ASCO: Genitourinary Cancers Symposium 2016

SAN FRANCISCO – Healthy dietary and lifestyle factors can add up substantially to reduce the risk of prostate cancer death among men who are treated for the disease, suggests a study reported at the Genitourinary Cancers Symposium.

A team led by Stacey A. Kenfield, Sc.D., analyzed data for 3,583 men participating in the Health Professionals Follow-Up Study who received a diagnosis of nonmetastatic prostate cancer between 1986 and 2008. They assessed whether the men had 11 protective dietary and lifestyle factors after diagnosis and associations with prostate cancer–specific mortality.

Susan London/Frontline Medical News

Results showed that men having 8 to 11 of the protective factors were 75% less likely to die from the disease than were those having 0 to 3 of them. But full adoption wasn’t necessary to see benefit: Risk fell by 29% with each additional factor.

“Exercising vigorously regularly, not smoking, having a health body weight and a diet high in cruciferous vegetables and healthy sources of fat, having moderate amounts of coffee and wine, and avoiding processed meat, poultry with skin, whole milk, and excess supplemental selenium seem to be good for reducing one’s risk of lethal prostate cancer,” said Dr. Kenfield of the University of California, San Francisco.

“I would say, try to adopt as many as you can, but understandably, it’s hard to do all 11, as there was no one in this study who did at diagnosis,” she added.

Dr. Kenfield and her colleagues, along with the Prostate Cancer Foundation, have developed a booklet available online for patients and caregivers that covers many of the factors highlighted by the study.

In the Health Professionals Follow-Up Study, data were collected on smoking, weight, and physical activity every 2 years, and on diet every 4 years.

Drawing on the literature, the investigators assessed 11 protective factors: body mass index of less than 30 kg/m², getting at least 3 hours of vigorous physical activity per week (or brisk walking for at least 7 hours per week), not currently smoking (or having quit at least a decade ago), consuming fewer than two servings per week of processed red meat, not consuming any poultry with skin, consuming at least one serving per day of cruciferous vegetables, getting less than 140 micrograms/day of selenium in supplements, consuming at least three servings per week of nuts or oil-based salad dressing, drinking fewer than four servings per week of whole milk, drinking at least four servings per day of coffee, and drinking at least seven servings of wine per week.

The investigators updated men’s status regarding these factors at the above intervals, but excluded data near the end of life to avoid bias introduced by adoption of healthy behaviors in response to facing terminal illness, Dr. Kenfield explained at the symposium, which was sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

The prevalence of the various protective factors at diagnosis ranged widely, from 8% of men drinking at least seven servings of wine per week to 97% of men consuming fewer than four servings per week of whole milk, according to data reported in a poster session. The majority of men, 61%, had five or six of the protective factors.

During a median follow-up of 11 years, nearly 7% of the men died from prostate cancer. In multivariate analyses in which men having 0-3 of the protective factors were the reference group, those having 4-7 factors had a 48% lower risk of death from prostate cancer (hazard ratio, 0.52) and those having 8-11 factors had a 75% lower risk (HR, 0.25). Furthermore, risk fell with each additional protective factor (HR, 0.71).

Findings were similar when the investigators assessed only the food factors, only the drink factors, and only the lifestyle factors separately.

“There are not a lot of studies that have looked at these factors in association with prostate cancer death,” noted Dr. Kenfield. In fact, only a few U.S. cohorts have collected sufficient data after diagnosis to perform this type of analysis.

“We are hoping that there will be more data in the future, especially from Europe. They have a lot of different cohorts that have smoking, exercise, and diet data,” she concluded.

SAN FRANCISCO – Healthy dietary and lifestyle factors can add up substantially to reduce the risk of prostate cancer death among men who are treated for the disease, suggests a study reported at the Genitourinary Cancers Symposium.

A team led by Stacey A. Kenfield, Sc.D., analyzed data for 3,583 men participating in the Health Professionals Follow-Up Study who received a diagnosis of nonmetastatic prostate cancer between 1986 and 2008. They assessed whether the men had 11 protective dietary and lifestyle factors after diagnosis and associations with prostate cancer–specific mortality.

Susan London/Frontline Medical News

Results showed that men having 8 to 11 of the protective factors were 75% less likely to die from the disease than were those having 0 to 3 of them. But full adoption wasn’t necessary to see benefit: Risk fell by 29% with each additional factor.

“Exercising vigorously regularly, not smoking, having a health body weight and a diet high in cruciferous vegetables and healthy sources of fat, having moderate amounts of coffee and wine, and avoiding processed meat, poultry with skin, whole milk, and excess supplemental selenium seem to be good for reducing one’s risk of lethal prostate cancer,” said Dr. Kenfield of the University of California, San Francisco.

“I would say, try to adopt as many as you can, but understandably, it’s hard to do all 11, as there was no one in this study who did at diagnosis,” she added.

Dr. Kenfield and her colleagues, along with the Prostate Cancer Foundation, have developed a booklet available online for patients and caregivers that covers many of the factors highlighted by the study.

In the Health Professionals Follow-Up Study, data were collected on smoking, weight, and physical activity every 2 years, and on diet every 4 years.

Drawing on the literature, the investigators assessed 11 protective factors: body mass index of less than 30 kg/m², getting at least 3 hours of vigorous physical activity per week (or brisk walking for at least 7 hours per week), not currently smoking (or having quit at least a decade ago), consuming fewer than two servings per week of processed red meat, not consuming any poultry with skin, consuming at least one serving per day of cruciferous vegetables, getting less than 140 micrograms/day of selenium in supplements, consuming at least three servings per week of nuts or oil-based salad dressing, drinking fewer than four servings per week of whole milk, drinking at least four servings per day of coffee, and drinking at least seven servings of wine per week.

The investigators updated men’s status regarding these factors at the above intervals, but excluded data near the end of life to avoid bias introduced by adoption of healthy behaviors in response to facing terminal illness, Dr. Kenfield explained at the symposium, which was sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

The prevalence of the various protective factors at diagnosis ranged widely, from 8% of men drinking at least seven servings of wine per week to 97% of men consuming fewer than four servings per week of whole milk, according to data reported in a poster session. The majority of men, 61%, had five or six of the protective factors.

During a median follow-up of 11 years, nearly 7% of the men died from prostate cancer. In multivariate analyses in which men having 0-3 of the protective factors were the reference group, those having 4-7 factors had a 48% lower risk of death from prostate cancer (hazard ratio, 0.52) and those having 8-11 factors had a 75% lower risk (HR, 0.25). Furthermore, risk fell with each additional protective factor (HR, 0.71).

Findings were similar when the investigators assessed only the food factors, only the drink factors, and only the lifestyle factors separately.

“There are not a lot of studies that have looked at these factors in association with prostate cancer death,” noted Dr. Kenfield. In fact, only a few U.S. cohorts have collected sufficient data after diagnosis to perform this type of analysis.

“We are hoping that there will be more data in the future, especially from Europe. They have a lot of different cohorts that have smoking, exercise, and diet data,” she concluded.

SAN FRANCISCO – Healthy dietary and lifestyle factors can add up substantially to reduce the risk of prostate cancer death among men who are treated for the disease, suggests a study reported at the Genitourinary Cancers Symposium.

A team led by Stacey A. Kenfield, Sc.D., analyzed data for 3,583 men participating in the Health Professionals Follow-Up Study who received a diagnosis of nonmetastatic prostate cancer between 1986 and 2008. They assessed whether the men had 11 protective dietary and lifestyle factors after diagnosis and associations with prostate cancer–specific mortality.

Susan London/Frontline Medical News

Results showed that men having 8 to 11 of the protective factors were 75% less likely to die from the disease than were those having 0 to 3 of them. But full adoption wasn’t necessary to see benefit: Risk fell by 29% with each additional factor.

“Exercising vigorously regularly, not smoking, having a health body weight and a diet high in cruciferous vegetables and healthy sources of fat, having moderate amounts of coffee and wine, and avoiding processed meat, poultry with skin, whole milk, and excess supplemental selenium seem to be good for reducing one’s risk of lethal prostate cancer,” said Dr. Kenfield of the University of California, San Francisco.

“I would say, try to adopt as many as you can, but understandably, it’s hard to do all 11, as there was no one in this study who did at diagnosis,” she added.

Dr. Kenfield and her colleagues, along with the Prostate Cancer Foundation, have developed a booklet available online for patients and caregivers that covers many of the factors highlighted by the study.

In the Health Professionals Follow-Up Study, data were collected on smoking, weight, and physical activity every 2 years, and on diet every 4 years.

Drawing on the literature, the investigators assessed 11 protective factors: body mass index of less than 30 kg/m², getting at least 3 hours of vigorous physical activity per week (or brisk walking for at least 7 hours per week), not currently smoking (or having quit at least a decade ago), consuming fewer than two servings per week of processed red meat, not consuming any poultry with skin, consuming at least one serving per day of cruciferous vegetables, getting less than 140 micrograms/day of selenium in supplements, consuming at least three servings per week of nuts or oil-based salad dressing, drinking fewer than four servings per week of whole milk, drinking at least four servings per day of coffee, and drinking at least seven servings of wine per week.

The investigators updated men’s status regarding these factors at the above intervals, but excluded data near the end of life to avoid bias introduced by adoption of healthy behaviors in response to facing terminal illness, Dr. Kenfield explained at the symposium, which was sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

The prevalence of the various protective factors at diagnosis ranged widely, from 8% of men drinking at least seven servings of wine per week to 97% of men consuming fewer than four servings per week of whole milk, according to data reported in a poster session. The majority of men, 61%, had five or six of the protective factors.

During a median follow-up of 11 years, nearly 7% of the men died from prostate cancer. In multivariate analyses in which men having 0-3 of the protective factors were the reference group, those having 4-7 factors had a 48% lower risk of death from prostate cancer (hazard ratio, 0.52) and those having 8-11 factors had a 75% lower risk (HR, 0.25). Furthermore, risk fell with each additional protective factor (HR, 0.71).

Findings were similar when the investigators assessed only the food factors, only the drink factors, and only the lifestyle factors separately.

“There are not a lot of studies that have looked at these factors in association with prostate cancer death,” noted Dr. Kenfield. In fact, only a few U.S. cohorts have collected sufficient data after diagnosis to perform this type of analysis.

“We are hoping that there will be more data in the future, especially from Europe. They have a lot of different cohorts that have smoking, exercise, and diet data,” she concluded.

SAN FRANCISCO – Depriving hormone-sensitive prostate cancer of testosterone and then hitting it with a supraphysiologic dose keeps the disease under control and nets good quality of life, results of a phase II trial suggest.

With this alternating strategy, called bipolar androgen therapy, nearly 60% of men in the trial achieved a prostate-specific antigen level of less than 4 ng/mL after two rounds of therapy, first author Dr. Michael T. Schweizer reported at the Genitourinary Cancers Symposium. Moreover, men had improvements in quality of life after receiving the testosterone.

Susan London/Frontline Medical News

Many view androgen deprivation therapy (ADT) as the standard of care for such metastatic or biochemically recurrent disease, he explained in an interview. “In a sense, this is kind of analogous to forced intermittent androgen deprivation therapy, whereas instead of allowing testosterone levels to slowly recover, like is done in clinical practice, we administer high doses of testosterone.”

The prostate-specific antigen results achieved “are relatively comparable to what you see with prior intermittent androgen deprivation therapy studies. So this looks like it may be as good as intermittent therapy, and it has the added benefit of improved quality of life,” said Dr. Schweizer of the University of Washington and Fred Hutchinson Cancer Research Center, both in Seattle.

“This data is preliminary, and I don’t think it should be used to guide treatment. But we think that it’s promising enough as a justification for a future prospective study, ideally a randomized trial,” he added. “Additional studies should probably include additional biomarker assessments to see if we can discover predictors for response to this type of therapy.”

In a previous trial, Dr. Schweizer and his colleagues tested bipolar androgen therapy in men with castration-resistant disease, finding a paradoxical antitumor effect, with a high response rate and some patients staying on the therapy for more than a year (Sci Transl Med. 2015 Jan 7;7:269ra2).

The new trial was conducted among 33 men who had a biochemical recurrence only, or had metastatic disease with a low tumor burden, and had not received therapy for advanced disease with a second-line hormonal agent or ADT. Most had previously undergone radical prostatectomy, radiation therapy, or both.

During a 6-month lead-in phase, they received ADT. “The idea behind that was that would allow for the androgen receptor to adaptively up-regulate, one of the molecular events we think sensitizes cells to this form of therapy,” he explained at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Overall, 29 men achieved a prostate-specific antigen suppression to less than 4 ng/mL or a value at least 50% below their baseline value, and therefore went on to receive two rounds of bipolar androgen therapy: monthly injections of testosterone cypionate or testosterone enanthate for 3 months, followed by ADT for 3 months.

At the end of the study, 59% had a prostate-specific antigen level of less than 4 ng/mL, exceeding the trial’s prespecified value for success of 40% based on previous trials.

“It seemed like this therapy did quickly approximate the results of what you would expect from men with biochemical disease receiving intermittent androgen deprivation therapy,” Dr. Schweizer said. Among the 10 men who had RECIST-evaluable disease, 8 had a response to the therapy.

