022 on the impact of a plant-based diet on prostate cancer.* The review, which included 5 interventional studies and 11 observational studies, found that consuming a plant-based diet was associated with improvements in general health for men with prostate cancer. The observational studies found either a lower risk of prostate cancer or no significant difference.
“Patients often ask if there is anything that they can do to reduce the risk of recurrence, and it is great to be able to tell patients that a healthy lifestyle including plant-based foods and physical activity is helpful,” Dr. Gupta said.
The review’s coauthor, Stacy Loeb, MD, also of NYU Langone Health, said the new study was “a well-done observational study by experts in nutritional epidemiology from UCSF. It adds to a large body of evidence showing that plant-based diets improve health outcomes.”
“In the short-term, purchasing plant-based protein sources, such as beans and lentils, is less expensive than buying meat. Plant-based diets also reduce the risk of obesity, diabetes, and cardiovascular disease, which are associated with hundreds of thousands of dollars over a lifetime,” she said.
Limitations of the new study included the small number of non-White participants and self-reporting of diet. The study doesn’t examine the cost of various diets or the availability of plant-based foods like fresh produce, which can be limited in some neighborhoods.
Ms. Liu and colleagues plan to conduct a study that examines postdiagnostic plant-based diets in relation to prostate cancer–specific mortality. She and her team will also examine the plant-based dietary indices in relation to prostate cancer–specific quality of life at 2, 5, and 10 years from baseline.
The study authors, Dr. Loeb, and Dr. Gupta report no disclosures.
Correction, 3/17/23: An earlier version of this article misstated the name of NYU Langone Health.
The findings, which were reported at the 2023 ASCO Genitourinary Cancers Symposium in February, are based on a study of 2,038 men (median age, 64 years) with prostate cancer at stage T1, T2, or T3a.
“Consuming a whole foods plant-based diet may be an option to decrease risk for recurrence and improve overall survivorship,” said Vivian N. Liu, a clinical research coordinator at the University of California, San Francisco, who presented the findings.
The patients were interviewed about their diets at about 31.5 months after diagnosis. The study group was broken down into four groups based on how much of their diet consisted of a plant-based diet. Men in the highest quintile group who consumed at least 2.4 servings daily of fruit, 4.2 servings of vegetables, 2.6 servings of dairy, and 1.2 servings of meat (not seafood), had a 52% lower risk of progression (hazard ratio, 0.48; 95% confidence interval, 0.36-0.65; P-trend < 0.001) and a 53% lower risk of recurrence (HR, 0.47; 95% CI, 0.32-0.68; P-trend < 0.001), which was statistically significant. This compares with men in the lowest quintile who consumed 0.8 servings a day of fruit, 2.1 servings of vegetables, 3.1 servings of dairy, and 1.4 servings of meat. The findings were adjusted for total caloric intake, race, and smoking status.
For men over 65 years old, researchers found that a plant-based diet was associated with lower risk of recurrence (HR, 0.41; 95% CI, 0.24-0.7; P-trend = 0.03). And for those who exercised daily – in this case walking at a fast pace more than 3 times a week – a plant-based diet had a 56% (HR, 0.33; 95% CI, 0.26-0.73) lower risk of progression in the highest quintile group and a 59% decrease in recurrence (HR, 0.41; 95% CI, 0.25-0.68).
A new analysis like this, Ms. Liu said, “could guide people to make better, more healthful choices across their whole diet rather than adding or removing select foods.”
The primary endpoint was progression including recurrence, secondary treatment, bone metastases, and death due to prostate cancer, and the secondary endpoint was recurrence (PSA > 0.2ng/mL at 2 consecutive follow-up visits or during secondary treatment). At 7.4 years follow-up, there were 204 cases of progression.
“Fruits and vegetables contain antioxidants and anti-inflammatory components as well as dietary fiber that improve glucose control and reduce inflammation,” Ms. Liu said. In contrast, she said, animal-based foods may increase insulin resistance and insulin levels and boost levels of insulin-like growth factor 1, which is associated with prostate cancer risk. More studies, especially randomized controlled trials, are needed to provide evidence whether healthful plant-based foods and prostate cancer progression are connected.
NYU Langone Health urologist Natasha Gupta, MD, published a systematic review in 2022 on the impact of a plant-based diet on prostate cancer.* The review, which included 5 interventional studies and 11 observational studies, found that consuming a plant-based diet was associated with improvements in general health for men with prostate cancer. The observational studies found either a lower risk of prostate cancer or no significant difference.
“Patients often ask if there is anything that they can do to reduce the risk of recurrence, and it is great to be able to tell patients that a healthy lifestyle including plant-based foods and physical activity is helpful,” Dr. Gupta said.
The review’s coauthor, Stacy Loeb, MD, also of NYU Langone Health, said the new study was “a well-done observational study by experts in nutritional epidemiology from UCSF. It adds to a large body of evidence showing that plant-based diets improve health outcomes.”
“In the short-term, purchasing plant-based protein sources, such as beans and lentils, is less expensive than buying meat. Plant-based diets also reduce the risk of obesity, diabetes, and cardiovascular disease, which are associated with hundreds of thousands of dollars over a lifetime,” she said.
Limitations of the new study included the small number of non-White participants and self-reporting of diet. The study doesn’t examine the cost of various diets or the availability of plant-based foods like fresh produce, which can be limited in some neighborhoods.
Ms. Liu and colleagues plan to conduct a study that examines postdiagnostic plant-based diets in relation to prostate cancer–specific mortality. She and her team will also examine the plant-based dietary indices in relation to prostate cancer–specific quality of life at 2, 5, and 10 years from baseline.
The study authors, Dr. Loeb, and Dr. Gupta report no disclosures.
Correction, 3/17/23: An earlier version of this article misstated the name of NYU Langone Health.
FROM ASCO GU 2023
Prostate cancer subgroup may benefit from intensified therapy
SAN FRANCISCO – For patients with prostate cancer who have unfavorable features and a detectable PSA following a radical prostatectomy, the standard of care is treatment with 6 months of a gonadotropin-releasing hormone (GnRH) agonist with salvage radiation therapy (SRT), as established by the GETUG-AFU 16 trial.
A new trial, dubbed FORMULA-509, explored whether outcomes could be improved by intensifying the drug treatment by adding 6 months of abiraterone acetate plus prednisone as well as apalutamide on top of the GnRH agonist alongside the salvage radiotherapy.
However, the combination did significantly improve PFS and MFS in a subset of men with PSA levels greater than 0.5 ng/mL.
“Although this primary analysis did not meet the prespecified threshold for statistical significance, it does strongly suggest that the addition of abiraterone acetate/prednisone/apalutamide to salvage radiotherapy plus 6 months of ADT [androgen deprivation therapy] may improve progression-free survival and metastasis-free survival,” said lead author Paul L. Nguyen, MD, of the Dana-Farber Cancer Institute in Boston, and professor of radiation oncology at Harvard Medical School.
“This may be particularly evident in the subgroup of patients with PSA greater that 0.5 ng/mL where a preplanned subgroup analysis by stratification factors observed a statistically significant benefit for both progression-free survival and metastasis-free survival,” he said. “Six months of intensified ADT with next generation anti-androgens may provide an attractive alternative to lengthening ADT for patients with rising PSA and unfavorable features after radical prostatectomy.”
The study results were presented at the ASCO Genitourinary Cancers Symposium.
Benefit in subset
The FORMULA-509 trial included 305 patients with PSA ≥ 0.1 ng/mL who had undergone a radical prostatectomy, and who had one or more unfavorable risk features (Gleason 8-10 disease, PSA > 0.5 ng/mL, pT3/T4, pN1 or radiographic N1, PSA doubling time < 10 months, negative margins, persistent PSA, gross local/regional disease).
“This was a pretty high-risk population,” Dr. Nguyen emphasized, as 35% had Gleason score of 9, about a third (31%) a PSA >0.5, and 29% were pathologic node positive.
All patients received salvage radiotherapy plus 6 months of GnRH agonist (bicalutamide 50 mg), and half were randomly assigned to also receive abiraterone acetate/prednisone 1,000 mg/5 mg + apalutamide 240 mg daily.
At a median follow-up of 34 months, the 3-year PFS rate was 74.9% in the AAP-apalutamide arm vs. 68.5% for the control group (hazard ratio [HR], 0.71; P = .06), and the 3-year MFS rate was 90.6% vs. 87.2%, respectively (HR, 0.57; P = .05).
In the subset of patients with a PSA greater than 0.5 ng/mL, the 3-year PFS and MFS rates were significantly higher with in the AAP-apalutamide group: the 3-year PFS rate was 67.2% vs. 46.8% (HR, 0.50; P = .03), and the 3-year MFS rate was 84.3% vs. 66.1% (HR, 0.32; P = .02).
Adverse events were consistent with the known safety profiles of the agents being studied, Dr. Nguyen noted. The most common toxicities for AAP-apalutamide vs. controls were hypertension (21.8% vs. 13.3%), maculopapular rash (11.5% vs. 0.6%), diarrhea (8.5% vs. 4.8%), and fatigue (7.9% vs. 6.1%).
Dr. Nguyen noted that even though “we’re not supposed to compare clinical trials,” the results of this study appeared to compare favorably with those of another trial, RADICALS-HD, which was presented at the 2022 European Society of Medical Oncology Congress. That study showed that in patients undergoing postoperative radiation therapy, 24 months of ADT was superior to 6 months of ADT in improving both time to salvage ADT and MFS.
However, Dr. Nguyen emphasized that it would have to be formally tested, to see if “FORMULA-509 is performing in the ballpark of what 24 months of ADT would do.
“And I think that compared to 6 months of ADT, we can say it is certainly performing in the ballpark,” he said. “So, for patients with higher risk features, intensifying 6 months of ADT, I think, may be an appealing alternative to lengthening the ADT duration to 24 months.”
He added that this concept would be formally tested in the upcoming PROSTATE IQ study.
Strong evidence, standardization needed
In a discussion of the paper, Tyler Seibert, MD, PhD, of the University of California San Diego, said that “escalation by 24 months has the strongest evidence today, specifically from the RADICALS-HD trial, with more than 1,500 men with 10 years of follow-up and a clear statistically significant result.
“Intensification for 6 months is a very compelling concept, as most patients are not getting 2 years of androgen deprivation therapy at this point post prostatectomy,” he continued. “While we await the long term follow-up of this study and the pending PROSTATE IQ trial, and if only 6 months of therapy is acceptable or feasible, the FORMULA-509 [trial] provides convincing evidence that select patients would benefit from intensification with AAP and apalutamide.”
Another expert weighed in on the data. Approached by this news organization for an independent comment, Jeff M. Michalski, MD, MBA, professor of radiation oncology at Washington University, St Louis, and president of the American Society of Radiation Oncology, noted a few issues in the study.
He said that standards had changed since this study was first approved and had begun accrual several years ago. “In context of today’s era, the current standard is to do a PET scan if patients have a chemical failure after surgery,” he said. “The PSA levels of patients who were treated [in this trial] were very high, and many patients do not want to wait until they reach that level.”
Dr. Michalski also pointed out the number of patients getting radiation was less than the number who had node-positive disease. “This shows that patients had received suboptimal therapy late in the disease,” he said.
Overall, most patients in the study did not receive lymph node radiation, even though they had high-risk features. “A recent study of almost 1,800 patients that was published in The Lancet found that there is a benefit to pelvic lymph node radiation,” he said. “Because it wasn’t mandated, most of the patients did not receive pelvic lymph node radiation, which we now understand offers some benefit.”
The reasons for not giving pelvic radiation to these men is unclear. “Treatment was left at the discretion of the physician and this could create bias,” Dr. Michalski said. “It could drive one arm more than another.”
The study also wasn’t controlled for pelvic radiation. “Most of the nodal positive patients received it, but the other patients were undertreated,” he noted.
Dr. Michalski added that he hopes that in the forthcoming PROSTATE IQ study, lymph node radiation and imaging are standardized.
The trial was supported by Janssen Oncology. Dr. Nguyen disclosed relationships with, and/or support from, Volatilyx, Bayer, Blue Earth Diagnostics, Boston Scientific, Janssen Oncology, Myovant Sciences, Astellas Pharma, and Janssen. Dr. Seibert disclosed relationships with, and/or support from, CorTechs Labs, Varian Medical Systems, and GE Healthcare.
A version of this article first appeared on Medscape.com.
SAN FRANCISCO – For patients with prostate cancer who have unfavorable features and a detectable PSA following a radical prostatectomy, the standard of care is treatment with 6 months of a gonadotropin-releasing hormone (GnRH) agonist with salvage radiation therapy (SRT), as established by the GETUG-AFU 16 trial.
A new trial, dubbed FORMULA-509, explored whether outcomes could be improved by intensifying the drug treatment by adding 6 months of abiraterone acetate plus prednisone as well as apalutamide on top of the GnRH agonist alongside the salvage radiotherapy.
However, the combination did significantly improve PFS and MFS in a subset of men with PSA levels greater than 0.5 ng/mL.
“Although this primary analysis did not meet the prespecified threshold for statistical significance, it does strongly suggest that the addition of abiraterone acetate/prednisone/apalutamide to salvage radiotherapy plus 6 months of ADT [androgen deprivation therapy] may improve progression-free survival and metastasis-free survival,” said lead author Paul L. Nguyen, MD, of the Dana-Farber Cancer Institute in Boston, and professor of radiation oncology at Harvard Medical School.
“This may be particularly evident in the subgroup of patients with PSA greater that 0.5 ng/mL where a preplanned subgroup analysis by stratification factors observed a statistically significant benefit for both progression-free survival and metastasis-free survival,” he said. “Six months of intensified ADT with next generation anti-androgens may provide an attractive alternative to lengthening ADT for patients with rising PSA and unfavorable features after radical prostatectomy.”
The study results were presented at the ASCO Genitourinary Cancers Symposium.
Benefit in subset
The FORMULA-509 trial included 305 patients with PSA ≥ 0.1 ng/mL who had undergone a radical prostatectomy, and who had one or more unfavorable risk features (Gleason 8-10 disease, PSA > 0.5 ng/mL, pT3/T4, pN1 or radiographic N1, PSA doubling time < 10 months, negative margins, persistent PSA, gross local/regional disease).
“This was a pretty high-risk population,” Dr. Nguyen emphasized, as 35% had Gleason score of 9, about a third (31%) a PSA >0.5, and 29% were pathologic node positive.
All patients received salvage radiotherapy plus 6 months of GnRH agonist (bicalutamide 50 mg), and half were randomly assigned to also receive abiraterone acetate/prednisone 1,000 mg/5 mg + apalutamide 240 mg daily.
At a median follow-up of 34 months, the 3-year PFS rate was 74.9% in the AAP-apalutamide arm vs. 68.5% for the control group (hazard ratio [HR], 0.71; P = .06), and the 3-year MFS rate was 90.6% vs. 87.2%, respectively (HR, 0.57; P = .05).
In the subset of patients with a PSA greater than 0.5 ng/mL, the 3-year PFS and MFS rates were significantly higher with in the AAP-apalutamide group: the 3-year PFS rate was 67.2% vs. 46.8% (HR, 0.50; P = .03), and the 3-year MFS rate was 84.3% vs. 66.1% (HR, 0.32; P = .02).
Adverse events were consistent with the known safety profiles of the agents being studied, Dr. Nguyen noted. The most common toxicities for AAP-apalutamide vs. controls were hypertension (21.8% vs. 13.3%), maculopapular rash (11.5% vs. 0.6%), diarrhea (8.5% vs. 4.8%), and fatigue (7.9% vs. 6.1%).
Dr. Nguyen noted that even though “we’re not supposed to compare clinical trials,” the results of this study appeared to compare favorably with those of another trial, RADICALS-HD, which was presented at the 2022 European Society of Medical Oncology Congress. That study showed that in patients undergoing postoperative radiation therapy, 24 months of ADT was superior to 6 months of ADT in improving both time to salvage ADT and MFS.
However, Dr. Nguyen emphasized that it would have to be formally tested, to see if “FORMULA-509 is performing in the ballpark of what 24 months of ADT would do.
“And I think that compared to 6 months of ADT, we can say it is certainly performing in the ballpark,” he said. “So, for patients with higher risk features, intensifying 6 months of ADT, I think, may be an appealing alternative to lengthening the ADT duration to 24 months.”
He added that this concept would be formally tested in the upcoming PROSTATE IQ study.
Strong evidence, standardization needed
In a discussion of the paper, Tyler Seibert, MD, PhD, of the University of California San Diego, said that “escalation by 24 months has the strongest evidence today, specifically from the RADICALS-HD trial, with more than 1,500 men with 10 years of follow-up and a clear statistically significant result.
“Intensification for 6 months is a very compelling concept, as most patients are not getting 2 years of androgen deprivation therapy at this point post prostatectomy,” he continued. “While we await the long term follow-up of this study and the pending PROSTATE IQ trial, and if only 6 months of therapy is acceptable or feasible, the FORMULA-509 [trial] provides convincing evidence that select patients would benefit from intensification with AAP and apalutamide.”
Another expert weighed in on the data. Approached by this news organization for an independent comment, Jeff M. Michalski, MD, MBA, professor of radiation oncology at Washington University, St Louis, and president of the American Society of Radiation Oncology, noted a few issues in the study.
He said that standards had changed since this study was first approved and had begun accrual several years ago. “In context of today’s era, the current standard is to do a PET scan if patients have a chemical failure after surgery,” he said. “The PSA levels of patients who were treated [in this trial] were very high, and many patients do not want to wait until they reach that level.”
Dr. Michalski also pointed out the number of patients getting radiation was less than the number who had node-positive disease. “This shows that patients had received suboptimal therapy late in the disease,” he said.
Overall, most patients in the study did not receive lymph node radiation, even though they had high-risk features. “A recent study of almost 1,800 patients that was published in The Lancet found that there is a benefit to pelvic lymph node radiation,” he said. “Because it wasn’t mandated, most of the patients did not receive pelvic lymph node radiation, which we now understand offers some benefit.”
The reasons for not giving pelvic radiation to these men is unclear. “Treatment was left at the discretion of the physician and this could create bias,” Dr. Michalski said. “It could drive one arm more than another.”
The study also wasn’t controlled for pelvic radiation. “Most of the nodal positive patients received it, but the other patients were undertreated,” he noted.
Dr. Michalski added that he hopes that in the forthcoming PROSTATE IQ study, lymph node radiation and imaging are standardized.
The trial was supported by Janssen Oncology. Dr. Nguyen disclosed relationships with, and/or support from, Volatilyx, Bayer, Blue Earth Diagnostics, Boston Scientific, Janssen Oncology, Myovant Sciences, Astellas Pharma, and Janssen. Dr. Seibert disclosed relationships with, and/or support from, CorTechs Labs, Varian Medical Systems, and GE Healthcare.
A version of this article first appeared on Medscape.com.
SAN FRANCISCO – For patients with prostate cancer who have unfavorable features and a detectable PSA following a radical prostatectomy, the standard of care is treatment with 6 months of a gonadotropin-releasing hormone (GnRH) agonist with salvage radiation therapy (SRT), as established by the GETUG-AFU 16 trial.
A new trial, dubbed FORMULA-509, explored whether outcomes could be improved by intensifying the drug treatment by adding 6 months of abiraterone acetate plus prednisone as well as apalutamide on top of the GnRH agonist alongside the salvage radiotherapy.
However, the combination did significantly improve PFS and MFS in a subset of men with PSA levels greater than 0.5 ng/mL.