The patients also experienced an improvement in quality of life, going from the end of the lead-in phase to the end of the first round of testosterone. Specifically, they had median improvements in the Functional Assessment of Cancer Therapy-Prostate (FACT-P) (3.5 points, P = .04) and in the International Index of Erectile Function (IIEF) (10 points, P less than .001).

Among all 29 men receiving at least one dose of testosterone, 79% had an adverse event thought to be at least possibly related to the hormone, most commonly hot flashes (52%), edema (38%), and weight gain (14%), according to Dr. Schweizer, who disclosed that he had no relevant conflicts of interest. However, all events were grade 1 or 2 in severity.

SAN FRANCISCO – Depriving hormone-sensitive prostate cancer of testosterone and then hitting it with a supraphysiologic dose keeps the disease under control and nets good quality of life, results of a phase II trial suggest.

With this alternating strategy, called bipolar androgen therapy, nearly 60% of men in the trial achieved a prostate-specific antigen level of less than 4 ng/mL after two rounds of therapy, first author Dr. Michael T. Schweizer reported at the Genitourinary Cancers Symposium. Moreover, men had improvements in quality of life after receiving the testosterone.

Susan London/Frontline Medical News

Many view androgen deprivation therapy (ADT) as the standard of care for such metastatic or biochemically recurrent disease, he explained in an interview. “In a sense, this is kind of analogous to forced intermittent androgen deprivation therapy, whereas instead of allowing testosterone levels to slowly recover, like is done in clinical practice, we administer high doses of testosterone.”

The prostate-specific antigen results achieved “are relatively comparable to what you see with prior intermittent androgen deprivation therapy studies. So this looks like it may be as good as intermittent therapy, and it has the added benefit of improved quality of life,” said Dr. Schweizer of the University of Washington and Fred Hutchinson Cancer Research Center, both in Seattle.

“This data is preliminary, and I don’t think it should be used to guide treatment. But we think that it’s promising enough as a justification for a future prospective study, ideally a randomized trial,” he added. “Additional studies should probably include additional biomarker assessments to see if we can discover predictors for response to this type of therapy.”

In a previous trial, Dr. Schweizer and his colleagues tested bipolar androgen therapy in men with castration-resistant disease, finding a paradoxical antitumor effect, with a high response rate and some patients staying on the therapy for more than a year (Sci Transl Med. 2015 Jan 7;7:269ra2).

The new trial was conducted among 33 men who had a biochemical recurrence only, or had metastatic disease with a low tumor burden, and had not received therapy for advanced disease with a second-line hormonal agent or ADT. Most had previously undergone radical prostatectomy, radiation therapy, or both.

During a 6-month lead-in phase, they received ADT. “The idea behind that was that would allow for the androgen receptor to adaptively up-regulate, one of the molecular events we think sensitizes cells to this form of therapy,” he explained at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Overall, 29 men achieved a prostate-specific antigen suppression to less than 4 ng/mL or a value at least 50% below their baseline value, and therefore went on to receive two rounds of bipolar androgen therapy: monthly injections of testosterone cypionate or testosterone enanthate for 3 months, followed by ADT for 3 months.

At the end of the study, 59% had a prostate-specific antigen level of less than 4 ng/mL, exceeding the trial’s prespecified value for success of 40% based on previous trials.

“It seemed like this therapy did quickly approximate the results of what you would expect from men with biochemical disease receiving intermittent androgen deprivation therapy,” Dr. Schweizer said. Among the 10 men who had RECIST-evaluable disease, 8 had a response to the therapy.

The patients also experienced an improvement in quality of life, going from the end of the lead-in phase to the end of the first round of testosterone. Specifically, they had median improvements in the Functional Assessment of Cancer Therapy-Prostate (FACT-P) (3.5 points, P = .04) and in the International Index of Erectile Function (IIEF) (10 points, P less than .001).

Among all 29 men receiving at least one dose of testosterone, 79% had an adverse event thought to be at least possibly related to the hormone, most commonly hot flashes (52%), edema (38%), and weight gain (14%), according to Dr. Schweizer, who disclosed that he had no relevant conflicts of interest. However, all events were grade 1 or 2 in severity.

SAN FRANCISCO – Depriving hormone-sensitive prostate cancer of testosterone and then hitting it with a supraphysiologic dose keeps the disease under control and nets good quality of life, results of a phase II trial suggest.

With this alternating strategy, called bipolar androgen therapy, nearly 60% of men in the trial achieved a prostate-specific antigen level of less than 4 ng/mL after two rounds of therapy, first author Dr. Michael T. Schweizer reported at the Genitourinary Cancers Symposium. Moreover, men had improvements in quality of life after receiving the testosterone.

Susan London/Frontline Medical News

Many view androgen deprivation therapy (ADT) as the standard of care for such metastatic or biochemically recurrent disease, he explained in an interview. “In a sense, this is kind of analogous to forced intermittent androgen deprivation therapy, whereas instead of allowing testosterone levels to slowly recover, like is done in clinical practice, we administer high doses of testosterone.”

The prostate-specific antigen results achieved “are relatively comparable to what you see with prior intermittent androgen deprivation therapy studies. So this looks like it may be as good as intermittent therapy, and it has the added benefit of improved quality of life,” said Dr. Schweizer of the University of Washington and Fred Hutchinson Cancer Research Center, both in Seattle.

“This data is preliminary, and I don’t think it should be used to guide treatment. But we think that it’s promising enough as a justification for a future prospective study, ideally a randomized trial,” he added. “Additional studies should probably include additional biomarker assessments to see if we can discover predictors for response to this type of therapy.”

In a previous trial, Dr. Schweizer and his colleagues tested bipolar androgen therapy in men with castration-resistant disease, finding a paradoxical antitumor effect, with a high response rate and some patients staying on the therapy for more than a year (Sci Transl Med. 2015 Jan 7;7:269ra2).

The new trial was conducted among 33 men who had a biochemical recurrence only, or had metastatic disease with a low tumor burden, and had not received therapy for advanced disease with a second-line hormonal agent or ADT. Most had previously undergone radical prostatectomy, radiation therapy, or both.

During a 6-month lead-in phase, they received ADT. “The idea behind that was that would allow for the androgen receptor to adaptively up-regulate, one of the molecular events we think sensitizes cells to this form of therapy,” he explained at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Overall, 29 men achieved a prostate-specific antigen suppression to less than 4 ng/mL or a value at least 50% below their baseline value, and therefore went on to receive two rounds of bipolar androgen therapy: monthly injections of testosterone cypionate or testosterone enanthate for 3 months, followed by ADT for 3 months.

At the end of the study, 59% had a prostate-specific antigen level of less than 4 ng/mL, exceeding the trial’s prespecified value for success of 40% based on previous trials.

“It seemed like this therapy did quickly approximate the results of what you would expect from men with biochemical disease receiving intermittent androgen deprivation therapy,” Dr. Schweizer said. Among the 10 men who had RECIST-evaluable disease, 8 had a response to the therapy.

The patients also experienced an improvement in quality of life, going from the end of the lead-in phase to the end of the first round of testosterone. Specifically, they had median improvements in the Functional Assessment of Cancer Therapy-Prostate (FACT-P) (3.5 points, P = .04) and in the International Index of Erectile Function (IIEF) (10 points, P less than .001).

Among all 29 men receiving at least one dose of testosterone, 79% had an adverse event thought to be at least possibly related to the hormone, most commonly hot flashes (52%), edema (38%), and weight gain (14%), according to Dr. Schweizer, who disclosed that he had no relevant conflicts of interest. However, all events were grade 1 or 2 in severity.

SAN FRANCISCO – Statins do not reduce the effectiveness of abiraterone acetate in men with castration-resistant prostate cancer, and they may even prove to add to therapy, according to data reported at the Genitourinary Cancers Symposium.

In a retrospective cohort study of 224 patients treated with abiraterone, duration of abiraterone acetate therapy, used as a surrogate for time to disease progression, was 5 months longer for men taking statins.

Prior work in patients with hormone-sensitive disease has suggested that statins compete with the androgen dehydroepiandrosterone sulfate – a precursor of more potent androgens – for cellular uptake via the SLCO2B1 transporter (JAMA Oncol. 2015 Jul;1:495-504). But “contrary to our initial hypothesis and the preclinical data that drove our initial hypothesis, there was a trend toward longer abiraterone duration in statin users,” commented Dr. Lauren C. Harshman of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, and Harvard Medical School, both in Boston. “(A statin) may be additive with abiraterone’s effect on androgen biosynthesis. Alternatively, statins could be inhibiting abiraterone’s uptake by the liver and might be prolonging the drug exposure,” she said at the 2016 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

While the findings are “intriguing,” they are not yet ready for clinical application, according to Dr. Harshman, and “need to be validated before you would ever start a statin purely for prostate cancer treatment.”

Based on preclinical data, the researchers had hypothesized that statins would compete with abiraterone for cellular influx by SLCO2B1, thereby reducing abiraterone’s inhibition of androgen biosynthesis and its clinical efficacy.

They analyzed data from men treated for predominantly metastatic castration-resistant prostate cancer with abiraterone (Zytiga) at Dana-Farber between 2008 and 2015. In about three-fourths of cases, abiraterone was being given as the first treatment for castration-resistant disease. Overall, 41% of men were taking statins when they began abiraterone.

With a median follow-up of 27.8 months, the median duration of abiraterone therapy was 14.2 months for statin users and 9.2 months for nonusers, according to data reported in a poster session. In a multivariate analysis, statin use continued to predict a longer duration of abiraterone therapy, although the prolongation was not statistically significant.

Findings were much the same, with a trend toward greater benefit for statin users, among the subset of patients who had not previously received enzalutamide or docetaxel chemotherapy (21.3 vs. 14.8 months).

“We are working with another center to add numbers to see if we see a similar trend,” concluded Dr. Harshman, who disclosed that she receives research funding from Janssen, the maker of abiraterone (Zytiga). “We are thinking about how to test this prospectively, whether in a randomized trial or some sort of trial where you might add abiraterone plus statins.”

The investigators are also analyzing the impact of single-nucleotide polymorphisms in the SLCO transporter on abiraterone’s efficacy in patients with castration-resistant prostate cancer, she said.

SAN FRANCISCO – Statins do not reduce the effectiveness of abiraterone acetate in men with castration-resistant prostate cancer, and they may even prove to add to therapy, according to data reported at the Genitourinary Cancers Symposium.

In a retrospective cohort study of 224 patients treated with abiraterone, duration of abiraterone acetate therapy, used as a surrogate for time to disease progression, was 5 months longer for men taking statins.

Prior work in patients with hormone-sensitive disease has suggested that statins compete with the androgen dehydroepiandrosterone sulfate – a precursor of more potent androgens – for cellular uptake via the SLCO2B1 transporter (JAMA Oncol. 2015 Jul;1:495-504). But “contrary to our initial hypothesis and the preclinical data that drove our initial hypothesis, there was a trend toward longer abiraterone duration in statin users,” commented Dr. Lauren C. Harshman of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, and Harvard Medical School, both in Boston. “(A statin) may be additive with abiraterone’s effect on androgen biosynthesis. Alternatively, statins could be inhibiting abiraterone’s uptake by the liver and might be prolonging the drug exposure,” she said at the 2016 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

While the findings are “intriguing,” they are not yet ready for clinical application, according to Dr. Harshman, and “need to be validated before you would ever start a statin purely for prostate cancer treatment.”

Based on preclinical data, the researchers had hypothesized that statins would compete with abiraterone for cellular influx by SLCO2B1, thereby reducing abiraterone’s inhibition of androgen biosynthesis and its clinical efficacy.

They analyzed data from men treated for predominantly metastatic castration-resistant prostate cancer with abiraterone (Zytiga) at Dana-Farber between 2008 and 2015. In about three-fourths of cases, abiraterone was being given as the first treatment for castration-resistant disease. Overall, 41% of men were taking statins when they began abiraterone.

With a median follow-up of 27.8 months, the median duration of abiraterone therapy was 14.2 months for statin users and 9.2 months for nonusers, according to data reported in a poster session. In a multivariate analysis, statin use continued to predict a longer duration of abiraterone therapy, although the prolongation was not statistically significant.

Findings were much the same, with a trend toward greater benefit for statin users, among the subset of patients who had not previously received enzalutamide or docetaxel chemotherapy (21.3 vs. 14.8 months).

“We are working with another center to add numbers to see if we see a similar trend,” concluded Dr. Harshman, who disclosed that she receives research funding from Janssen, the maker of abiraterone (Zytiga). “We are thinking about how to test this prospectively, whether in a randomized trial or some sort of trial where you might add abiraterone plus statins.”

The investigators are also analyzing the impact of single-nucleotide polymorphisms in the SLCO transporter on abiraterone’s efficacy in patients with castration-resistant prostate cancer, she said.

SAN FRANCISCO – Statins do not reduce the effectiveness of abiraterone acetate in men with castration-resistant prostate cancer, and they may even prove to add to therapy, according to data reported at the Genitourinary Cancers Symposium.