“Although this primary analysis did not meet the prespecified threshold for statistical significance, it does strongly suggest that the addition of abiraterone acetate/prednisone/apalutamide to salvage radiotherapy plus 6 months of ADT [androgen deprivation therapy] may improve progression-free survival and metastasis-free survival,” said lead author Paul L. Nguyen, MD, of the Dana-Farber Cancer Institute in Boston, and professor of radiation oncology at Harvard Medical School.
“This may be particularly evident in the subgroup of patients with PSA greater that 0.5 ng/mL where a preplanned subgroup analysis by stratification factors observed a statistically significant benefit for both progression-free survival and metastasis-free survival,” he said. “Six months of intensified ADT with next generation anti-androgens may provide an attractive alternative to lengthening ADT for patients with rising PSA and unfavorable features after radical prostatectomy.”
The study results were presented at the ASCO Genitourinary Cancers Symposium.
Benefit in subset
The FORMULA-509 trial included 305 patients with PSA ≥ 0.1 ng/mL who had undergone a radical prostatectomy, and who had one or more unfavorable risk features (Gleason 8-10 disease, PSA > 0.5 ng/mL, pT3/T4, pN1 or radiographic N1, PSA doubling time < 10 months, negative margins, persistent PSA, gross local/regional disease).
“This was a pretty high-risk population,” Dr. Nguyen emphasized, as 35% had Gleason score of 9, about a third (31%) a PSA >0.5, and 29% were pathologic node positive.
All patients received salvage radiotherapy plus 6 months of GnRH agonist (bicalutamide 50 mg), and half were randomly assigned to also receive abiraterone acetate/prednisone 1,000 mg/5 mg + apalutamide 240 mg daily.
At a median follow-up of 34 months, the 3-year PFS rate was 74.9% in the AAP-apalutamide arm vs. 68.5% for the control group (hazard ratio [HR], 0.71; P = .06), and the 3-year MFS rate was 90.6% vs. 87.2%, respectively (HR, 0.57; P = .05).
In the subset of patients with a PSA greater than 0.5 ng/mL, the 3-year PFS and MFS rates were significantly higher with in the AAP-apalutamide group: the 3-year PFS rate was 67.2% vs. 46.8% (HR, 0.50; P = .03), and the 3-year MFS rate was 84.3% vs. 66.1% (HR, 0.32; P = .02).
Adverse events were consistent with the known safety profiles of the agents being studied, Dr. Nguyen noted. The most common toxicities for AAP-apalutamide vs. controls were hypertension (21.8% vs. 13.3%), maculopapular rash (11.5% vs. 0.6%), diarrhea (8.5% vs. 4.8%), and fatigue (7.9% vs. 6.1%).
Dr. Nguyen noted that even though “we’re not supposed to compare clinical trials,” the results of this study appeared to compare favorably with those of another trial, RADICALS-HD, which was presented at the 2022 European Society of Medical Oncology Congress. That study showed that in patients undergoing postoperative radiation therapy, 24 months of ADT was superior to 6 months of ADT in improving both time to salvage ADT and MFS.
However, Dr. Nguyen emphasized that it would have to be formally tested, to see if “FORMULA-509 is performing in the ballpark of what 24 months of ADT would do.
“And I think that compared to 6 months of ADT, we can say it is certainly performing in the ballpark,” he said. “So, for patients with higher risk features, intensifying 6 months of ADT, I think, may be an appealing alternative to lengthening the ADT duration to 24 months.”
He added that this concept would be formally tested in the upcoming PROSTATE IQ study.
Strong evidence, standardization needed
In a discussion of the paper, Tyler Seibert, MD, PhD, of the University of California San Diego, said that “escalation by 24 months has the strongest evidence today, specifically from the RADICALS-HD trial, with more than 1,500 men with 10 years of follow-up and a clear statistically significant result.
“Intensification for 6 months is a very compelling concept, as most patients are not getting 2 years of androgen deprivation therapy at this point post prostatectomy,” he continued. “While we await the long term follow-up of this study and the pending PROSTATE IQ trial, and if only 6 months of therapy is acceptable or feasible, the FORMULA-509 [trial] provides convincing evidence that select patients would benefit from intensification with AAP and apalutamide.”
Another expert weighed in on the data. Approached by this news organization for an independent comment, Jeff M. Michalski, MD, MBA, professor of radiation oncology at Washington University, St Louis, and president of the American Society of Radiation Oncology, noted a few issues in the study.
He said that standards had changed since this study was first approved and had begun accrual several years ago. “In context of today’s era, the current standard is to do a PET scan if patients have a chemical failure after surgery,” he said. “The PSA levels of patients who were treated [in this trial] were very high, and many patients do not want to wait until they reach that level.”
Dr. Michalski also pointed out the number of patients getting radiation was less than the number who had node-positive disease. “This shows that patients had received suboptimal therapy late in the disease,” he said.
Overall, most patients in the study did not receive lymph node radiation, even though they had high-risk features. “A recent study of almost 1,800 patients that was published in The Lancet found that there is a benefit to pelvic lymph node radiation,” he said. “Because it wasn’t mandated, most of the patients did not receive pelvic lymph node radiation, which we now understand offers some benefit.”
The reasons for not giving pelvic radiation to these men is unclear. “Treatment was left at the discretion of the physician and this could create bias,” Dr. Michalski said. “It could drive one arm more than another.”
The study also wasn’t controlled for pelvic radiation. “Most of the nodal positive patients received it, but the other patients were undertreated,” he noted.
Dr. Michalski added that he hopes that in the forthcoming PROSTATE IQ study, lymph node radiation and imaging are standardized.
The trial was supported by Janssen Oncology. Dr. Nguyen disclosed relationships with, and/or support from, Volatilyx, Bayer, Blue Earth Diagnostics, Boston Scientific, Janssen Oncology, Myovant Sciences, Astellas Pharma, and Janssen. Dr. Seibert disclosed relationships with, and/or support from, CorTechs Labs, Varian Medical Systems, and GE Healthcare.
A version of this article first appeared on Medscape.com.
AT ASCO GU 2023
Talazoparib add-on improves outcomes in metastatic prostate cancer
in the TALAPRO-2 trial.
As determined on the basis of imaging, PFS was 37% better for talazoparib plus enzalutamide than for enzalutamide monotherapy. Combination therapy proved superior regardless of homologous recombination repair (HRR) pathway status, noted the authors.
“Not only did the combination therapy delay disease progression, it also significantly delayed progression of PSA [prostate-specific antigen] readings and the time until chemotherapy was needed compared to the control group,” said lead study author Neeraj Agarwal, MD, professor of medicine and director of the genitourinary oncology program at the Huntsman Cancer Institute, University of Utah, Salt Lake City.
“This is important because advanced prostate cancer can be associated with pain, fractures, suffering, and death. The current standard of care treatments were approved almost a decade ago, leaving a huge, unmet need for novel drugs in this setting,” he said.
The new results could pave the way for a prostate cancer indication for talazoparib; the company has said that it will submit these data to regulatory authorities. At present, the drug is approved only for use in BRCA+ breast cancer, an indication that was approved in 2018.
The findings were presented at the 2023 ASCO Genitourinary Cancers Symposium.
Overall, talazoparib plus enzalutamide resulted in a statistically significant and clinically meaningful improvement in PFS over placebo plus enzalutamide. “Results from the primary analysis of the TALAPRO-2 trial support the use of talazoparib plus enzalutamide as a first-line treatment in patients with mCRPC regardless of HRR gene alteration status,” Dr. Agarwal and colleagues concluded.
However, one expert disagreed with the authors’ conclusion regarding HHR pathway status. On the basis of imaging, PFS was 54% better in HHR-deficient patients in the combination therapy group. It was 30% better for patients with HHR-nondeficient tumors or tumors without known HHR status based on imaging and 34% better based on tumor tissue testing.
“There was a huge magnitude in benefit based on HHR, and I think HRR status matters,” commented Elena Castro, MD, PhD, Instituto de Investigación Biomédica de Málaga (Spain), who served as the invited discussant.
“We need to understand the benefit of ARPi [androgen receptor pathway inhibition] and PARP inhibitors better,” she said. “The balance between side effects and benefit depends on HRR status.”
Dr. Castro also noted that the treatment landscape has changed. ARPi is now a standard of care for metastatic prostate cancer, both for hormone-sensitive and castration-resistant disease. “So the question is, does the addition of a PARP inhibitor induce responses after progression to an ARPi in HHR-nondeficient tumors?”
Study details
In the TALAPRO-2 trial, Dr. Agarwal and colleagues randomly assigned 805 patients to receive either talazoparib 0.5 mg or placebo. All patients in the cohort received enzalutamide 160 mg daily.
Participants had mCRPC and were unselected for genetic alterations in DNA damage repair pathways directly or indirectly involved with HRR. They were aged 36-91 years (median age, 71). The cohort was enrolled from 25 countries, including the United States, Canada, Europe, South America, and countries in the Asia-Pacific region.
The men were stratified on the basis of prior use of abiraterone or docetaxel for castration-sensitive prostate cancer and HRR gene alteration status. The study’s primary endpoint was imaging-based PFS (ibPFS) by blinded independent central review (BICR).
Overall, median ibPFS by BICR was significantly improved in the combination group in comparison with the patients who received placebo; it was not reached versus 21.9 months (hazard ratio, 0.63; P < .001). It was also significantly improved among the HRR-deficient subgroup (HR, 0.46; P < .001) as well as in the HRR-nondeficient or unknown (HR, 0.70; P = .004) and HRR-nondeficient patients by tumor tissue testing (HR, 0.66; P = .009).
Talazoparib plus enzalutamide was also favored with regard to other endpoints. Dr. Agarwal noted that, while overall survival data are as yet immature, objective response rates, PSA response of at least 50%, and time to PSA progression and use of subsequent cytotoxic chemotherapy and antineoplastic therapy significantly favored the talazoparib group.
The objective response rate was 61.7% versus 43.9% (P = .005), with 37.5% versus 18.2% complete responses.
“The higher rates of complete response suggest a cooperative effect of talazoparib plus enzalutamide treatment,” he explained.
High rate of adverse events
The rate of treatment-emergent adverse events was higher among patients who received talazoparib plus enzalutamide; 71.9% of the patients who received talazoparib plus enzalutamide experienced grade 3-4 TEAEs versus 40.6%. The most common grade 3 or greater TEAEs in the talazoparib group were anemia, low neutrophil counts, and low platelet counts. Hypertension, anemia, and fatigue were the most common in the placebo group. Talazoparib was discontinued in 19.1% of patients because of TEAEs. Enzalutamide was discontinued in 10.8% of patients in the combination group versus 11.0% in the placebo group.
Dr. Agarwal pointed out that there were TEAEs of special interest for talazoparib. “Myelodysplastic syndrome was reported in one patient during the safety reporting period, and acute myeloid leukemia was reported in one patient during the follow-up period,” he said.
Additionally, pulmonary embolism was reported in 10 (2.5%) patients (grade 3 in 9 patients) in the talazoparib arm and in 3 (0.7%) patients (all grade 3) in the placebo arm.
Results less relevant
Commenting on the study, Matthew Zibelman, MD, associate professor, department of hematology/oncology, Fox Chase Cancer Center, Philadelphia, noted that these results represent an “intriguing finding for men with mCRPC, particularly in conjunction with the previously reported PROPEL study results.
“However, given that many patients receive an androgen receptor inhibitor now for metastatic castration-sensitive prostate cancer, these results are less relevant to current practice,” Dr. Zibelman said.
“Demonstration of an overall survival benefit of the combination would be optimal to change standard of care vs potential sequential therapy.”
The study was sponsored by Pfizer, manufacturer of enzalutamide and talazoparib. Dr. Agarwal has relationships with numerous pharmaceutical companies. Dr. Castro has relationships with Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Janssen-Cilag, Merck, MSD Oncology, Novartis and Pfizer, and Roche. Dr. Zibelman has relationships with Bristol-Myers Squibb, Exelixis, Pfizer, Jannsen, EMD Serono, and Blue Earth.
A version of this article first appeared on Medscape.com.
in the TALAPRO-2 trial.
As determined on the basis of imaging, PFS was 37% better for talazoparib plus enzalutamide than for enzalutamide monotherapy. Combination therapy proved superior regardless of homologous recombination repair (HRR) pathway status, noted the authors.
“Not only did the combination therapy delay disease progression, it also significantly delayed progression of PSA [prostate-specific antigen] readings and the time until chemotherapy was needed compared to the control group,” said lead study author Neeraj Agarwal, MD, professor of medicine and director of the genitourinary oncology program at the Huntsman Cancer Institute, University of Utah, Salt Lake City.
“This is important because advanced prostate cancer can be associated with pain, fractures, suffering, and death. The current standard of care treatments were approved almost a decade ago, leaving a huge, unmet need for novel drugs in this setting,” he said.
The new results could pave the way for a prostate cancer indication for talazoparib; the company has said that it will submit these data to regulatory authorities. At present, the drug is approved only for use in BRCA+ breast cancer, an indication that was approved in 2018.
The findings were presented at the 2023 ASCO Genitourinary Cancers Symposium.
Overall, talazoparib plus enzalutamide resulted in a statistically significant and clinically meaningful improvement in PFS over placebo plus enzalutamide. “Results from the primary analysis of the TALAPRO-2 trial support the use of talazoparib plus enzalutamide as a first-line treatment in patients with mCRPC regardless of HRR gene alteration status,” Dr. Agarwal and colleagues concluded.
However, one expert disagreed with the authors’ conclusion regarding HHR pathway status. On the basis of imaging, PFS was 54% better in HHR-deficient patients in the combination therapy group. It was 30% better for patients with HHR-nondeficient tumors or tumors without known HHR status based on imaging and 34% better based on tumor tissue testing.
“There was a huge magnitude in benefit based on HHR, and I think HRR status matters,” commented Elena Castro, MD, PhD, Instituto de Investigación Biomédica de Málaga (Spain), who served as the invited discussant.
“We need to understand the benefit of ARPi [androgen receptor pathway inhibition] and PARP inhibitors better,” she said. “The balance between side effects and benefit depends on HRR status.”
Dr. Castro also noted that the treatment landscape has changed. ARPi is now a standard of care for metastatic prostate cancer, both for hormone-sensitive and castration-resistant disease. “So the question is, does the addition of a PARP inhibitor induce responses after progression to an ARPi in HHR-nondeficient tumors?”
Study details
In the TALAPRO-2 trial, Dr. Agarwal and colleagues randomly assigned 805 patients to receive either talazoparib 0.5 mg or placebo. All patients in the cohort received enzalutamide 160 mg daily.
Participants had mCRPC and were unselected for genetic alterations in DNA damage repair pathways directly or indirectly involved with HRR. They were aged 36-91 years (median age, 71). The cohort was enrolled from 25 countries, including the United States, Canada, Europe, South America, and countries in the Asia-Pacific region.
The men were stratified on the basis of prior use of abiraterone or docetaxel for castration-sensitive prostate cancer and HRR gene alteration status. The study’s primary endpoint was imaging-based PFS (ibPFS) by blinded independent central review (BICR).
Overall, median ibPFS by BICR was significantly improved in the combination group in comparison with the patients who received placebo; it was not reached versus 21.9 months (hazard ratio, 0.63; P < .001). It was also significantly improved among the HRR-deficient subgroup (HR, 0.46; P < .001) as well as in the HRR-nondeficient or unknown (HR, 0.70; P = .004) and HRR-nondeficient patients by tumor tissue testing (HR, 0.66; P = .009).
Talazoparib plus enzalutamide was also favored with regard to other endpoints. Dr. Agarwal noted that, while overall survival data are as yet immature, objective response rates, PSA response of at least 50%, and time to PSA progression and use of subsequent cytotoxic chemotherapy and antineoplastic therapy significantly favored the talazoparib group.
The objective response rate was 61.7% versus 43.9% (P = .005), with 37.5% versus 18.2% complete responses.
“The higher rates of complete response suggest a cooperative effect of talazoparib plus enzalutamide treatment,” he explained.
High rate of adverse events
The rate of treatment-emergent adverse events was higher among patients who received talazoparib plus enzalutamide; 71.9% of the patients who received talazoparib plus enzalutamide experienced grade 3-4 TEAEs versus 40.6%. The most common grade 3 or greater TEAEs in the talazoparib group were anemia, low neutrophil counts, and low platelet counts. Hypertension, anemia, and fatigue were the most common in the placebo group. Talazoparib was discontinued in 19.1% of patients because of TEAEs. Enzalutamide was discontinued in 10.8% of patients in the combination group versus 11.0% in the placebo group.
Dr. Agarwal pointed out that there were TEAEs of special interest for talazoparib. “Myelodysplastic syndrome was reported in one patient during the safety reporting period, and acute myeloid leukemia was reported in one patient during the follow-up period,” he said.
Additionally, pulmonary embolism was reported in 10 (2.5%) patients (grade 3 in 9 patients) in the talazoparib arm and in 3 (0.7%) patients (all grade 3) in the placebo arm.
Results less relevant
Commenting on the study, Matthew Zibelman, MD, associate professor, department of hematology/oncology, Fox Chase Cancer Center, Philadelphia, noted that these results represent an “intriguing finding for men with mCRPC, particularly in conjunction with the previously reported PROPEL study results.
“However, given that many patients receive an androgen receptor inhibitor now for metastatic castration-sensitive prostate cancer, these results are less relevant to current practice,” Dr. Zibelman said.
“Demonstration of an overall survival benefit of the combination would be optimal to change standard of care vs potential sequential therapy.”
The study was sponsored by Pfizer, manufacturer of enzalutamide and talazoparib. Dr. Agarwal has relationships with numerous pharmaceutical companies. Dr. Castro has relationships with Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Janssen-Cilag, Merck, MSD Oncology, Novartis and Pfizer, and Roche. Dr. Zibelman has relationships with Bristol-Myers Squibb, Exelixis, Pfizer, Jannsen, EMD Serono, and Blue Earth.
A version of this article first appeared on Medscape.com.
in the TALAPRO-2 trial.
As determined on the basis of imaging, PFS was 37% better for talazoparib plus enzalutamide than for enzalutamide monotherapy. Combination therapy proved superior regardless of homologous recombination repair (HRR) pathway status, noted the authors.
“Not only did the combination therapy delay disease progression, it also significantly delayed progression of PSA [prostate-specific antigen] readings and the time until chemotherapy was needed compared to the control group,” said lead study author Neeraj Agarwal, MD, professor of medicine and director of the genitourinary oncology program at the Huntsman Cancer Institute, University of Utah, Salt Lake City.
“This is important because advanced prostate cancer can be associated with pain, fractures, suffering, and death. The current standard of care treatments were approved almost a decade ago, leaving a huge, unmet need for novel drugs in this setting,” he said.
The new results could pave the way for a prostate cancer indication for talazoparib; the company has said that it will submit these data to regulatory authorities. At present, the drug is approved only for use in BRCA+ breast cancer, an indication that was approved in 2018.
The findings were presented at the 2023 ASCO Genitourinary Cancers Symposium.
Overall, talazoparib plus enzalutamide resulted in a statistically significant and clinically meaningful improvement in PFS over placebo plus enzalutamide. “Results from the primary analysis of the TALAPRO-2 trial support the use of talazoparib plus enzalutamide as a first-line treatment in patients with mCRPC regardless of HRR gene alteration status,” Dr. Agarwal and colleagues concluded.
However, one expert disagreed with the authors’ conclusion regarding HHR pathway status. On the basis of imaging, PFS was 54% better in HHR-deficient patients in the combination therapy group. It was 30% better for patients with HHR-nondeficient tumors or tumors without known HHR status based on imaging and 34% better based on tumor tissue testing.