In a retrospective cohort study of 224 patients treated with abiraterone, duration of abiraterone acetate therapy, used as a surrogate for time to disease progression, was 5 months longer for men taking statins.

Prior work in patients with hormone-sensitive disease has suggested that statins compete with the androgen dehydroepiandrosterone sulfate – a precursor of more potent androgens – for cellular uptake via the SLCO2B1 transporter (JAMA Oncol. 2015 Jul;1:495-504). But “contrary to our initial hypothesis and the preclinical data that drove our initial hypothesis, there was a trend toward longer abiraterone duration in statin users,” commented Dr. Lauren C. Harshman of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, and Harvard Medical School, both in Boston. “(A statin) may be additive with abiraterone’s effect on androgen biosynthesis. Alternatively, statins could be inhibiting abiraterone’s uptake by the liver and might be prolonging the drug exposure,” she said at the 2016 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

While the findings are “intriguing,” they are not yet ready for clinical application, according to Dr. Harshman, and “need to be validated before you would ever start a statin purely for prostate cancer treatment.”

Based on preclinical data, the researchers had hypothesized that statins would compete with abiraterone for cellular influx by SLCO2B1, thereby reducing abiraterone’s inhibition of androgen biosynthesis and its clinical efficacy.

They analyzed data from men treated for predominantly metastatic castration-resistant prostate cancer with abiraterone (Zytiga) at Dana-Farber between 2008 and 2015. In about three-fourths of cases, abiraterone was being given as the first treatment for castration-resistant disease. Overall, 41% of men were taking statins when they began abiraterone.

With a median follow-up of 27.8 months, the median duration of abiraterone therapy was 14.2 months for statin users and 9.2 months for nonusers, according to data reported in a poster session. In a multivariate analysis, statin use continued to predict a longer duration of abiraterone therapy, although the prolongation was not statistically significant.

Findings were much the same, with a trend toward greater benefit for statin users, among the subset of patients who had not previously received enzalutamide or docetaxel chemotherapy (21.3 vs. 14.8 months).

“We are working with another center to add numbers to see if we see a similar trend,” concluded Dr. Harshman, who disclosed that she receives research funding from Janssen, the maker of abiraterone (Zytiga). “We are thinking about how to test this prospectively, whether in a randomized trial or some sort of trial where you might add abiraterone plus statins.”

The investigators are also analyzing the impact of single-nucleotide polymorphisms in the SLCO transporter on abiraterone’s efficacy in patients with castration-resistant prostate cancer, she said.

SAN FRANCISCO – A new gene signature may take some of the guesswork out of selecting men with localized prostate cancer for adjuvant androgen deprivation therapy (ADT), according to a study reported at the 2016 Genitourinary Cancers Symposium.

The signature captures expression of 12 genes involved in neuroendocrine differentiation, which is known to be a marker of resistance to hormone therapy, according to first author Dr. R. Jeffrey Karnes of the Mayo Clinic, Rochester, Minn.

Susan London/Frontline Medical News

Results of the study of 785 men treated with radical prostatectomy for high-risk disease indicated that among the group given adjuvant ADT, those with a high signature were 71% more likely to experience failure of this therapy, as evidenced by the development of metastases, than did their peers with a low signature.

“If you were considering treatment with androgen deprivation therapy in an adjuvant fashion for disease that meets certain criteria, such as lymph node invasion, and some people will treat patients with seminal vesicle invasion, and you profile their tumor and they have a high score, a high androgen-resistance signature, you might want to consider something else,” Dr. Karnes said in an interview. “This is hypothesis generating, but the next steps are maybe looking at the signature in a randomized trial.”

In addition, it will be helpful to evaluate the predictive value of the signature when assessed in biopsy tissue and, at the other extreme, when assessed in metastases that are already present at the time of diagnosis, he said.

In the latter setting, “if a patient has a high signature, maybe that’s somebody you definitely – irrespective of the volume of [his] disease – want to treat [him] with chemohormonal therapy if [he] had a high signature, because this is sort of a marker of an innate or inherent resistance to castration.”

For the study, Dr. Karnes and his colleagues used the Decipher Genomics Resource Information Database (GRID) to analyze gene expression profiles of primary tumors from men treated with radical prostatectomy, with or without radiation therapy, for high-risk prostate adenocarcinoma.

They developed the gene signature in 360 men and validated it in 425 men. Overall, about a third of the cohort received ADT.

During follow-up, 35% of the men developed metastases (49% of those given ADT and 29% of those not given ADT), according to data reported in a poster session at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

In Kaplan-Meier analysis among men treated with ADT, those with a high ADT resistance signature were more likely to develop metastases (P = .03). In contrast, among men not treated with ADT, the signature did not predict this outcome.

In a multivariate analysis, a high ADT resistance signature was associated with an elevated risk of metastases for men given ADT even after taking into account a variety of clinicopathologic features, surgical margin status, and receipt of various treatments (hazard ratio, 1.71; P = .02).

SAN FRANCISCO – A new gene signature may take some of the guesswork out of selecting men with localized prostate cancer for adjuvant androgen deprivation therapy (ADT), according to a study reported at the 2016 Genitourinary Cancers Symposium.

The signature captures expression of 12 genes involved in neuroendocrine differentiation, which is known to be a marker of resistance to hormone therapy, according to first author Dr. R. Jeffrey Karnes of the Mayo Clinic, Rochester, Minn.

Susan London/Frontline Medical News

Results of the study of 785 men treated with radical prostatectomy for high-risk disease indicated that among the group given adjuvant ADT, those with a high signature were 71% more likely to experience failure of this therapy, as evidenced by the development of metastases, than did their peers with a low signature.

“If you were considering treatment with androgen deprivation therapy in an adjuvant fashion for disease that meets certain criteria, such as lymph node invasion, and some people will treat patients with seminal vesicle invasion, and you profile their tumor and they have a high score, a high androgen-resistance signature, you might want to consider something else,” Dr. Karnes said in an interview. “This is hypothesis generating, but the next steps are maybe looking at the signature in a randomized trial.”

In addition, it will be helpful to evaluate the predictive value of the signature when assessed in biopsy tissue and, at the other extreme, when assessed in metastases that are already present at the time of diagnosis, he said.

In the latter setting, “if a patient has a high signature, maybe that’s somebody you definitely – irrespective of the volume of [his] disease – want to treat [him] with chemohormonal therapy if [he] had a high signature, because this is sort of a marker of an innate or inherent resistance to castration.”

For the study, Dr. Karnes and his colleagues used the Decipher Genomics Resource Information Database (GRID) to analyze gene expression profiles of primary tumors from men treated with radical prostatectomy, with or without radiation therapy, for high-risk prostate adenocarcinoma.

They developed the gene signature in 360 men and validated it in 425 men. Overall, about a third of the cohort received ADT.

During follow-up, 35% of the men developed metastases (49% of those given ADT and 29% of those not given ADT), according to data reported in a poster session at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

In Kaplan-Meier analysis among men treated with ADT, those with a high ADT resistance signature were more likely to develop metastases (P = .03). In contrast, among men not treated with ADT, the signature did not predict this outcome.

In a multivariate analysis, a high ADT resistance signature was associated with an elevated risk of metastases for men given ADT even after taking into account a variety of clinicopathologic features, surgical margin status, and receipt of various treatments (hazard ratio, 1.71; P = .02).

SAN FRANCISCO – A new gene signature may take some of the guesswork out of selecting men with localized prostate cancer for adjuvant androgen deprivation therapy (ADT), according to a study reported at the 2016 Genitourinary Cancers Symposium.

The signature captures expression of 12 genes involved in neuroendocrine differentiation, which is known to be a marker of resistance to hormone therapy, according to first author Dr. R. Jeffrey Karnes of the Mayo Clinic, Rochester, Minn.

Susan London/Frontline Medical News

Results of the study of 785 men treated with radical prostatectomy for high-risk disease indicated that among the group given adjuvant ADT, those with a high signature were 71% more likely to experience failure of this therapy, as evidenced by the development of metastases, than did their peers with a low signature.

“If you were considering treatment with androgen deprivation therapy in an adjuvant fashion for disease that meets certain criteria, such as lymph node invasion, and some people will treat patients with seminal vesicle invasion, and you profile their tumor and they have a high score, a high androgen-resistance signature, you might want to consider something else,” Dr. Karnes said in an interview. “This is hypothesis generating, but the next steps are maybe looking at the signature in a randomized trial.”

In addition, it will be helpful to evaluate the predictive value of the signature when assessed in biopsy tissue and, at the other extreme, when assessed in metastases that are already present at the time of diagnosis, he said.

In the latter setting, “if a patient has a high signature, maybe that’s somebody you definitely – irrespective of the volume of [his] disease – want to treat [him] with chemohormonal therapy if [he] had a high signature, because this is sort of a marker of an innate or inherent resistance to castration.”

For the study, Dr. Karnes and his colleagues used the Decipher Genomics Resource Information Database (GRID) to analyze gene expression profiles of primary tumors from men treated with radical prostatectomy, with or without radiation therapy, for high-risk prostate adenocarcinoma.

They developed the gene signature in 360 men and validated it in 425 men. Overall, about a third of the cohort received ADT.

During follow-up, 35% of the men developed metastases (49% of those given ADT and 29% of those not given ADT), according to data reported in a poster session at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

In Kaplan-Meier analysis among men treated with ADT, those with a high ADT resistance signature were more likely to develop metastases (P = .03). In contrast, among men not treated with ADT, the signature did not predict this outcome.

In a multivariate analysis, a high ADT resistance signature was associated with an elevated risk of metastases for men given ADT even after taking into account a variety of clinicopathologic features, surgical margin status, and receipt of various treatments (hazard ratio, 1.71; P = .02).

SAN FRANCISCO – Hypofractionated radiation therapy, which delivers fewer, larger fractions relative to conventional radiation therapy, can be considered a new standard of care for localized prostate cancer, according to a pair of phase III noninferiority randomized trials reported at the Genitourinary Cancers Symposium.

The Radiation Therapy Oncology Group’s 0415 trial, conducted among men with low-risk disease, found that the 5-year rate of disease-free survival with a 70-Gy hypofractionated regimen was noninferior to that with a conventional regimen (86% vs. 85%). And a trial conducted by the U.K. CHHiP Trial Management Group among men with mainly intermediate-risk disease found that the 5-year rate of freedom from biochemical failure or prostate cancer recurrence with a 60-Gy hypofractionated regimen was noninferior to that with a conventional regimen (90.6% vs. 88.3%).

The trade-offs were small increases in the rates of some gastrointestinal and genitourinary toxicities with the hypofractionated regimens.

“Both of these trials now clearly establish that modest hypofractionated regimens are noninferior for biochemical failure, with modest to no change in toxicity. This is probably ready for prime time,” contended invited discussant Dr. Daniel A. Hamstra, a radiation oncologist with Texas Oncology in Irving. “Hypofractionation provides a cost- and resource-effective treatment that is easier and more convenient for patients.”

Among the points yet to be ironed out are identification of the optimal regimen and implementation of hypofractionation in the United States, he noted; uptake of hypofractionated radiation therapy in breast cancer has been slow, even though research there is about 5 to 10 years ahead of that in prostate cancer. “It will be intriguing to see what happens in the United States, whether or not this type of modest hypofractionation takes off,” he said at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

RTOG 0415 trial

In the first trial, NRG Oncology’s RTOG 0415, investigators led by Dr. W. Robert Lee, a radiation oncologist at Duke University, Durham, N.C., randomized 1,115 men with low-risk prostate cancer to a conventional regimen (73.8 Gy given in 41 fractions over 8.2 weeks) or a hypofractionated regimen (70 Gy given in 28 fractions over 5.6 weeks). None received androgen suppression.

With a median follow-up of 5.8 years, the 5-year rate of disease-free survival (the trial’s primary endpoint) was 85% with conventional radiation therapy and 86% with hypofractionated radiation therapy. The absolute difference of 1% and the hazard ratio of 0.85 in favor of hypofractionation fell well within the predefined noninferiority margins of 7.65%, and 1.52, respectively.

The 5-year rates of biochemical recurrence were 8% with conventional radiation and 6% with hypofractionated radiation (hazard ratio, 0.77).

The two regimens did not differ significantly with respect to the rates of grade 3 or 4 early gastrointestinal and genitourinary adverse events. The hypofractionated regimen was associated with a higher rate of late gastrointestinal adverse events (P = .002), driven by more grade 2 events (18.3% vs. 11.4%), and a trend toward a higher rate of late genitourinary adverse events (P = .06), also driven mainly by more grade 2 events (26.2% vs. 20.5%).

“In men with low-risk prostate cancer, 70 Gy in 28 fractions is not inferior to 73.8 Gy in 41 fractions, albeit with a slight increase in grade 2 GI or GU toxicity,” Dr. Lee concluded. “It will be of great interest to determine if the small increase in grade 2 toxicity is manifest in patient-reported quality of life.”

When asked by an attendee whether the evidence from the two trials is sufficient to make hypofractionation standard of care, he said, “If you have a regimen that has been demonstrated in multiple phase III studies to be better or equivalent, then that can be considered a standard of care.”