“There was a huge magnitude in benefit based on HHR, and I think HRR status matters,” commented Elena Castro, MD, PhD, Instituto de Investigación Biomédica de Málaga (Spain), who served as the invited discussant.
“We need to understand the benefit of ARPi [androgen receptor pathway inhibition] and PARP inhibitors better,” she said. “The balance between side effects and benefit depends on HRR status.”
Dr. Castro also noted that the treatment landscape has changed. ARPi is now a standard of care for metastatic prostate cancer, both for hormone-sensitive and castration-resistant disease. “So the question is, does the addition of a PARP inhibitor induce responses after progression to an ARPi in HHR-nondeficient tumors?”
Study details
In the TALAPRO-2 trial, Dr. Agarwal and colleagues randomly assigned 805 patients to receive either talazoparib 0.5 mg or placebo. All patients in the cohort received enzalutamide 160 mg daily.
Participants had mCRPC and were unselected for genetic alterations in DNA damage repair pathways directly or indirectly involved with HRR. They were aged 36-91 years (median age, 71). The cohort was enrolled from 25 countries, including the United States, Canada, Europe, South America, and countries in the Asia-Pacific region.
The men were stratified on the basis of prior use of abiraterone or docetaxel for castration-sensitive prostate cancer and HRR gene alteration status. The study’s primary endpoint was imaging-based PFS (ibPFS) by blinded independent central review (BICR).
Overall, median ibPFS by BICR was significantly improved in the combination group in comparison with the patients who received placebo; it was not reached versus 21.9 months (hazard ratio, 0.63; P < .001). It was also significantly improved among the HRR-deficient subgroup (HR, 0.46; P < .001) as well as in the HRR-nondeficient or unknown (HR, 0.70; P = .004) and HRR-nondeficient patients by tumor tissue testing (HR, 0.66; P = .009).
Talazoparib plus enzalutamide was also favored with regard to other endpoints. Dr. Agarwal noted that, while overall survival data are as yet immature, objective response rates, PSA response of at least 50%, and time to PSA progression and use of subsequent cytotoxic chemotherapy and antineoplastic therapy significantly favored the talazoparib group.
The objective response rate was 61.7% versus 43.9% (P = .005), with 37.5% versus 18.2% complete responses.
“The higher rates of complete response suggest a cooperative effect of talazoparib plus enzalutamide treatment,” he explained.
High rate of adverse events
The rate of treatment-emergent adverse events was higher among patients who received talazoparib plus enzalutamide; 71.9% of the patients who received talazoparib plus enzalutamide experienced grade 3-4 TEAEs versus 40.6%. The most common grade 3 or greater TEAEs in the talazoparib group were anemia, low neutrophil counts, and low platelet counts. Hypertension, anemia, and fatigue were the most common in the placebo group. Talazoparib was discontinued in 19.1% of patients because of TEAEs. Enzalutamide was discontinued in 10.8% of patients in the combination group versus 11.0% in the placebo group.
Dr. Agarwal pointed out that there were TEAEs of special interest for talazoparib. “Myelodysplastic syndrome was reported in one patient during the safety reporting period, and acute myeloid leukemia was reported in one patient during the follow-up period,” he said.
Additionally, pulmonary embolism was reported in 10 (2.5%) patients (grade 3 in 9 patients) in the talazoparib arm and in 3 (0.7%) patients (all grade 3) in the placebo arm.
Results less relevant
Commenting on the study, Matthew Zibelman, MD, associate professor, department of hematology/oncology, Fox Chase Cancer Center, Philadelphia, noted that these results represent an “intriguing finding for men with mCRPC, particularly in conjunction with the previously reported PROPEL study results.
“However, given that many patients receive an androgen receptor inhibitor now for metastatic castration-sensitive prostate cancer, these results are less relevant to current practice,” Dr. Zibelman said.
“Demonstration of an overall survival benefit of the combination would be optimal to change standard of care vs potential sequential therapy.”
The study was sponsored by Pfizer, manufacturer of enzalutamide and talazoparib. Dr. Agarwal has relationships with numerous pharmaceutical companies. Dr. Castro has relationships with Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Janssen-Cilag, Merck, MSD Oncology, Novartis and Pfizer, and Roche. Dr. Zibelman has relationships with Bristol-Myers Squibb, Exelixis, Pfizer, Jannsen, EMD Serono, and Blue Earth.
A version of this article first appeared on Medscape.com.
AT ASCO GU 2023
Adjuvant nivolumab as standard of care in resected bladder cancer
Extended follow-up data from the phase 3 CheckMate 274 trial continue to show that, compared with placebo, nivolumab improves disease-free survival, nonurothelial tract recurrence-free survival (NUTRFS), and distant metastasis-free survival (DMFS) in patients with high-risk, muscle-invasive urothelial cancer after undergoing radical surgery.
The benefit was observed in both in the intent-to-treat population (ITT) and in the subset of patients with programmed death–ligand 1 (PD-L1) expression of at least 1%.
“In the ITT population, median disease-free survival with nivolumab was doubled compared to placebo,” said lead author Matthew Galsky, MD, director of genitourinary medical oncology and codirector of the Center of Excellence for Bladder Cancer at Tisch Cancer Institute, New York. “For the patients with high PD-L1 expression, the median disease-free survival with nivolumab reached 52.6 months, more than six times that of the placebo arm.
“These results further support adjuvant nivolumab as a standard of care in high-risk muscle-invasive urothelial cancer after resection,” he concluded.
Dr. Galsky presented the findings at the 2023 ASCO Genitourinary Cancers Symposium.
Practice changing
The earlier results of this study have already led to an approval from the Food and Drug Administration. In August 2021, nivolumab became the first adjuvant immunotherapy for use in patients with urothelial carcinoma at high risk for recurrence after radical resection
“This is a practice-changing study,” said Scot Niglio, MD, medical oncologist, New York University Perlmutter Cancer Center, who was approached for an independent comment.
“For decades, there were limited to zero treatment options in the postsurgical setting for urothelial cancer patients with a high recurrence risk,” he said.
The standard of care for muscle-invasive urothelial carcinoma is surgery, which may include neoadjuvant cisplatin-based chemotherapy, but most patients will experience disease recurrence, he explained.
“When urothelial cancer recurs outside the urinary tract, the prognosis quickly changes from curable to incurable,” he said, “making this area of research paramount.”
Dr. Niglio emphasized that these updated results show continued benefit from nivolumab on disease-free survival, as well as nonurothelial tract recurrence-free survival and distant metastasis-free survival, supporting its use as standard of care therapy.
“Even though the overall survival data is still maturing, the current data remains promising,” he said. “Patients with urothelial cancer meeting the criteria for high risk now have a treatment option to mitigate the potential of distant recurrence.”
In his own practice, Dr. Niglio added that he will “continue to discuss adjuvant nivolumab as a potential treatment option with all patients who are eligible based on this study.”
Met all endpoints
The Checkmate 274 trial involved 353 patients (of whom 140 patients had PD-L1 ≥ 1%) randomly assigned to take nivolumab 240 mg every 2 weeks and 356 patients (with 142 patients with PD-L1 ≥ 1%) randomized to placebo. All patients had pathologic evidence of urothelial cancer at high risk of recurrence and Eastern Cooperative Oncology Group performance status (ECOG PS) of1 or less.
Previous results, at a median follow-up of about 20 months, show that the study met its primary endpoint, showing significant prolongation of disease-free survival in the intention-to-treat population, with nivolumab at 21 months versus placebo at 10.9 months (hazard ratio, 0.70; P < .001).
When the analysis considered only patients with tumors expressing PD-L1 of at least 1%, the median disease-free survival was even higher (not reached vs. 10.8 months; HR, 0.53; P < .001).
Nivolumab was also superior to placebo for NUTRFS, in both in the entire ITT population and in the subset with PD-L1–positive tumors.
The latest results come from a median follow-up of 36.1 months. The median disease-free survival was 22 months with nivolumab, compared with 10.9 months with placebo in ITT patients and 52.6 months on nivolumab versus 8.4 months in patients with PD-L1 of at least 1%.
Nivolumab was superior to placebo for secondary and exploratory endpoints, NUTRFS (ITT: HR, 0.72 and PD-L1 ≥ 1%: HR, 0.53) and DMFS (ITT: HR, 0.74; PD-L1 ≥ 1%: HR, 0.58). However, overall survival data remained immature and will be assessed as a future data cutoff, Dr. Galsky explained.
The updated analysis also included another exploratory endpoint, progression-free survival 2 (PFS2), defined as time from randomization to disease progression after subsequent next-line systemic therapy, start of second subsequent next-line systemic therapy, or death.
Median PFS2 was 61.2 months for all-patients who received nivolumab versus 47.1 months with placebo (HR, 0.79). In the PD-L1 of 1% or greater subgroup, median PFS2 was not reached with nivolumab versus 39.4 months with placebo (HR, 0.54).
Grade 3-4 treatment-related adverse events occurred in 18.2% and 7.2% of patients (nivolumab vs. placebo), and this was consistent with the primary analysis. “No new safety signals were identified,” said Dr. Galsky.
The CheckMate 274 trial was funded by Bristol-Myers Squibb, manufacturer of nivolumab. Dr. Galsky reported relationships with numerous pharmaceutical companies.
A version of this article first appeared on Medscape.com.
Extended follow-up data from the phase 3 CheckMate 274 trial continue to show that, compared with placebo, nivolumab improves disease-free survival, nonurothelial tract recurrence-free survival (NUTRFS), and distant metastasis-free survival (DMFS) in patients with high-risk, muscle-invasive urothelial cancer after undergoing radical surgery.
The benefit was observed in both in the intent-to-treat population (ITT) and in the subset of patients with programmed death–ligand 1 (PD-L1) expression of at least 1%.
“In the ITT population, median disease-free survival with nivolumab was doubled compared to placebo,” said lead author Matthew Galsky, MD, director of genitourinary medical oncology and codirector of the Center of Excellence for Bladder Cancer at Tisch Cancer Institute, New York. “For the patients with high PD-L1 expression, the median disease-free survival with nivolumab reached 52.6 months, more than six times that of the placebo arm.