Dr. Lee speculated that concerns that 5 years is not a sufficient follow-up may stem from past events in the field. “It’s perhaps related to the worry that radiation oncology really deservedly has about large dose per fraction given our history in the ‘70s and ‘80s when we tried to do things quicker. But if you remember, those toxicities were seen very early,” he elaborated.

“And my question back is, how many patients for how long do you need?” he said, given the more than 4,000 patients with 5-year follow-up in the two trials reported, plus an additional 1,700 expected from a similar Canadian study shortly. “How many patients are enough? Do you need 10,000 patients for 15 years?”

CHHiP trial

In the second trial – Conventional or Hypofractionated High-Dose, Intensity-Modulated Radiotherapy for Prostate Cancer (CHHiP) – Dr. David P. Dearnaley, leader of the Clinical Academic Radiotherapy Team at the Institute of Cancer Research, London, and his colleagues studied 3,216 men who predominantly had intermediate-risk disease, most of whom first received hormone treatment.

They were randomized evenly to three radiation therapy regimens: a conventional regimen of 74 Gy in 37 fractions over 7.4 weeks, a hypofractionated regimen of 60 Gy in 20 fractions over 4 weeks, or a hypofractionated regimen of 57 Gy in 19 fractions over 3.8 weeks.

With a median follow-up of 62 months, the 5-year rate of freedom from biochemical failure or prostate cancer recurrence was 88.3% with the conventional regimen, 90.6% with the 60-Gy hypofractionated regimen, and 85.9% with the 57-Gy hypofractionated regimen.

Compared with the conventional regimen, the 60-Gy hypofractionated schedule yielded a hazard ratio of 0.84, which fell well within the predefined hazard ratio of 1.208 for noninferiority (P = .004). In contrast, the 57-Gy hypofractionated schedule yielded a hazard ratio of 1.20, which was inconclusive.

When the two hypofractionated regimens were compared with each other, the 57-Gy one was inferior to the 60-Gy one, yielding a higher risk of biochemical failure or prostate cancer recurrence (HR, 1.44; P = .003).

Results for prostate cancer mortality and all-cause mortality did not differ significantly, but numbers of events were fairly small, so “we’ll have to wait and see,” Dr. Dearnaley said.

The three regimens yielded similar rates of acute bladder toxicity of various grades, but the timing of the peak rate was earlier with hypofractionation. In contrast, acute bowel toxicity occurred not only earlier, but also at higher rates (P less than .001) with the hypofractionated regimens.

At 5 years, late bowel toxicity with the hypofractionated regimens did not differ from that with the conventional regimen; however, comparing the hypofractionation regimens, the 60-Gy one yielded a higher rate than the 57-Gy one. Similarly, for late bladder toxicity, the rate of grade 2 or worse events was higher with 60 Gy.

The trial population was somewhat heterogeneous, Dr. Dearnaley acknowledged. “We will be doing a multivariate analysis to look at all of these very detailed histopathological features, in addition to a translational study where we want to look at molecular characterization of these patients. We’ve got biopsies on most of them for that.”

“We believe that modest hypofractionation using 60 Gy in 20 fractions delivered with high-quality radiotherapy techniques can now be recommended as a new standard of care in patients with this type of intermediate- and low- and high-risk cancer,” he concluded.

“As we move toward image-guided radiotherapy – and I don’t mean just by using fiducials, I mean by using the MR scans – we can start to boost dominant lesions. And I think the effectiveness of 57 Gy in treating lower amounts of volume of cancer within the prostate may mean that we can get the best therapeutic ratio by lowering the dose a little bit to 57 Gy, but boosting our dominant lesions,” Dr. Dearnaley added.

He agreed with Dr. Lee that collectively, the findings at 5 years of follow-up are sufficient to propel hypofractionation into standard of care, noting that trials of dose escalation show that the hazard ratio for biochemical control remains stable between 5 and 10 years. Additionally, in his opinion, survival is not the right endpoint when it comes to investigating fractionation.

“So because the [prostate-specific antigen] data is robust and I don’t think that’s going to change, the critical issue is actually that of side effects. You can get late, late side effects, and I do think we have to be a little bit cautious about those,” Dr. Dearnaley said, although data from the first patients enrolled in CHHiP in 2001 have not raised any concerns.

“My view is the evidence is sufficiently robust in that large number of patients to change practice now,” he concluded.

SAN FRANCISCO – Hypofractionated radiation therapy, which delivers fewer, larger fractions relative to conventional radiation therapy, can be considered a new standard of care for localized prostate cancer, according to a pair of phase III noninferiority randomized trials reported at the Genitourinary Cancers Symposium.

The Radiation Therapy Oncology Group’s 0415 trial, conducted among men with low-risk disease, found that the 5-year rate of disease-free survival with a 70-Gy hypofractionated regimen was noninferior to that with a conventional regimen (86% vs. 85%). And a trial conducted by the U.K. CHHiP Trial Management Group among men with mainly intermediate-risk disease found that the 5-year rate of freedom from biochemical failure or prostate cancer recurrence with a 60-Gy hypofractionated regimen was noninferior to that with a conventional regimen (90.6% vs. 88.3%).

The trade-offs were small increases in the rates of some gastrointestinal and genitourinary toxicities with the hypofractionated regimens.

“Both of these trials now clearly establish that modest hypofractionated regimens are noninferior for biochemical failure, with modest to no change in toxicity. This is probably ready for prime time,” contended invited discussant Dr. Daniel A. Hamstra, a radiation oncologist with Texas Oncology in Irving. “Hypofractionation provides a cost- and resource-effective treatment that is easier and more convenient for patients.”

Among the points yet to be ironed out are identification of the optimal regimen and implementation of hypofractionation in the United States, he noted; uptake of hypofractionated radiation therapy in breast cancer has been slow, even though research there is about 5 to 10 years ahead of that in prostate cancer. “It will be intriguing to see what happens in the United States, whether or not this type of modest hypofractionation takes off,” he said at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

RTOG 0415 trial

In the first trial, NRG Oncology’s RTOG 0415, investigators led by Dr. W. Robert Lee, a radiation oncologist at Duke University, Durham, N.C., randomized 1,115 men with low-risk prostate cancer to a conventional regimen (73.8 Gy given in 41 fractions over 8.2 weeks) or a hypofractionated regimen (70 Gy given in 28 fractions over 5.6 weeks). None received androgen suppression.

With a median follow-up of 5.8 years, the 5-year rate of disease-free survival (the trial’s primary endpoint) was 85% with conventional radiation therapy and 86% with hypofractionated radiation therapy. The absolute difference of 1% and the hazard ratio of 0.85 in favor of hypofractionation fell well within the predefined noninferiority margins of 7.65%, and 1.52, respectively.

The 5-year rates of biochemical recurrence were 8% with conventional radiation and 6% with hypofractionated radiation (hazard ratio, 0.77).

The two regimens did not differ significantly with respect to the rates of grade 3 or 4 early gastrointestinal and genitourinary adverse events. The hypofractionated regimen was associated with a higher rate of late gastrointestinal adverse events (P = .002), driven by more grade 2 events (18.3% vs. 11.4%), and a trend toward a higher rate of late genitourinary adverse events (P = .06), also driven mainly by more grade 2 events (26.2% vs. 20.5%).

“In men with low-risk prostate cancer, 70 Gy in 28 fractions is not inferior to 73.8 Gy in 41 fractions, albeit with a slight increase in grade 2 GI or GU toxicity,” Dr. Lee concluded. “It will be of great interest to determine if the small increase in grade 2 toxicity is manifest in patient-reported quality of life.”

When asked by an attendee whether the evidence from the two trials is sufficient to make hypofractionation standard of care, he said, “If you have a regimen that has been demonstrated in multiple phase III studies to be better or equivalent, then that can be considered a standard of care.”

Dr. Lee speculated that concerns that 5 years is not a sufficient follow-up may stem from past events in the field. “It’s perhaps related to the worry that radiation oncology really deservedly has about large dose per fraction given our history in the ‘70s and ‘80s when we tried to do things quicker. But if you remember, those toxicities were seen very early,” he elaborated.

“And my question back is, how many patients for how long do you need?” he said, given the more than 4,000 patients with 5-year follow-up in the two trials reported, plus an additional 1,700 expected from a similar Canadian study shortly. “How many patients are enough? Do you need 10,000 patients for 15 years?”

CHHiP trial

In the second trial – Conventional or Hypofractionated High-Dose, Intensity-Modulated Radiotherapy for Prostate Cancer (CHHiP) – Dr. David P. Dearnaley, leader of the Clinical Academic Radiotherapy Team at the Institute of Cancer Research, London, and his colleagues studied 3,216 men who predominantly had intermediate-risk disease, most of whom first received hormone treatment.

They were randomized evenly to three radiation therapy regimens: a conventional regimen of 74 Gy in 37 fractions over 7.4 weeks, a hypofractionated regimen of 60 Gy in 20 fractions over 4 weeks, or a hypofractionated regimen of 57 Gy in 19 fractions over 3.8 weeks.

With a median follow-up of 62 months, the 5-year rate of freedom from biochemical failure or prostate cancer recurrence was 88.3% with the conventional regimen, 90.6% with the 60-Gy hypofractionated regimen, and 85.9% with the 57-Gy hypofractionated regimen.

Compared with the conventional regimen, the 60-Gy hypofractionated schedule yielded a hazard ratio of 0.84, which fell well within the predefined hazard ratio of 1.208 for noninferiority (P = .004). In contrast, the 57-Gy hypofractionated schedule yielded a hazard ratio of 1.20, which was inconclusive.

When the two hypofractionated regimens were compared with each other, the 57-Gy one was inferior to the 60-Gy one, yielding a higher risk of biochemical failure or prostate cancer recurrence (HR, 1.44; P = .003).

Results for prostate cancer mortality and all-cause mortality did not differ significantly, but numbers of events were fairly small, so “we’ll have to wait and see,” Dr. Dearnaley said.

The three regimens yielded similar rates of acute bladder toxicity of various grades, but the timing of the peak rate was earlier with hypofractionation. In contrast, acute bowel toxicity occurred not only earlier, but also at higher rates (P less than .001) with the hypofractionated regimens.

At 5 years, late bowel toxicity with the hypofractionated regimens did not differ from that with the conventional regimen; however, comparing the hypofractionation regimens, the 60-Gy one yielded a higher rate than the 57-Gy one. Similarly, for late bladder toxicity, the rate of grade 2 or worse events was higher with 60 Gy.

The trial population was somewhat heterogeneous, Dr. Dearnaley acknowledged. “We will be doing a multivariate analysis to look at all of these very detailed histopathological features, in addition to a translational study where we want to look at molecular characterization of these patients. We’ve got biopsies on most of them for that.”

“We believe that modest hypofractionation using 60 Gy in 20 fractions delivered with high-quality radiotherapy techniques can now be recommended as a new standard of care in patients with this type of intermediate- and low- and high-risk cancer,” he concluded.

“As we move toward image-guided radiotherapy – and I don’t mean just by using fiducials, I mean by using the MR scans – we can start to boost dominant lesions. And I think the effectiveness of 57 Gy in treating lower amounts of volume of cancer within the prostate may mean that we can get the best therapeutic ratio by lowering the dose a little bit to 57 Gy, but boosting our dominant lesions,” Dr. Dearnaley added.

He agreed with Dr. Lee that collectively, the findings at 5 years of follow-up are sufficient to propel hypofractionation into standard of care, noting that trials of dose escalation show that the hazard ratio for biochemical control remains stable between 5 and 10 years. Additionally, in his opinion, survival is not the right endpoint when it comes to investigating fractionation.

“So because the [prostate-specific antigen] data is robust and I don’t think that’s going to change, the critical issue is actually that of side effects. You can get late, late side effects, and I do think we have to be a little bit cautious about those,” Dr. Dearnaley said, although data from the first patients enrolled in CHHiP in 2001 have not raised any concerns.

“My view is the evidence is sufficiently robust in that large number of patients to change practice now,” he concluded.

SAN FRANCISCO – Hypofractionated radiation therapy, which delivers fewer, larger fractions relative to conventional radiation therapy, can be considered a new standard of care for localized prostate cancer, according to a pair of phase III noninferiority randomized trials reported at the Genitourinary Cancers Symposium.

The Radiation Therapy Oncology Group’s 0415 trial, conducted among men with low-risk disease, found that the 5-year rate of disease-free survival with a 70-Gy hypofractionated regimen was noninferior to that with a conventional regimen (86% vs. 85%). And a trial conducted by the U.K. CHHiP Trial Management Group among men with mainly intermediate-risk disease found that the 5-year rate of freedom from biochemical failure or prostate cancer recurrence with a 60-Gy hypofractionated regimen was noninferior to that with a conventional regimen (90.6% vs. 88.3%).

The trade-offs were small increases in the rates of some gastrointestinal and genitourinary toxicities with the hypofractionated regimens.

“Both of these trials now clearly establish that modest hypofractionated regimens are noninferior for biochemical failure, with modest to no change in toxicity. This is probably ready for prime time,” contended invited discussant Dr. Daniel A. Hamstra, a radiation oncologist with Texas Oncology in Irving. “Hypofractionation provides a cost- and resource-effective treatment that is easier and more convenient for patients.”

Among the points yet to be ironed out are identification of the optimal regimen and implementation of hypofractionation in the United States, he noted; uptake of hypofractionated radiation therapy in breast cancer has been slow, even though research there is about 5 to 10 years ahead of that in prostate cancer. “It will be intriguing to see what happens in the United States, whether or not this type of modest hypofractionation takes off,” he said at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

RTOG 0415 trial

In the first trial, NRG Oncology’s RTOG 0415, investigators led by Dr. W. Robert Lee, a radiation oncologist at Duke University, Durham, N.C., randomized 1,115 men with low-risk prostate cancer to a conventional regimen (73.8 Gy given in 41 fractions over 8.2 weeks) or a hypofractionated regimen (70 Gy given in 28 fractions over 5.6 weeks). None received androgen suppression.

With a median follow-up of 5.8 years, the 5-year rate of disease-free survival (the trial’s primary endpoint) was 85% with conventional radiation therapy and 86% with hypofractionated radiation therapy. The absolute difference of 1% and the hazard ratio of 0.85 in favor of hypofractionation fell well within the predefined noninferiority margins of 7.65%, and 1.52, respectively.

The 5-year rates of biochemical recurrence were 8% with conventional radiation and 6% with hypofractionated radiation (hazard ratio, 0.77).

The two regimens did not differ significantly with respect to the rates of grade 3 or 4 early gastrointestinal and genitourinary adverse events. The hypofractionated regimen was associated with a higher rate of late gastrointestinal adverse events (P = .002), driven by more grade 2 events (18.3% vs. 11.4%), and a trend toward a higher rate of late genitourinary adverse events (P = .06), also driven mainly by more grade 2 events (26.2% vs. 20.5%).

“In men with low-risk prostate cancer, 70 Gy in 28 fractions is not inferior to 73.8 Gy in 41 fractions, albeit with a slight increase in grade 2 GI or GU toxicity,” Dr. Lee concluded. “It will be of great interest to determine if the small increase in grade 2 toxicity is manifest in patient-reported quality of life.”

When asked by an attendee whether the evidence from the two trials is sufficient to make hypofractionation standard of care, he said, “If you have a regimen that has been demonstrated in multiple phase III studies to be better or equivalent, then that can be considered a standard of care.”

Dr. Lee speculated that concerns that 5 years is not a sufficient follow-up may stem from past events in the field. “It’s perhaps related to the worry that radiation oncology really deservedly has about large dose per fraction given our history in the ‘70s and ‘80s when we tried to do things quicker. But if you remember, those toxicities were seen very early,” he elaborated.

“And my question back is, how many patients for how long do you need?” he said, given the more than 4,000 patients with 5-year follow-up in the two trials reported, plus an additional 1,700 expected from a similar Canadian study shortly. “How many patients are enough? Do you need 10,000 patients for 15 years?”

CHHiP trial

In the second trial – Conventional or Hypofractionated High-Dose, Intensity-Modulated Radiotherapy for Prostate Cancer (CHHiP) – Dr. David P. Dearnaley, leader of the Clinical Academic Radiotherapy Team at the Institute of Cancer Research, London, and his colleagues studied 3,216 men who predominantly had intermediate-risk disease, most of whom first received hormone treatment.

They were randomized evenly to three radiation therapy regimens: a conventional regimen of 74 Gy in 37 fractions over 7.4 weeks, a hypofractionated regimen of 60 Gy in 20 fractions over 4 weeks, or a hypofractionated regimen of 57 Gy in 19 fractions over 3.8 weeks.

With a median follow-up of 62 months, the 5-year rate of freedom from biochemical failure or prostate cancer recurrence was 88.3% with the conventional regimen, 90.6% with the 60-Gy hypofractionated regimen, and 85.9% with the 57-Gy hypofractionated regimen.

Compared with the conventional regimen, the 60-Gy hypofractionated schedule yielded a hazard ratio of 0.84, which fell well within the predefined hazard ratio of 1.208 for noninferiority (P = .004). In contrast, the 57-Gy hypofractionated schedule yielded a hazard ratio of 1.20, which was inconclusive.

When the two hypofractionated regimens were compared with each other, the 57-Gy one was inferior to the 60-Gy one, yielding a higher risk of biochemical failure or prostate cancer recurrence (HR, 1.44; P = .003).

Results for prostate cancer mortality and all-cause mortality did not differ significantly, but numbers of events were fairly small, so “we’ll have to wait and see,” Dr. Dearnaley said.

The three regimens yielded similar rates of acute bladder toxicity of various grades, but the timing of the peak rate was earlier with hypofractionation. In contrast, acute bowel toxicity occurred not only earlier, but also at higher rates (P less than .001) with the hypofractionated regimens.

At 5 years, late bowel toxicity with the hypofractionated regimens did not differ from that with the conventional regimen; however, comparing the hypofractionation regimens, the 60-Gy one yielded a higher rate than the 57-Gy one. Similarly, for late bladder toxicity, the rate of grade 2 or worse events was higher with 60 Gy.

The trial population was somewhat heterogeneous, Dr. Dearnaley acknowledged. “We will be doing a multivariate analysis to look at all of these very detailed histopathological features, in addition to a translational study where we want to look at molecular characterization of these patients. We’ve got biopsies on most of them for that.”

“We believe that modest hypofractionation using 60 Gy in 20 fractions delivered with high-quality radiotherapy techniques can now be recommended as a new standard of care in patients with this type of intermediate- and low- and high-risk cancer,” he concluded.

“As we move toward image-guided radiotherapy – and I don’t mean just by using fiducials, I mean by using the MR scans – we can start to boost dominant lesions. And I think the effectiveness of 57 Gy in treating lower amounts of volume of cancer within the prostate may mean that we can get the best therapeutic ratio by lowering the dose a little bit to 57 Gy, but boosting our dominant lesions,” Dr. Dearnaley added.

He agreed with Dr. Lee that collectively, the findings at 5 years of follow-up are sufficient to propel hypofractionation into standard of care, noting that trials of dose escalation show that the hazard ratio for biochemical control remains stable between 5 and 10 years. Additionally, in his opinion, survival is not the right endpoint when it comes to investigating fractionation.

“So because the [prostate-specific antigen] data is robust and I don’t think that’s going to change, the critical issue is actually that of side effects. You can get late, late side effects, and I do think we have to be a little bit cautious about those,” Dr. Dearnaley said, although data from the first patients enrolled in CHHiP in 2001 have not raised any concerns.

“My view is the evidence is sufficiently robust in that large number of patients to change practice now,” he concluded.

SAN FRANCISCO – Men who undergo treatment for metastatic testicular cancer and are alive and disease free a few years later have an excellent prognosis, regardless of their initial risk group, and don’t need CT surveillance, new data suggest.

In the apparent first conditional survival analysis to stratify adult patients according to the International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification system, investigators led by Dr. Jenny J. Ko studied 942 men with this cancer treated over a 22-year period.

Results reported at the 2016 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology showed that those who were still alive and free of disease at 2 years after diagnosis had a 98%-99% probability of remaining so over the next 2 years.

“This study has implications for survivorship, including counseling of patients; applying for life, disability, or medical insurance; and determining the frequency of surveillance imaging post therapy,” said Dr. Ko of the British Columbia Cancer Agency, Abbotsford. “Our study provides support for no further routine CT imaging beyond 2 years post first-line curative treatment in this patient population, which is consistent with the [National Comprehensive Cancer Network] guideline,” she said.

In additional findings, the patients had better outcomes than those seen in the original study used to derive the IGCCCG risk classification system nearly two decades ago (J Clin Oncol. 1997;15:594-603). This improvement “may be due to the better supportive care, standardized use of modern chemotherapy regimens, and better risk stratification in the contemporary cohort,” she proposed.

Invited discussant Dr. Christian K. Kollmannsberger, a medical oncologist with the BC Cancer Agency’s Vancouver Cancer Centre and the University of British Columbia, Vancouver, noted that the findings are consistent with those of other contemporary studies in this patient population, showing that most relapses occur in the first 2 years and that outcomes have improved in recent years.

The NCCN guidelines therefore endorse a lower frequency of clinical exams and imaging after 2 years, “but I think the other guidelines need to follow, and we need to really adopt our guidelines based on the results we have and lighten the burden for our patients,” he maintained.

Additionally, the overall better outcomes for patients in the contemporary era should be taken into consideration when designing new trials, according to Dr. Kollmannsberger.

“We have had numerous discussions in the past how to best statistically design our first-line trials. Should we use the IGCCCG classification data or not? And I think it’s time to move away from that and to use the updated data in order to design the appropriate trial,” he said, adding that the risk classification system is being revised to incorporate new data.

In their study, Dr. Ko and her colleagues reviewed the charts of men with a diagnosis of metastatic testicular germ cell tumors treated at five tertiary cancer centers in Canada, the United States, and Australia between 1990 and 2012.

At increments of 6 months (corresponding to typical assessment time points in men receiving first-line therapy), they calculated the probability of subsequently remaining alive among survivors and the probability of subsequently remaining alive without disease among survivors who had not experienced relapse.

Results for the entire population showed that, with a median follow-up of 99 months, the 5-year rate of overall survival was 95%, 93%, and 64% among patients with, respectively, favorable-, intermediate-, and poor-risk disease at diagnosis according to IGCCCG criteria, she reported. The corresponding disease-free survival rates were 88%, 81%, and 54%.

At baseline, the 2-year conditional overall survival was 97%, 94%, and 71% in patients with favorable-, intermediate-, and poor-risk disease, respectively. The differences diminished over time, and by 2 years out, corresponding values were 99%, 99%, and 93%, and no longer significantly different.

Similarly, at baseline, the 2-year conditional disease-free survival rate was 91%, 84%, and 55% in patients with favorable-, intermediate-, and poor-risk disease, respectively. By 2 years out, it was 98%, 99%, and 98%.

Findings were similar for men with seminoma and with nonseminoma tumor types.

Dr. Ko disclosed that she had no relevant conflicts of interest. Dr. Kollmannsberger disclosed that he receives honoraria from Bristol-Myers Squibb, Novartis, and Pfizer, and that he has consulting or advisory roles with Bristol-Myers Squibb, Novartis, Pfizer, and Seattle Genetics.

SAN FRANCISCO – Men who undergo treatment for metastatic testicular cancer and are alive and disease free a few years later have an excellent prognosis, regardless of their initial risk group, and don’t need CT surveillance, new data suggest.

In the apparent first conditional survival analysis to stratify adult patients according to the International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification system, investigators led by Dr. Jenny J. Ko studied 942 men with this cancer treated over a 22-year period.

Results reported at the 2016 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology showed that those who were still alive and free of disease at 2 years after diagnosis had a 98%-99% probability of remaining so over the next 2 years.

“This study has implications for survivorship, including counseling of patients; applying for life, disability, or medical insurance; and determining the frequency of surveillance imaging post therapy,” said Dr. Ko of the British Columbia Cancer Agency, Abbotsford. “Our study provides support for no further routine CT imaging beyond 2 years post first-line curative treatment in this patient population, which is consistent with the [National Comprehensive Cancer Network] guideline,” she said.

In additional findings, the patients had better outcomes than those seen in the original study used to derive the IGCCCG risk classification system nearly two decades ago (J Clin Oncol. 1997;15:594-603). This improvement “may be due to the better supportive care, standardized use of modern chemotherapy regimens, and better risk stratification in the contemporary cohort,” she proposed.

Invited discussant Dr. Christian K. Kollmannsberger, a medical oncologist with the BC Cancer Agency’s Vancouver Cancer Centre and the University of British Columbia, Vancouver, noted that the findings are consistent with those of other contemporary studies in this patient population, showing that most relapses occur in the first 2 years and that outcomes have improved in recent years.

The NCCN guidelines therefore endorse a lower frequency of clinical exams and imaging after 2 years, “but I think the other guidelines need to follow, and we need to really adopt our guidelines based on the results we have and lighten the burden for our patients,” he maintained.

Additionally, the overall better outcomes for patients in the contemporary era should be taken into consideration when designing new trials, according to Dr. Kollmannsberger.

“We have had numerous discussions in the past how to best statistically design our first-line trials. Should we use the IGCCCG classification data or not? And I think it’s time to move away from that and to use the updated data in order to design the appropriate trial,” he said, adding that the risk classification system is being revised to incorporate new data.

In their study, Dr. Ko and her colleagues reviewed the charts of men with a diagnosis of metastatic testicular germ cell tumors treated at five tertiary cancer centers in Canada, the United States, and Australia between 1990 and 2012.

At increments of 6 months (corresponding to typical assessment time points in men receiving first-line therapy), they calculated the probability of subsequently remaining alive among survivors and the probability of subsequently remaining alive without disease among survivors who had not experienced relapse.

Results for the entire population showed that, with a median follow-up of 99 months, the 5-year rate of overall survival was 95%, 93%, and 64% among patients with, respectively, favorable-, intermediate-, and poor-risk disease at diagnosis according to IGCCCG criteria, she reported. The corresponding disease-free survival rates were 88%, 81%, and 54%.