“These results further support adjuvant nivolumab as a standard of care in high-risk muscle-invasive urothelial cancer after resection,” he concluded.
Dr. Galsky presented the findings at the 2023 ASCO Genitourinary Cancers Symposium.
Practice changing
The earlier results of this study have already led to an approval from the Food and Drug Administration. In August 2021, nivolumab became the first adjuvant immunotherapy for use in patients with urothelial carcinoma at high risk for recurrence after radical resection
“This is a practice-changing study,” said Scot Niglio, MD, medical oncologist, New York University Perlmutter Cancer Center, who was approached for an independent comment.
“For decades, there were limited to zero treatment options in the postsurgical setting for urothelial cancer patients with a high recurrence risk,” he said.
The standard of care for muscle-invasive urothelial carcinoma is surgery, which may include neoadjuvant cisplatin-based chemotherapy, but most patients will experience disease recurrence, he explained.
“When urothelial cancer recurs outside the urinary tract, the prognosis quickly changes from curable to incurable,” he said, “making this area of research paramount.”
Dr. Niglio emphasized that these updated results show continued benefit from nivolumab on disease-free survival, as well as nonurothelial tract recurrence-free survival and distant metastasis-free survival, supporting its use as standard of care therapy.
“Even though the overall survival data is still maturing, the current data remains promising,” he said. “Patients with urothelial cancer meeting the criteria for high risk now have a treatment option to mitigate the potential of distant recurrence.”
In his own practice, Dr. Niglio added that he will “continue to discuss adjuvant nivolumab as a potential treatment option with all patients who are eligible based on this study.”
Met all endpoints
The Checkmate 274 trial involved 353 patients (of whom 140 patients had PD-L1 ≥ 1%) randomly assigned to take nivolumab 240 mg every 2 weeks and 356 patients (with 142 patients with PD-L1 ≥ 1%) randomized to placebo. All patients had pathologic evidence of urothelial cancer at high risk of recurrence and Eastern Cooperative Oncology Group performance status (ECOG PS) of1 or less.
Previous results, at a median follow-up of about 20 months, show that the study met its primary endpoint, showing significant prolongation of disease-free survival in the intention-to-treat population, with nivolumab at 21 months versus placebo at 10.9 months (hazard ratio, 0.70; P < .001).
When the analysis considered only patients with tumors expressing PD-L1 of at least 1%, the median disease-free survival was even higher (not reached vs. 10.8 months; HR, 0.53; P < .001).
Nivolumab was also superior to placebo for NUTRFS, in both in the entire ITT population and in the subset with PD-L1–positive tumors.
The latest results come from a median follow-up of 36.1 months. The median disease-free survival was 22 months with nivolumab, compared with 10.9 months with placebo in ITT patients and 52.6 months on nivolumab versus 8.4 months in patients with PD-L1 of at least 1%.
Nivolumab was superior to placebo for secondary and exploratory endpoints, NUTRFS (ITT: HR, 0.72 and PD-L1 ≥ 1%: HR, 0.53) and DMFS (ITT: HR, 0.74; PD-L1 ≥ 1%: HR, 0.58). However, overall survival data remained immature and will be assessed as a future data cutoff, Dr. Galsky explained.
The updated analysis also included another exploratory endpoint, progression-free survival 2 (PFS2), defined as time from randomization to disease progression after subsequent next-line systemic therapy, start of second subsequent next-line systemic therapy, or death.
Median PFS2 was 61.2 months for all-patients who received nivolumab versus 47.1 months with placebo (HR, 0.79). In the PD-L1 of 1% or greater subgroup, median PFS2 was not reached with nivolumab versus 39.4 months with placebo (HR, 0.54).
Grade 3-4 treatment-related adverse events occurred in 18.2% and 7.2% of patients (nivolumab vs. placebo), and this was consistent with the primary analysis. “No new safety signals were identified,” said Dr. Galsky.
The CheckMate 274 trial was funded by Bristol-Myers Squibb, manufacturer of nivolumab. Dr. Galsky reported relationships with numerous pharmaceutical companies.
A version of this article first appeared on Medscape.com.
Extended follow-up data from the phase 3 CheckMate 274 trial continue to show that, compared with placebo, nivolumab improves disease-free survival, nonurothelial tract recurrence-free survival (NUTRFS), and distant metastasis-free survival (DMFS) in patients with high-risk, muscle-invasive urothelial cancer after undergoing radical surgery.
The benefit was observed in both in the intent-to-treat population (ITT) and in the subset of patients with programmed death–ligand 1 (PD-L1) expression of at least 1%.
“In the ITT population, median disease-free survival with nivolumab was doubled compared to placebo,” said lead author Matthew Galsky, MD, director of genitourinary medical oncology and codirector of the Center of Excellence for Bladder Cancer at Tisch Cancer Institute, New York. “For the patients with high PD-L1 expression, the median disease-free survival with nivolumab reached 52.6 months, more than six times that of the placebo arm.
“These results further support adjuvant nivolumab as a standard of care in high-risk muscle-invasive urothelial cancer after resection,” he concluded.
Dr. Galsky presented the findings at the 2023 ASCO Genitourinary Cancers Symposium.
Practice changing
The earlier results of this study have already led to an approval from the Food and Drug Administration. In August 2021, nivolumab became the first adjuvant immunotherapy for use in patients with urothelial carcinoma at high risk for recurrence after radical resection
“This is a practice-changing study,” said Scot Niglio, MD, medical oncologist, New York University Perlmutter Cancer Center, who was approached for an independent comment.
“For decades, there were limited to zero treatment options in the postsurgical setting for urothelial cancer patients with a high recurrence risk,” he said.
The standard of care for muscle-invasive urothelial carcinoma is surgery, which may include neoadjuvant cisplatin-based chemotherapy, but most patients will experience disease recurrence, he explained.
“When urothelial cancer recurs outside the urinary tract, the prognosis quickly changes from curable to incurable,” he said, “making this area of research paramount.”
Dr. Niglio emphasized that these updated results show continued benefit from nivolumab on disease-free survival, as well as nonurothelial tract recurrence-free survival and distant metastasis-free survival, supporting its use as standard of care therapy.
“Even though the overall survival data is still maturing, the current data remains promising,” he said. “Patients with urothelial cancer meeting the criteria for high risk now have a treatment option to mitigate the potential of distant recurrence.”
In his own practice, Dr. Niglio added that he will “continue to discuss adjuvant nivolumab as a potential treatment option with all patients who are eligible based on this study.”
Met all endpoints
The Checkmate 274 trial involved 353 patients (of whom 140 patients had PD-L1 ≥ 1%) randomly assigned to take nivolumab 240 mg every 2 weeks and 356 patients (with 142 patients with PD-L1 ≥ 1%) randomized to placebo. All patients had pathologic evidence of urothelial cancer at high risk of recurrence and Eastern Cooperative Oncology Group performance status (ECOG PS) of1 or less.
Previous results, at a median follow-up of about 20 months, show that the study met its primary endpoint, showing significant prolongation of disease-free survival in the intention-to-treat population, with nivolumab at 21 months versus placebo at 10.9 months (hazard ratio, 0.70; P < .001).
When the analysis considered only patients with tumors expressing PD-L1 of at least 1%, the median disease-free survival was even higher (not reached vs. 10.8 months; HR, 0.53; P < .001).
Nivolumab was also superior to placebo for NUTRFS, in both in the entire ITT population and in the subset with PD-L1–positive tumors.
The latest results come from a median follow-up of 36.1 months. The median disease-free survival was 22 months with nivolumab, compared with 10.9 months with placebo in ITT patients and 52.6 months on nivolumab versus 8.4 months in patients with PD-L1 of at least 1%.
Nivolumab was superior to placebo for secondary and exploratory endpoints, NUTRFS (ITT: HR, 0.72 and PD-L1 ≥ 1%: HR, 0.53) and DMFS (ITT: HR, 0.74; PD-L1 ≥ 1%: HR, 0.58). However, overall survival data remained immature and will be assessed as a future data cutoff, Dr. Galsky explained.
The updated analysis also included another exploratory endpoint, progression-free survival 2 (PFS2), defined as time from randomization to disease progression after subsequent next-line systemic therapy, start of second subsequent next-line systemic therapy, or death.
Median PFS2 was 61.2 months for all-patients who received nivolumab versus 47.1 months with placebo (HR, 0.79). In the PD-L1 of 1% or greater subgroup, median PFS2 was not reached with nivolumab versus 39.4 months with placebo (HR, 0.54).
Grade 3-4 treatment-related adverse events occurred in 18.2% and 7.2% of patients (nivolumab vs. placebo), and this was consistent with the primary analysis. “No new safety signals were identified,” said Dr. Galsky.
The CheckMate 274 trial was funded by Bristol-Myers Squibb, manufacturer of nivolumab. Dr. Galsky reported relationships with numerous pharmaceutical companies.
A version of this article first appeared on Medscape.com.
AT ASCO GU 2023
Rucaparib benefit in BRCA+ prostate cancer confirmed
The finding, which comes from the TRITON3 clinical trial, provides evidence of clinical benefit for an indication for rucaparib that was granted an accelerated approval in May 2020.
“Rucaparib reduced the risk of progression or death by half in patients with BRCA alterations,” said lead author Alan H. Bryce, MD, medical director of the Genomic Oncology Clinic at Mayo Clinic Arizona, in Phoenix.
For the subgroup of patients with BRCA alterations, the median PFS was 11.2 months with rucaparib vs. 6.4 months (hazard ratio, 0.50; P < .001) among those who received physician’s choice of therapy, which included docetaxel or a second-generation ARPI, such as abiraterone or enzalutamide.
In another subgroup of patients whose disease had ATM alterations, the median PFS was 8.1 months with rucaparib vs. 6.8 months with physician’s choice of drug. The difference was not statistically significant.