At baseline, the 2-year conditional overall survival was 97%, 94%, and 71% in patients with favorable-, intermediate-, and poor-risk disease, respectively. The differences diminished over time, and by 2 years out, corresponding values were 99%, 99%, and 93%, and no longer significantly different.

Similarly, at baseline, the 2-year conditional disease-free survival rate was 91%, 84%, and 55% in patients with favorable-, intermediate-, and poor-risk disease, respectively. By 2 years out, it was 98%, 99%, and 98%.

Findings were similar for men with seminoma and with nonseminoma tumor types.

Dr. Ko disclosed that she had no relevant conflicts of interest. Dr. Kollmannsberger disclosed that he receives honoraria from Bristol-Myers Squibb, Novartis, and Pfizer, and that he has consulting or advisory roles with Bristol-Myers Squibb, Novartis, Pfizer, and Seattle Genetics.

SAN FRANCISCO – Men who undergo treatment for metastatic testicular cancer and are alive and disease free a few years later have an excellent prognosis, regardless of their initial risk group, and don’t need CT surveillance, new data suggest.

In the apparent first conditional survival analysis to stratify adult patients according to the International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification system, investigators led by Dr. Jenny J. Ko studied 942 men with this cancer treated over a 22-year period.

Results reported at the 2016 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology showed that those who were still alive and free of disease at 2 years after diagnosis had a 98%-99% probability of remaining so over the next 2 years.

“This study has implications for survivorship, including counseling of patients; applying for life, disability, or medical insurance; and determining the frequency of surveillance imaging post therapy,” said Dr. Ko of the British Columbia Cancer Agency, Abbotsford. “Our study provides support for no further routine CT imaging beyond 2 years post first-line curative treatment in this patient population, which is consistent with the [National Comprehensive Cancer Network] guideline,” she said.

In additional findings, the patients had better outcomes than those seen in the original study used to derive the IGCCCG risk classification system nearly two decades ago (J Clin Oncol. 1997;15:594-603). This improvement “may be due to the better supportive care, standardized use of modern chemotherapy regimens, and better risk stratification in the contemporary cohort,” she proposed.

Invited discussant Dr. Christian K. Kollmannsberger, a medical oncologist with the BC Cancer Agency’s Vancouver Cancer Centre and the University of British Columbia, Vancouver, noted that the findings are consistent with those of other contemporary studies in this patient population, showing that most relapses occur in the first 2 years and that outcomes have improved in recent years.

The NCCN guidelines therefore endorse a lower frequency of clinical exams and imaging after 2 years, “but I think the other guidelines need to follow, and we need to really adopt our guidelines based on the results we have and lighten the burden for our patients,” he maintained.

Additionally, the overall better outcomes for patients in the contemporary era should be taken into consideration when designing new trials, according to Dr. Kollmannsberger.

“We have had numerous discussions in the past how to best statistically design our first-line trials. Should we use the IGCCCG classification data or not? And I think it’s time to move away from that and to use the updated data in order to design the appropriate trial,” he said, adding that the risk classification system is being revised to incorporate new data.

In their study, Dr. Ko and her colleagues reviewed the charts of men with a diagnosis of metastatic testicular germ cell tumors treated at five tertiary cancer centers in Canada, the United States, and Australia between 1990 and 2012.

At increments of 6 months (corresponding to typical assessment time points in men receiving first-line therapy), they calculated the probability of subsequently remaining alive among survivors and the probability of subsequently remaining alive without disease among survivors who had not experienced relapse.

Results for the entire population showed that, with a median follow-up of 99 months, the 5-year rate of overall survival was 95%, 93%, and 64% among patients with, respectively, favorable-, intermediate-, and poor-risk disease at diagnosis according to IGCCCG criteria, she reported. The corresponding disease-free survival rates were 88%, 81%, and 54%.

At baseline, the 2-year conditional overall survival was 97%, 94%, and 71% in patients with favorable-, intermediate-, and poor-risk disease, respectively. The differences diminished over time, and by 2 years out, corresponding values were 99%, 99%, and 93%, and no longer significantly different.

Similarly, at baseline, the 2-year conditional disease-free survival rate was 91%, 84%, and 55% in patients with favorable-, intermediate-, and poor-risk disease, respectively. By 2 years out, it was 98%, 99%, and 98%.

Findings were similar for men with seminoma and with nonseminoma tumor types.

Dr. Ko disclosed that she had no relevant conflicts of interest. Dr. Kollmannsberger disclosed that he receives honoraria from Bristol-Myers Squibb, Novartis, and Pfizer, and that he has consulting or advisory roles with Bristol-Myers Squibb, Novartis, Pfizer, and Seattle Genetics.

SAN FRANCISCO – Men with metastatic hormone-naive prostate cancer have better outcomes when given the nonsteroidal anti-inflammatory drug celecoxib and the bisphosphonate zoledronic acid in addition to standard therapy, according to data from the randomized STAMPEDE trial.

The 1,245 men treated on three trial arms had high-risk locally advanced or metastatic prostate cancer and had not previously received any hormone therapy.

Prespecified analyses showed that when added to standard of care (androgen deprivation therapy and, optionally, radiation therapy), neither celecoxib alone nor the combination of celecoxib and zoledronic acid improved outcomes in the entire trial population, Dr. Nicholas D. James reported at the 2016 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology. But among men who had metastases at baseline, the combination reduced the risk of failure-free survival events by 23% and the risk of death by 24%.

“At the very least, we feel that this data merits further evaluation, particularly as these drugs are widely used and widely available,” commented Dr. James, director of the cancer research unit at the University of Warwick, Coventry, England.

The findings help provide a big picture when viewed together with those from previously reported STAMPEDE trial arms that tested addition of docetaxel (found effective) and of zoledronic acid alone (found ineffective), he noted (Lancet. 2015 Dec 21).

“It does look as though there is a possibility of [a] synergistic or an additive effect here” of celecoxib and zoledronic acid in the patients with metastases, he said. Also, the magnitude of benefit with the combination was similar to that of docetaxel when it came to overall survival, albeit somewhat less when it came to failure-free survival.

Invited discussant Dr. A. Oliver Sartor, the Laborde Professor for Cancer Research and medical director at the Tulane Cancer Center in New Orleans, commented, “We now know from a number of studies that docetaxel and ADT [androgen deprivation therapy] prolong survival, and I believe it should be the standard of care for ‘chemo-fit’ patients with metastatic hormone-sensitive disease.”

Implications of the new findings are unclear, he said. “Neither zoledronic acid nor celecoxib is standard of care today within these hormone-sensitive patients, and I just suspect this combination is unlikely to become standard of care going forward.” In particular, celecoxib has a black box warning for cardiovascular events, which makes its use problematic in the litigious U.S. environment.

At the end of the day, there are likely higher-priority research questions to be addressed in hormone-sensitive disease, according to Dr. Sartor. “Abiraterone, enzalutamide, and radium all need testing,” he said. “And from a global perspective, this disease state is incredibly important. North America and Western Europe are not really the center of the universe. There are lots of people out there who get diagnosed with hormone-sensitive metastatic disease, and they need better therapies than ADT, which is the standard worldwide.”

Giving some background to the research, Dr. James explained that zoledronic acid (Zometa) was chosen because it is known to reduce skeletal-related events in men with bone metastases of castration-refractory disease and was being studied for prevention of metastases. Celecoxib (Celebrex) was chosen in part because it inhibits cyclo-oxygenase-2 (COX-2), which is associated with tumor growth and invasiveness, along with epidemiologic data linking use of nonsteroidal anti-inflammatory drugs with lower prostate cancer risk.

The new analyses were based on 622 men who received only standard of care, 312 who additionally received celecoxib, and 311 who additionally received celecoxib plus zoledronic acid. Overall, 61% had metastases at baseline.

With a median follow-up of 63 months, 55% of men were alive, 36% had died of prostate cancer, and 9% had died of other causes, Dr. James reported.

The addition of celecoxib alone did not improve failure-free survival or overall survival, compared with standard of care alone, either in the whole trial population or in the subgroups with and without metastases.

And the addition of both celecoxib and zoledronic acid did not improve either outcome in the entire trial population overall. But here, there were interaction trends according to the presence of metastases.

Patients with metastases who received celecoxib and zoledronic acid had reductions in the risks of failure-free survival events (hazard ratio, 0.77; P = .008) and overall survival events (hazard ratio, 0.78; P = .04) relative to peers who received standard of care alone. In contrast, patients without metastases did not benefit.

Adverse events of grades 3-5 occurred in about one-third of patients in each treatment arm, with no significant differences in incidence. “In particular, for cardiac disorders, there is no evidence of cardiac toxicity,” Dr. James noted. “But we had excluded patients with a significant history of MIs, heart failure, and so on, so these are patients with a good cardiovascular status going into the trial.”

In terms of salvage therapies, the three arms were essentially the same with respect to the time to first subsequent therapy post progression and the time to first life-prolonging therapy. And among the patients receiving life-prolonging therapies, there was similar exposure to various agents, such as docetaxel and abiraterone.

Dr. James and Dr. Sartor disclosed that they receive honoraria and/or have consulting or advisory roles with numerous pharmaceutical companies.

SAN FRANCISCO – Men with metastatic hormone-naive prostate cancer have better outcomes when given the nonsteroidal anti-inflammatory drug celecoxib and the bisphosphonate zoledronic acid in addition to standard therapy, according to data from the randomized STAMPEDE trial.

The 1,245 men treated on three trial arms had high-risk locally advanced or metastatic prostate cancer and had not previously received any hormone therapy.

Prespecified analyses showed that when added to standard of care (androgen deprivation therapy and, optionally, radiation therapy), neither celecoxib alone nor the combination of celecoxib and zoledronic acid improved outcomes in the entire trial population, Dr. Nicholas D. James reported at the 2016 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology. But among men who had metastases at baseline, the combination reduced the risk of failure-free survival events by 23% and the risk of death by 24%.

“At the very least, we feel that this data merits further evaluation, particularly as these drugs are widely used and widely available,” commented Dr. James, director of the cancer research unit at the University of Warwick, Coventry, England.

The findings help provide a big picture when viewed together with those from previously reported STAMPEDE trial arms that tested addition of docetaxel (found effective) and of zoledronic acid alone (found ineffective), he noted (Lancet. 2015 Dec 21).

“It does look as though there is a possibility of [a] synergistic or an additive effect here” of celecoxib and zoledronic acid in the patients with metastases, he said. Also, the magnitude of benefit with the combination was similar to that of docetaxel when it came to overall survival, albeit somewhat less when it came to failure-free survival.

Invited discussant Dr. A. Oliver Sartor, the Laborde Professor for Cancer Research and medical director at the Tulane Cancer Center in New Orleans, commented, “We now know from a number of studies that docetaxel and ADT [androgen deprivation therapy] prolong survival, and I believe it should be the standard of care for ‘chemo-fit’ patients with metastatic hormone-sensitive disease.”

Implications of the new findings are unclear, he said. “Neither zoledronic acid nor celecoxib is standard of care today within these hormone-sensitive patients, and I just suspect this combination is unlikely to become standard of care going forward.” In particular, celecoxib has a black box warning for cardiovascular events, which makes its use problematic in the litigious U.S. environment.

At the end of the day, there are likely higher-priority research questions to be addressed in hormone-sensitive disease, according to Dr. Sartor. “Abiraterone, enzalutamide, and radium all need testing,” he said. “And from a global perspective, this disease state is incredibly important. North America and Western Europe are not really the center of the universe. There are lots of people out there who get diagnosed with hormone-sensitive metastatic disease, and they need better therapies than ADT, which is the standard worldwide.”

Giving some background to the research, Dr. James explained that zoledronic acid (Zometa) was chosen because it is known to reduce skeletal-related events in men with bone metastases of castration-refractory disease and was being studied for prevention of metastases. Celecoxib (Celebrex) was chosen in part because it inhibits cyclo-oxygenase-2 (COX-2), which is associated with tumor growth and invasiveness, along with epidemiologic data linking use of nonsteroidal anti-inflammatory drugs with lower prostate cancer risk.

The new analyses were based on 622 men who received only standard of care, 312 who additionally received celecoxib, and 311 who additionally received celecoxib plus zoledronic acid. Overall, 61% had metastases at baseline.

With a median follow-up of 63 months, 55% of men were alive, 36% had died of prostate cancer, and 9% had died of other causes, Dr. James reported.

The addition of celecoxib alone did not improve failure-free survival or overall survival, compared with standard of care alone, either in the whole trial population or in the subgroups with and without metastases.

And the addition of both celecoxib and zoledronic acid did not improve either outcome in the entire trial population overall. But here, there were interaction trends according to the presence of metastases.

Patients with metastases who received celecoxib and zoledronic acid had reductions in the risks of failure-free survival events (hazard ratio, 0.77; P = .008) and overall survival events (hazard ratio, 0.78; P = .04) relative to peers who received standard of care alone. In contrast, patients without metastases did not benefit.

Adverse events of grades 3-5 occurred in about one-third of patients in each treatment arm, with no significant differences in incidence. “In particular, for cardiac disorders, there is no evidence of cardiac toxicity,” Dr. James noted. “But we had excluded patients with a significant history of MIs, heart failure, and so on, so these are patients with a good cardiovascular status going into the trial.”

In terms of salvage therapies, the three arms were essentially the same with respect to the time to first subsequent therapy post progression and the time to first life-prolonging therapy. And among the patients receiving life-prolonging therapies, there was similar exposure to various agents, such as docetaxel and abiraterone.

Dr. James and Dr. Sartor disclosed that they receive honoraria and/or have consulting or advisory roles with numerous pharmaceutical companies.

SAN FRANCISCO – Men with metastatic hormone-naive prostate cancer have better outcomes when given the nonsteroidal anti-inflammatory drug celecoxib and the bisphosphonate zoledronic acid in addition to standard therapy, according to data from the randomized STAMPEDE trial.

The 1,245 men treated on three trial arms had high-risk locally advanced or metastatic prostate cancer and had not previously received any hormone therapy.

Prespecified analyses showed that when added to standard of care (androgen deprivation therapy and, optionally, radiation therapy), neither celecoxib alone nor the combination of celecoxib and zoledronic acid improved outcomes in the entire trial population, Dr. Nicholas D. James reported at the 2016 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology. But among men who had metastases at baseline, the combination reduced the risk of failure-free survival events by 23% and the risk of death by 24%.

“At the very least, we feel that this data merits further evaluation, particularly as these drugs are widely used and widely available,” commented Dr. James, director of the cancer research unit at the University of Warwick, Coventry, England.

The findings help provide a big picture when viewed together with those from previously reported STAMPEDE trial arms that tested addition of docetaxel (found effective) and of zoledronic acid alone (found ineffective), he noted (Lancet. 2015 Dec 21).

“It does look as though there is a possibility of [a] synergistic or an additive effect here” of celecoxib and zoledronic acid in the patients with metastases, he said. Also, the magnitude of benefit with the combination was similar to that of docetaxel when it came to overall survival, albeit somewhat less when it came to failure-free survival.

Invited discussant Dr. A. Oliver Sartor, the Laborde Professor for Cancer Research and medical director at the Tulane Cancer Center in New Orleans, commented, “We now know from a number of studies that docetaxel and ADT [androgen deprivation therapy] prolong survival, and I believe it should be the standard of care for ‘chemo-fit’ patients with metastatic hormone-sensitive disease.”

Implications of the new findings are unclear, he said. “Neither zoledronic acid nor celecoxib is standard of care today within these hormone-sensitive patients, and I just suspect this combination is unlikely to become standard of care going forward.” In particular, celecoxib has a black box warning for cardiovascular events, which makes its use problematic in the litigious U.S. environment.

At the end of the day, there are likely higher-priority research questions to be addressed in hormone-sensitive disease, according to Dr. Sartor. “Abiraterone, enzalutamide, and radium all need testing,” he said. “And from a global perspective, this disease state is incredibly important. North America and Western Europe are not really the center of the universe. There are lots of people out there who get diagnosed with hormone-sensitive metastatic disease, and they need better therapies than ADT, which is the standard worldwide.”

Giving some background to the research, Dr. James explained that zoledronic acid (Zometa) was chosen because it is known to reduce skeletal-related events in men with bone metastases of castration-refractory disease and was being studied for prevention of metastases. Celecoxib (Celebrex) was chosen in part because it inhibits cyclo-oxygenase-2 (COX-2), which is associated with tumor growth and invasiveness, along with epidemiologic data linking use of nonsteroidal anti-inflammatory drugs with lower prostate cancer risk.

The new analyses were based on 622 men who received only standard of care, 312 who additionally received celecoxib, and 311 who additionally received celecoxib plus zoledronic acid. Overall, 61% had metastases at baseline.

With a median follow-up of 63 months, 55% of men were alive, 36% had died of prostate cancer, and 9% had died of other causes, Dr. James reported.

The addition of celecoxib alone did not improve failure-free survival or overall survival, compared with standard of care alone, either in the whole trial population or in the subgroups with and without metastases.

And the addition of both celecoxib and zoledronic acid did not improve either outcome in the entire trial population overall. But here, there were interaction trends according to the presence of metastases.

Patients with metastases who received celecoxib and zoledronic acid had reductions in the risks of failure-free survival events (hazard ratio, 0.77; P = .008) and overall survival events (hazard ratio, 0.78; P = .04) relative to peers who received standard of care alone. In contrast, patients without metastases did not benefit.

Adverse events of grades 3-5 occurred in about one-third of patients in each treatment arm, with no significant differences in incidence. “In particular, for cardiac disorders, there is no evidence of cardiac toxicity,” Dr. James noted. “But we had excluded patients with a significant history of MIs, heart failure, and so on, so these are patients with a good cardiovascular status going into the trial.”

In terms of salvage therapies, the three arms were essentially the same with respect to the time to first subsequent therapy post progression and the time to first life-prolonging therapy. And among the patients receiving life-prolonging therapies, there was similar exposure to various agents, such as docetaxel and abiraterone.

Dr. James and Dr. Sartor disclosed that they receive honoraria and/or have consulting or advisory roles with numerous pharmaceutical companies.

SAN FRANCISCO – The immune checkpoint inhibitor atezolizumab is highly active and well tolerated in patients with platinum-treated advanced urothelial carcinoma and may in fact change management of this disease, according to a phase II trial reported at the 2016 Genitourinary Cancers Symposium.

The trial, IMvigor 210, was conducted in Europe, Canada, and the United States among patients who had locally advanced or metastatic urothelial carcinoma. Lead investigator Dr. Jean H. Hoffman-Censits reported findings for the trial’s second cohort, which enrolled 310 patients who had had progression on or after platinum-based chemotherapy, with no limit on the number of lines of prior therapy.

At 3-week intervals, the patients received atezolizumab, an investigational antibody that targets programmed death–ligand 1 (PD-L1), preventing it from binding to the programmed death–1 (PD-1) receptor on T cells and thereby enhancing their activity, Dr. Hoffman-Censits reported at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

The overall response rate was 15% in the entire cohort and 26% in the subset of patients whose immune cells had high expression of PD-L1 by immunohistochemistry. Values in all prespecified groups exceeded the bar of 10% that the investigators had selected on the basis of second-line trials, even though many patients in IMvigor were being treated in later lines.

Atezolizumab was well tolerated. Overall, 16% of patients experienced grade 3 or 4 treatment-related adverse events; only 4% of patients stopping treatment because of such events, reported Dr. Hoffman-Censits of the Kimmel Cancer Center, Thomas Jefferson University Hospital in Philadelphia.

“Given the current landscape of chemotherapy options for our patients with urothelial cancer progressing following platinum chemotherapy, this primary analysis of IMvigor 210 demonstrates that atezolizumab has the potential to change the standard of care for metastatic urothelial cancers,” Dr. Hoffman-Censits maintained. “Higher PD-L1 [immune cell] status was associated with higher response rates, but low PD-L1 status or poor prognostic factors did not preclude responses,” she noted.

A pair of ongoing randomized phase III trials are testing atezolizumab in metastatic urothelial carcinoma and as adjuvant therapy in muscle-invasive bladder cancer. Also, there is now an expanded-access trial for patients with platinum-treated metastatic urothelial carcinoma.

“We look forward to the results of these trials, which will continue to define the role of atezolizumab in the treatment of patients with urothelial cancers,” she concluded.

Invited discussant Dr. William Y. Kim of the Lineberger Comprehensive Cancer Center, University of North Carolina, in Chapel Hill, noted that patients given immunotherapies such as atezolizumab can experience both pseudoprogression and delayed response, which may be misclassified with the RECIST criteria used in the trial. However, it is not yet clear whether immune-related response criteria will be useful in urothelial cancers.

“In IMvigor 210, we anxiously await the results of cohort one,” he said, referring to a separate group of patients who were not eligible for platinum chemotherapy. “Follow-up regarding the durability of these responses will be needed as well.”

Atezolizumab’s mechanism of action is attractive in urothelial cancer, Dr. Hoffman-Censits noted when introducing the trial.

“By inhibiting binding of PD-L1 to PD-1 and B7.1, atezolizumab can enhance T-cell priming and reinvigorate suppressed immune cells,” she explained. “However, by leaving the interaction between PD-L2 and PD-1 intact, atezolizumab can preserve peripheral immune homeostasis. Urothelial cancers have a high mutation burden, which potentially can lead to neoantigen formation, and those [new antigens] could be recognized by the immune system.”

Three-fourths of the 310 patients studied had bladder cancer. A total of 41% had previously received two or more therapies for metastatic disease.

Immunohistochemistry showed high PD-L1 staining of immune cells (5% or more positive) in 32% of patients, intermediate staining (between 1% and 5% positive) in 35%, and low staining (less than 1% positive) in 33%.

The overall response rate according to RECIST criteria with central review was 15% in the entire cohort, 18% in patients with intermediate or high PD-L1 staining, and 26% in patients with high PD-L1 staining.

“Surprisingly, complete responses were seen in this group,” Dr. Hoffman-Censits commented. “This is a phenomenon that is incredibly rare in second-line and beyond clinical trials.”

The rate of complete response was 5% in the entire cohort, 6% in patients with intermediate or high PD-L1 staining, and 11% in patients with high PD-L1 staining. Of note, some complete responses were seen even in those with low staining.

With a median follow-up of 11.7 months, the median duration of response had not been reached; fully 84% of patients who initially had a response still had an ongoing response at the time of data cutoff. Stable disease was likewise durable.

When patients were stratified by prognostic factors, the overall response rate was highest, at 23%, among those with lymph nodes as the only site of metastases.

Median progression-free survival was 2.1 months in the entire cohort and also regardless of PD-L1 staining. Median overall survival was 7.9 months in the entire cohort; it was longer for patients with high staining (11.4 months) than for peers with intermediate or low staining (6.7 months).

The 12-month overall survival rate was 36% for the entire cohort, 30% for patients with low or intermediate staining, and 48% for patients with high staining.

“Considering 12-month overall survival estimates for second-line chemo are approximately 20%, these data are truly exciting,” Dr. Hoffman-Censits said.

Analysis of adverse events showed that atezolizumab had a favorable safety profile. In particular, there were no immune-mediated adverse events deemed to be related to treatment. 

SAN FRANCISCO – The immune checkpoint inhibitor atezolizumab is highly active and well tolerated in patients with platinum-treated advanced urothelial carcinoma and may in fact change management of this disease, according to a phase II trial reported at the 2016 Genitourinary Cancers Symposium.

The trial, IMvigor 210, was conducted in Europe, Canada, and the United States among patients who had locally advanced or metastatic urothelial carcinoma. Lead investigator Dr. Jean H. Hoffman-Censits reported findings for the trial’s second cohort, which enrolled 310 patients who had had progression on or after platinum-based chemotherapy, with no limit on the number of lines of prior therapy.

At 3-week intervals, the patients received atezolizumab, an investigational antibody that targets programmed death–ligand 1 (PD-L1), preventing it from binding to the programmed death–1 (PD-1) receptor on T cells and thereby enhancing their activity, Dr. Hoffman-Censits reported at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

The overall response rate was 15% in the entire cohort and 26% in the subset of patients whose immune cells had high expression of PD-L1 by immunohistochemistry. Values in all prespecified groups exceeded the bar of 10% that the investigators had selected on the basis of second-line trials, even though many patients in IMvigor were being treated in later lines.

Atezolizumab was well tolerated. Overall, 16% of patients experienced grade 3 or 4 treatment-related adverse events; only 4% of patients stopping treatment because of such events, reported Dr. Hoffman-Censits of the Kimmel Cancer Center, Thomas Jefferson University Hospital in Philadelphia.

“Given the current landscape of chemotherapy options for our patients with urothelial cancer progressing following platinum chemotherapy, this primary analysis of IMvigor 210 demonstrates that atezolizumab has the potential to change the standard of care for metastatic urothelial cancers,” Dr. Hoffman-Censits maintained. “Higher PD-L1 [immune cell] status was associated with higher response rates, but low PD-L1 status or poor prognostic factors did not preclude responses,” she noted.

A pair of ongoing randomized phase III trials are testing atezolizumab in metastatic urothelial carcinoma and as adjuvant therapy in muscle-invasive bladder cancer. Also, there is now an expanded-access trial for patients with platinum-treated metastatic urothelial carcinoma.

“We look forward to the results of these trials, which will continue to define the role of atezolizumab in the treatment of patients with urothelial cancers,” she concluded.

Invited discussant Dr. William Y. Kim of the Lineberger Comprehensive Cancer Center, University of North Carolina, in Chapel Hill, noted that patients given immunotherapies such as atezolizumab can experience both pseudoprogression and delayed response, which may be misclassified with the RECIST criteria used in the trial. However, it is not yet clear whether immune-related response criteria will be useful in urothelial cancers.

“In IMvigor 210, we anxiously await the results of cohort one,” he said, referring to a separate group of patients who were not eligible for platinum chemotherapy. “Follow-up regarding the durability of these responses will be needed as well.”