However, the difference was significant in the intention-to-treat (ITT) population (comprising both subgroups), for whom the median PFS was 10.2 months with rucaparib vs. 6.4 months with physician’s choice of drug (HR, 0.61; P < .001 by log-rank test).
Dr. Bryce pointed out that three-quarters of the patients in the physician’s-choice arm who had progressive disease crossed over to rucaparib upon progression and that overall survival (OS) results are immature. At 62 months, median OS did not significantly differ in the BRCA subgroup (24.3 vs. 20.8 months favoring rucaparib; P = .21) or in the ITT group (23.6 vs. 20.9 months; P = .67).
Importantly, rucaparib was well tolerated. In all treatment groups, the most frequent adverse events were asthenia and fatigue, Bryce said. “There were no cases of myelodysplastic syndrome or acute myeloid leukemia reported.”
These results from the TRITON3 trial were presented at the 2023 ASCO Genitourinary Cancers Symposium and were published simultaneously in the New England Journal of Medicine.
Suggested benefit
Rucaparib is the first PARP inhibitor approved for use in patients with mCRPC that harbors deleterious BRCA mutations (germline and/or somatic) who have already been treated with androgen receptor–directed therapy and a taxane-based chemotherapy. This prostate cancer indication was granted an accelerated approval in May 2020 by the U.S. Food and Drug Administration on the basis of response rates and effect on levels of prostate-specific antigen (PSA) from the TRITON2 clinical trial, the forerunner of the current study.
The TRITON2 study was a single-arm clinical trial that involved three cohorts: 62 patients with a BRCA mutation (germline and/or somatic) and measurable disease; 115 patients with a BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease; and 209 patients with homologous recombination deficiency–positive mCRPC.
In an analysis of 115 patients with a deleterious BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease, the confirmed PSA response rate was 55%. For the patients with measurable disease and a BRCA mutation, the objective response rate was 44%. The objective response rate was similar for those with a germline BRCA mutation.
Study details
The current phase 3 randomized TRITON3 clinical trial was conducted to confirm the earlier findings and to expand upon the data in mCRPC. The participants in this trial were patients with mCRPC who had specific gene alterations, including BRCA and ATM alterations, who had experienced disease progression after androgen receptor–directed therapy but who had not yet received chemotherapy.
A total of 270 men were assigned to receive rucaparib (600 mg twice daily); 135 patients received their physician’s choice of medication. Within the two study arms, 302 patients had a BRCA alteration, and 103 patients had an ATM alteration. The ITT population consisted of all the patients who had been randomly assigned to either of the two groups. A prespecified subgroup included patients with a BRCA alteration.
The primary outcome was the median duration of imaging-based PSF, as determined through independent review. Key secondary outcomes were overall survival and objective response rate.
The most common adverse events in the rucaparib group were fatigue, nausea, and anemia or decreased hemoglobin. In the control group, the most common adverse events were fatigue, diarrhea, and neuropathy. The most common events of grade 3 or higher were anemia or decreased hemoglobin, neutropenia or a decreased neutrophil count, and fatigue in the rucaparib group, and fatigue and neutropenia or a decreased neutrophil count among control patients.
No changes in standard of care
In a discussion of the study, Elena Castro, MD, PhD, of the Instituto de Investigación Biomédica de Málaga, Campanillas, Spain, emphasized that there is a clear benefit from the use of PARP inhibitors (such as rucaparib) for patients with BRCA alterations.
However, she highlighted the absence of convincing overall survival data and the absence of a clear benefit on PFS in the subgroup of patients with ATM alterations.
“These data raise several questions,” she noted, “such as, do patients with ATM alterations benefit at all? And should PARP inhibitors [such as rucaparib] precede or follow docetaxel therapy?”
Because of the high crossover rate, it may be possible to evaluate the directionality of docetaxel followed by PARP inhibitors and the other way around, she suggested.
Dr. Castro said that patients with BRCA alterations benefit from PARP inhibitors and are likely to derive more benefit from them than from taxanes.
“But those with ATM alterations are unlikely to benefit from rucaparib more than from taxanes,” she said.
In a comment, Hank Ng, MD, medical oncologist, NYU Langone Perlmutter Cancer Center, New York, said he is not convinced that the findings from TRITON 3 represent a new standard of care in BRCA 1/2 mutations or ATM.
“Currently, we know that, for patients with prostate cancer with BRCA1/2 or ATM, the standard of care is an androgen receptor pathway inhibitor (ARPI), such as abiraterone or enzalutamide, then docetaxel, and then a PARP inhibitor like rucaparib,” he said.
(Currently, rucaparib is indicated for use in patients with mCRPC with BRCA alterations after they have already received an ARPI and taxane-based chemotherapy.)
Dr. Ng also questioned the control arm of the TRITON 3 trial. All the participants in the trial had already experienced disease progression after treatment with a second-generation ARPI. But the physician’s choice of therapy allowed them to move on to another ARPI or to docetaxel.
Dr. NG commented that, “in almost all cases, after progression of one ARPI, switching to another ARPI does not provide much benefit – from what is visible from this abstract – and only 56% patients received docetaxel, and thus 44% received a not-beneficial treatment,” he said.
“I am not sure what the docetaxel subgroup showed, but potentially, if those numbers are convincing, we could move this [rucaparib] ahead of docetaxel,” he speculated.
However, he also pointed out that an overall survival benefit has not yet been shown; so far, the benefit that has been shown is with respect to imaging-based PFS.
Dr. Ng does agree that rucaparib is indicated in the second line after progression with one ARPI for patients who are not candidates for chemotherapy. “But this has not yet shown me that we should absolutely be offering rucaparib before docetaxel,” he said.
TRITON3 was supported by Clovis Oncology, manufacturer of rucaparib. Dr. Bryce has relationships with Bayer, Foundation Medicine, Janssen, Merck, Myovant Sciences, and Novartis and holds a patent for therapeutic targeting of cancer patients with NRG1 rearrangements. Dr. Castro has relationships with Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Janssen-Cilag, Merck, MSD Oncology, Novartis, Pfizer, and Roche.
A version of this article first appeared on Medscape.com.
The finding, which comes from the TRITON3 clinical trial, provides evidence of clinical benefit for an indication for rucaparib that was granted an accelerated approval in May 2020.
“Rucaparib reduced the risk of progression or death by half in patients with BRCA alterations,” said lead author Alan H. Bryce, MD, medical director of the Genomic Oncology Clinic at Mayo Clinic Arizona, in Phoenix.
For the subgroup of patients with BRCA alterations, the median PFS was 11.2 months with rucaparib vs. 6.4 months (hazard ratio, 0.50; P < .001) among those who received physician’s choice of therapy, which included docetaxel or a second-generation ARPI, such as abiraterone or enzalutamide.
In another subgroup of patients whose disease had ATM alterations, the median PFS was 8.1 months with rucaparib vs. 6.8 months with physician’s choice of drug. The difference was not statistically significant.
However, the difference was significant in the intention-to-treat (ITT) population (comprising both subgroups), for whom the median PFS was 10.2 months with rucaparib vs. 6.4 months with physician’s choice of drug (HR, 0.61; P < .001 by log-rank test).
Dr. Bryce pointed out that three-quarters of the patients in the physician’s-choice arm who had progressive disease crossed over to rucaparib upon progression and that overall survival (OS) results are immature. At 62 months, median OS did not significantly differ in the BRCA subgroup (24.3 vs. 20.8 months favoring rucaparib; P = .21) or in the ITT group (23.6 vs. 20.9 months; P = .67).
Importantly, rucaparib was well tolerated. In all treatment groups, the most frequent adverse events were asthenia and fatigue, Bryce said. “There were no cases of myelodysplastic syndrome or acute myeloid leukemia reported.”
These results from the TRITON3 trial were presented at the 2023 ASCO Genitourinary Cancers Symposium and were published simultaneously in the New England Journal of Medicine.
Suggested benefit
Rucaparib is the first PARP inhibitor approved for use in patients with mCRPC that harbors deleterious BRCA mutations (germline and/or somatic) who have already been treated with androgen receptor–directed therapy and a taxane-based chemotherapy. This prostate cancer indication was granted an accelerated approval in May 2020 by the U.S. Food and Drug Administration on the basis of response rates and effect on levels of prostate-specific antigen (PSA) from the TRITON2 clinical trial, the forerunner of the current study.
The TRITON2 study was a single-arm clinical trial that involved three cohorts: 62 patients with a BRCA mutation (germline and/or somatic) and measurable disease; 115 patients with a BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease; and 209 patients with homologous recombination deficiency–positive mCRPC.
In an analysis of 115 patients with a deleterious BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease, the confirmed PSA response rate was 55%. For the patients with measurable disease and a BRCA mutation, the objective response rate was 44%. The objective response rate was similar for those with a germline BRCA mutation.
Study details
The current phase 3 randomized TRITON3 clinical trial was conducted to confirm the earlier findings and to expand upon the data in mCRPC. The participants in this trial were patients with mCRPC who had specific gene alterations, including BRCA and ATM alterations, who had experienced disease progression after androgen receptor–directed therapy but who had not yet received chemotherapy.
A total of 270 men were assigned to receive rucaparib (600 mg twice daily); 135 patients received their physician’s choice of medication. Within the two study arms, 302 patients had a BRCA alteration, and 103 patients had an ATM alteration. The ITT population consisted of all the patients who had been randomly assigned to either of the two groups. A prespecified subgroup included patients with a BRCA alteration.
The primary outcome was the median duration of imaging-based PSF, as determined through independent review. Key secondary outcomes were overall survival and objective response rate.
The most common adverse events in the rucaparib group were fatigue, nausea, and anemia or decreased hemoglobin. In the control group, the most common adverse events were fatigue, diarrhea, and neuropathy. The most common events of grade 3 or higher were anemia or decreased hemoglobin, neutropenia or a decreased neutrophil count, and fatigue in the rucaparib group, and fatigue and neutropenia or a decreased neutrophil count among control patients.
No changes in standard of care
In a discussion of the study, Elena Castro, MD, PhD, of the Instituto de Investigación Biomédica de Málaga, Campanillas, Spain, emphasized that there is a clear benefit from the use of PARP inhibitors (such as rucaparib) for patients with BRCA alterations.
However, she highlighted the absence of convincing overall survival data and the absence of a clear benefit on PFS in the subgroup of patients with ATM alterations.
“These data raise several questions,” she noted, “such as, do patients with ATM alterations benefit at all? And should PARP inhibitors [such as rucaparib] precede or follow docetaxel therapy?”
Because of the high crossover rate, it may be possible to evaluate the directionality of docetaxel followed by PARP inhibitors and the other way around, she suggested.
Dr. Castro said that patients with BRCA alterations benefit from PARP inhibitors and are likely to derive more benefit from them than from taxanes.
“But those with ATM alterations are unlikely to benefit from rucaparib more than from taxanes,” she said.
In a comment, Hank Ng, MD, medical oncologist, NYU Langone Perlmutter Cancer Center, New York, said he is not convinced that the findings from TRITON 3 represent a new standard of care in BRCA 1/2 mutations or ATM.
“Currently, we know that, for patients with prostate cancer with BRCA1/2 or ATM, the standard of care is an androgen receptor pathway inhibitor (ARPI), such as abiraterone or enzalutamide, then docetaxel, and then a PARP inhibitor like rucaparib,” he said.
(Currently, rucaparib is indicated for use in patients with mCRPC with BRCA alterations after they have already received an ARPI and taxane-based chemotherapy.)
Dr. Ng also questioned the control arm of the TRITON 3 trial. All the participants in the trial had already experienced disease progression after treatment with a second-generation ARPI. But the physician’s choice of therapy allowed them to move on to another ARPI or to docetaxel.
Dr. NG commented that, “in almost all cases, after progression of one ARPI, switching to another ARPI does not provide much benefit – from what is visible from this abstract – and only 56% patients received docetaxel, and thus 44% received a not-beneficial treatment,” he said.
“I am not sure what the docetaxel subgroup showed, but potentially, if those numbers are convincing, we could move this [rucaparib] ahead of docetaxel,” he speculated.
However, he also pointed out that an overall survival benefit has not yet been shown; so far, the benefit that has been shown is with respect to imaging-based PFS.
Dr. Ng does agree that rucaparib is indicated in the second line after progression with one ARPI for patients who are not candidates for chemotherapy. “But this has not yet shown me that we should absolutely be offering rucaparib before docetaxel,” he said.
TRITON3 was supported by Clovis Oncology, manufacturer of rucaparib. Dr. Bryce has relationships with Bayer, Foundation Medicine, Janssen, Merck, Myovant Sciences, and Novartis and holds a patent for therapeutic targeting of cancer patients with NRG1 rearrangements. Dr. Castro has relationships with Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Janssen-Cilag, Merck, MSD Oncology, Novartis, Pfizer, and Roche.
A version of this article first appeared on Medscape.com.
The finding, which comes from the TRITON3 clinical trial, provides evidence of clinical benefit for an indication for rucaparib that was granted an accelerated approval in May 2020.
“Rucaparib reduced the risk of progression or death by half in patients with BRCA alterations,” said lead author Alan H. Bryce, MD, medical director of the Genomic Oncology Clinic at Mayo Clinic Arizona, in Phoenix.
For the subgroup of patients with BRCA alterations, the median PFS was 11.2 months with rucaparib vs. 6.4 months (hazard ratio, 0.50; P < .001) among those who received physician’s choice of therapy, which included docetaxel or a second-generation ARPI, such as abiraterone or enzalutamide.
In another subgroup of patients whose disease had ATM alterations, the median PFS was 8.1 months with rucaparib vs. 6.8 months with physician’s choice of drug. The difference was not statistically significant.
However, the difference was significant in the intention-to-treat (ITT) population (comprising both subgroups), for whom the median PFS was 10.2 months with rucaparib vs. 6.4 months with physician’s choice of drug (HR, 0.61; P < .001 by log-rank test).
Dr. Bryce pointed out that three-quarters of the patients in the physician’s-choice arm who had progressive disease crossed over to rucaparib upon progression and that overall survival (OS) results are immature. At 62 months, median OS did not significantly differ in the BRCA subgroup (24.3 vs. 20.8 months favoring rucaparib; P = .21) or in the ITT group (23.6 vs. 20.9 months; P = .67).
Importantly, rucaparib was well tolerated. In all treatment groups, the most frequent adverse events were asthenia and fatigue, Bryce said. “There were no cases of myelodysplastic syndrome or acute myeloid leukemia reported.”
These results from the TRITON3 trial were presented at the 2023 ASCO Genitourinary Cancers Symposium and were published simultaneously in the New England Journal of Medicine.
Suggested benefit
Rucaparib is the first PARP inhibitor approved for use in patients with mCRPC that harbors deleterious BRCA mutations (germline and/or somatic) who have already been treated with androgen receptor–directed therapy and a taxane-based chemotherapy. This prostate cancer indication was granted an accelerated approval in May 2020 by the U.S. Food and Drug Administration on the basis of response rates and effect on levels of prostate-specific antigen (PSA) from the TRITON2 clinical trial, the forerunner of the current study.
The TRITON2 study was a single-arm clinical trial that involved three cohorts: 62 patients with a BRCA mutation (germline and/or somatic) and measurable disease; 115 patients with a BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease; and 209 patients with homologous recombination deficiency–positive mCRPC.
In an analysis of 115 patients with a deleterious BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease, the confirmed PSA response rate was 55%. For the patients with measurable disease and a BRCA mutation, the objective response rate was 44%. The objective response rate was similar for those with a germline BRCA mutation.
Study details
The current phase 3 randomized TRITON3 clinical trial was conducted to confirm the earlier findings and to expand upon the data in mCRPC. The participants in this trial were patients with mCRPC who had specific gene alterations, including BRCA and ATM alterations, who had experienced disease progression after androgen receptor–directed therapy but who had not yet received chemotherapy.
A total of 270 men were assigned to receive rucaparib (600 mg twice daily); 135 patients received their physician’s choice of medication. Within the two study arms, 302 patients had a BRCA alteration, and 103 patients had an ATM alteration. The ITT population consisted of all the patients who had been randomly assigned to either of the two groups. A prespecified subgroup included patients with a BRCA alteration.
The primary outcome was the median duration of imaging-based PSF, as determined through independent review. Key secondary outcomes were overall survival and objective response rate.
The most common adverse events in the rucaparib group were fatigue, nausea, and anemia or decreased hemoglobin. In the control group, the most common adverse events were fatigue, diarrhea, and neuropathy. The most common events of grade 3 or higher were anemia or decreased hemoglobin, neutropenia or a decreased neutrophil count, and fatigue in the rucaparib group, and fatigue and neutropenia or a decreased neutrophil count among control patients.
No changes in standard of care
In a discussion of the study, Elena Castro, MD, PhD, of the Instituto de Investigación Biomédica de Málaga, Campanillas, Spain, emphasized that there is a clear benefit from the use of PARP inhibitors (such as rucaparib) for patients with BRCA alterations.
However, she highlighted the absence of convincing overall survival data and the absence of a clear benefit on PFS in the subgroup of patients with ATM alterations.
“These data raise several questions,” she noted, “such as, do patients with ATM alterations benefit at all? And should PARP inhibitors [such as rucaparib] precede or follow docetaxel therapy?”
Because of the high crossover rate, it may be possible to evaluate the directionality of docetaxel followed by PARP inhibitors and the other way around, she suggested.
Dr. Castro said that patients with BRCA alterations benefit from PARP inhibitors and are likely to derive more benefit from them than from taxanes.
“But those with ATM alterations are unlikely to benefit from rucaparib more than from taxanes,” she said.
In a comment, Hank Ng, MD, medical oncologist, NYU Langone Perlmutter Cancer Center, New York, said he is not convinced that the findings from TRITON 3 represent a new standard of care in BRCA 1/2 mutations or ATM.
“Currently, we know that, for patients with prostate cancer with BRCA1/2 or ATM, the standard of care is an androgen receptor pathway inhibitor (ARPI), such as abiraterone or enzalutamide, then docetaxel, and then a PARP inhibitor like rucaparib,” he said.
(Currently, rucaparib is indicated for use in patients with mCRPC with BRCA alterations after they have already received an ARPI and taxane-based chemotherapy.)
Dr. Ng also questioned the control arm of the TRITON 3 trial. All the participants in the trial had already experienced disease progression after treatment with a second-generation ARPI. But the physician’s choice of therapy allowed them to move on to another ARPI or to docetaxel.
Dr. NG commented that, “in almost all cases, after progression of one ARPI, switching to another ARPI does not provide much benefit – from what is visible from this abstract – and only 56% patients received docetaxel, and thus 44% received a not-beneficial treatment,” he said.
“I am not sure what the docetaxel subgroup showed, but potentially, if those numbers are convincing, we could move this [rucaparib] ahead of docetaxel,” he speculated.
However, he also pointed out that an overall survival benefit has not yet been shown; so far, the benefit that has been shown is with respect to imaging-based PFS.
Dr. Ng does agree that rucaparib is indicated in the second line after progression with one ARPI for patients who are not candidates for chemotherapy. “But this has not yet shown me that we should absolutely be offering rucaparib before docetaxel,” he said.
TRITON3 was supported by Clovis Oncology, manufacturer of rucaparib. Dr. Bryce has relationships with Bayer, Foundation Medicine, Janssen, Merck, Myovant Sciences, and Novartis and holds a patent for therapeutic targeting of cancer patients with NRG1 rearrangements. Dr. Castro has relationships with Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Janssen-Cilag, Merck, MSD Oncology, Novartis, Pfizer, and Roche.
A version of this article first appeared on Medscape.com.
AT ASCO GU 2023