Atezolizumab’s mechanism of action is attractive in urothelial cancer, Dr. Hoffman-Censits noted when introducing the trial.

“By inhibiting binding of PD-L1 to PD-1 and B7.1, atezolizumab can enhance T-cell priming and reinvigorate suppressed immune cells,” she explained. “However, by leaving the interaction between PD-L2 and PD-1 intact, atezolizumab can preserve peripheral immune homeostasis. Urothelial cancers have a high mutation burden, which potentially can lead to neoantigen formation, and those [new antigens] could be recognized by the immune system.”

Three-fourths of the 310 patients studied had bladder cancer. A total of 41% had previously received two or more therapies for metastatic disease.

Immunohistochemistry showed high PD-L1 staining of immune cells (5% or more positive) in 32% of patients, intermediate staining (between 1% and 5% positive) in 35%, and low staining (less than 1% positive) in 33%.

The overall response rate according to RECIST criteria with central review was 15% in the entire cohort, 18% in patients with intermediate or high PD-L1 staining, and 26% in patients with high PD-L1 staining.

“Surprisingly, complete responses were seen in this group,” Dr. Hoffman-Censits commented. “This is a phenomenon that is incredibly rare in second-line and beyond clinical trials.”

The rate of complete response was 5% in the entire cohort, 6% in patients with intermediate or high PD-L1 staining, and 11% in patients with high PD-L1 staining. Of note, some complete responses were seen even in those with low staining.

With a median follow-up of 11.7 months, the median duration of response had not been reached; fully 84% of patients who initially had a response still had an ongoing response at the time of data cutoff. Stable disease was likewise durable.

When patients were stratified by prognostic factors, the overall response rate was highest, at 23%, among those with lymph nodes as the only site of metastases.

Median progression-free survival was 2.1 months in the entire cohort and also regardless of PD-L1 staining. Median overall survival was 7.9 months in the entire cohort; it was longer for patients with high staining (11.4 months) than for peers with intermediate or low staining (6.7 months).

The 12-month overall survival rate was 36% for the entire cohort, 30% for patients with low or intermediate staining, and 48% for patients with high staining.

“Considering 12-month overall survival estimates for second-line chemo are approximately 20%, these data are truly exciting,” Dr. Hoffman-Censits said.

Analysis of adverse events showed that atezolizumab had a favorable safety profile. In particular, there were no immune-mediated adverse events deemed to be related to treatment. 

SAN FRANCISCO – The immune checkpoint inhibitor atezolizumab is highly active and well tolerated in patients with platinum-treated advanced urothelial carcinoma and may in fact change management of this disease, according to a phase II trial reported at the 2016 Genitourinary Cancers Symposium.

The trial, IMvigor 210, was conducted in Europe, Canada, and the United States among patients who had locally advanced or metastatic urothelial carcinoma. Lead investigator Dr. Jean H. Hoffman-Censits reported findings for the trial’s second cohort, which enrolled 310 patients who had had progression on or after platinum-based chemotherapy, with no limit on the number of lines of prior therapy.

At 3-week intervals, the patients received atezolizumab, an investigational antibody that targets programmed death–ligand 1 (PD-L1), preventing it from binding to the programmed death–1 (PD-1) receptor on T cells and thereby enhancing their activity, Dr. Hoffman-Censits reported at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

The overall response rate was 15% in the entire cohort and 26% in the subset of patients whose immune cells had high expression of PD-L1 by immunohistochemistry. Values in all prespecified groups exceeded the bar of 10% that the investigators had selected on the basis of second-line trials, even though many patients in IMvigor were being treated in later lines.

Atezolizumab was well tolerated. Overall, 16% of patients experienced grade 3 or 4 treatment-related adverse events; only 4% of patients stopping treatment because of such events, reported Dr. Hoffman-Censits of the Kimmel Cancer Center, Thomas Jefferson University Hospital in Philadelphia.

“Given the current landscape of chemotherapy options for our patients with urothelial cancer progressing following platinum chemotherapy, this primary analysis of IMvigor 210 demonstrates that atezolizumab has the potential to change the standard of care for metastatic urothelial cancers,” Dr. Hoffman-Censits maintained. “Higher PD-L1 [immune cell] status was associated with higher response rates, but low PD-L1 status or poor prognostic factors did not preclude responses,” she noted.

A pair of ongoing randomized phase III trials are testing atezolizumab in metastatic urothelial carcinoma and as adjuvant therapy in muscle-invasive bladder cancer. Also, there is now an expanded-access trial for patients with platinum-treated metastatic urothelial carcinoma.

“We look forward to the results of these trials, which will continue to define the role of atezolizumab in the treatment of patients with urothelial cancers,” she concluded.

Invited discussant Dr. William Y. Kim of the Lineberger Comprehensive Cancer Center, University of North Carolina, in Chapel Hill, noted that patients given immunotherapies such as atezolizumab can experience both pseudoprogression and delayed response, which may be misclassified with the RECIST criteria used in the trial. However, it is not yet clear whether immune-related response criteria will be useful in urothelial cancers.

“In IMvigor 210, we anxiously await the results of cohort one,” he said, referring to a separate group of patients who were not eligible for platinum chemotherapy. “Follow-up regarding the durability of these responses will be needed as well.”

Atezolizumab’s mechanism of action is attractive in urothelial cancer, Dr. Hoffman-Censits noted when introducing the trial.

“By inhibiting binding of PD-L1 to PD-1 and B7.1, atezolizumab can enhance T-cell priming and reinvigorate suppressed immune cells,” she explained. “However, by leaving the interaction between PD-L2 and PD-1 intact, atezolizumab can preserve peripheral immune homeostasis. Urothelial cancers have a high mutation burden, which potentially can lead to neoantigen formation, and those [new antigens] could be recognized by the immune system.”

Three-fourths of the 310 patients studied had bladder cancer. A total of 41% had previously received two or more therapies for metastatic disease.

Immunohistochemistry showed high PD-L1 staining of immune cells (5% or more positive) in 32% of patients, intermediate staining (between 1% and 5% positive) in 35%, and low staining (less than 1% positive) in 33%.

The overall response rate according to RECIST criteria with central review was 15% in the entire cohort, 18% in patients with intermediate or high PD-L1 staining, and 26% in patients with high PD-L1 staining.

“Surprisingly, complete responses were seen in this group,” Dr. Hoffman-Censits commented. “This is a phenomenon that is incredibly rare in second-line and beyond clinical trials.”

The rate of complete response was 5% in the entire cohort, 6% in patients with intermediate or high PD-L1 staining, and 11% in patients with high PD-L1 staining. Of note, some complete responses were seen even in those with low staining.

With a median follow-up of 11.7 months, the median duration of response had not been reached; fully 84% of patients who initially had a response still had an ongoing response at the time of data cutoff. Stable disease was likewise durable.

When patients were stratified by prognostic factors, the overall response rate was highest, at 23%, among those with lymph nodes as the only site of metastases.

Median progression-free survival was 2.1 months in the entire cohort and also regardless of PD-L1 staining. Median overall survival was 7.9 months in the entire cohort; it was longer for patients with high staining (11.4 months) than for peers with intermediate or low staining (6.7 months).

The 12-month overall survival rate was 36% for the entire cohort, 30% for patients with low or intermediate staining, and 48% for patients with high staining.

“Considering 12-month overall survival estimates for second-line chemo are approximately 20%, these data are truly exciting,” Dr. Hoffman-Censits said.

Analysis of adverse events showed that atezolizumab had a favorable safety profile. In particular, there were no immune-mediated adverse events deemed to be related to treatment. 

SAN FRANCISCO – The immune checkpoint inhibitor nivolumab has a consistent survival benefit over everolimus among diverse patients with previously treated advanced clear-cell renal cell carcinoma, finds a subgroup analysis of the CheckMate 025 trial reported at the 2016 Genitourinary Cancers Symposium.

Patients in the open-label phase III trial had received one or two prior anti-angiogenic therapies, usually one of the tyrosine kinase inhibitors that target signaling through the vascular endothelial growth factor receptor.

In all, 821 patients were randomized to nivolumab (Opdivo), an antibody to the cell surface receptor programmed death 1 (PD-1), or everolimus (Afinitor), an inhibitor of the mammalian target of rapamycin that is considered a standard of care in this setting.

Previously reported results showed that the trial met its primary endpoint, with an overall survival favoring nivolumab among the entire trial population (hazard ratio, 0.73; P = .0018) (N Engl J Med. 2015;373:1803-13), ultimately resulting in FDA approval of the drug. Nivolumab also yielded a better response rate, fewer grade 3 and 4 adverse events, and improved quality of life.

Findings of the new subgroup analysis showed that compared with everolimus, nivolumab was associated with a roughly 20%-50% reduced risk of death across patients stratified by disease characteristics and prior therapies, reported lead author Dr. Robert J. Motzer of Memorial Sloan Kettering Cancer Center, New York.

“Consistent with the benefit observed in the overall population of CheckMate 025, nivolumab demonstrated an overall survival and objective response benefit across all key subgroups we examined … Nivolumab is a new standard of care for patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy, and we think it’s a good choice as a second-line agent,” he said at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

In the same session, investigators reported findings of a subgroup analysis of the METEOR trial, which compared cabozantinib (Cometriq), an oral multitargeted tyrosine kinase inhibitor, with everolimus in a similar patient population. Those data were much the same, showing a consistent progression-free survival benefit of cabozantinib across subgroups.

Weighing results of the two trials, session chair Dr. Toni K. Choueiri, director of the Kidney Cancer Center at the Dana-Farber Cancer Institute, Boston, asked, “For patients who progress on a first-line VEGFR TKI, let’s say sunitinib, is your agent of choice nivolumab or cabozantinib?”

“My treatment of choice in that patient would be nivolumab, [because of] the survival benefit, the tolerability, the durability of responses that we see when the responses do occur,” Dr. Motzer replied. “I also am attracted by a change in mechanism. A change in mechanism of action to a different type of drug is what I prefer.”

This choice would remain the same even if the METEOR trial eventually shows an overall survival benefit of cabozantinib, he added.

“Obviously, we have a number of different options here. I don’t think that there is any one right answer … Neither of these drugs has been compared to the other. Neither of them has been compared to axitinib. So it’s really an individual decision. It’s going to be a patient’s decision. It’s going to be a physician’s decision,” he said. “Hopefully, as we get more experience, more data, more trials, we’ll have more evidence to base our decision on.”

A session attendee asked, “Where do we go from here? What will the approval of cabozantinib and the use of cabozantinib mean for the development of the combination of everolimus and lenvatinib, which we’ve been working on?”

“We have a number of drugs that are coming into the armamentarium that are hopefully going to get approved. Nivolumab has been approved. Cabozantinib I anticipate will be approved. I don’t know about lenvatinib –we’ll have to see,” Dr. Motzer said, adding that axitinib is also in the mix.

“We would need some comparative trials. For lenvatinib, what we’d like to see is that going into the first-line setting perhaps combined with a checkpoint inhibitor. We are currently doing a study at our center with lenvatinib and pembrolizumab. I think that will be a great combination,” he added. “So you’re right, it’s a time where suddenly this year, we may have three new drugs for kidney cancer, and we need to sort that out. We have lots of good options for our patients now.”

Results of the CheckMate 025 subgroup analysis showed a lower risk of death with nivolumab compared with everolimus among patients whether their Memorial Sloan Kettering Cancer Center (MSKCC) risk score was favorable (hazard ratio, 0.80), intermediate (hazard ratio, 0.81), or poor (hazard ratio, 0.48).

Benefit was consistent in patients with bone metastases (hazard ratio, 0.72) and liver metastases (hazard ratio, 0.81).

Nivolumab was likewise superior to everolimus in the roughly 60% of patients who had previously received sunitinib (hazard ratio, 0.81) and in the roughly 30% who had previously received pazopanib (hazard ratio, 0.60).

And benefit was essentially the same whether patients had been on first-line therapy for less than 6 months, a poor prognostic marker (hazard ratio, 0.76), or for longer than that (hazard ratio, 0.78).

There was also an overall survival advantage in favor of nivolumab when patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score, number of sites of metastases, and number of prior anti-angiogenic therapies.

The previously published results showed an advantage in favor of nivolumab regardless of programmed death–ligand 1 (PD-L1) expression, Dr. Motzer noted.

The benefit in terms of overall response rate was also consistently in favor of nivolumab over everolimus across these diverse patient subgroups.

Dr. Motzer disclosed that he has a consulting or advisory role with Eisai, Novartis, and Pfizer; that he receives travel expenses from Bristol-Myers Squibb; and that his institution receives research funding from Bristol-Myers Squibb, Eisai, Genentech/Roche, GlaxoSmithKline, Novartis, and Pfizer. The trial was sponsored in part by Bristol-Myers Squibb in collaboration with Ono Pharmaceutical Co. Ltd.

SAN FRANCISCO – The immune checkpoint inhibitor nivolumab has a consistent survival benefit over everolimus among diverse patients with previously treated advanced clear-cell renal cell carcinoma, finds a subgroup analysis of the CheckMate 025 trial reported at the 2016 Genitourinary Cancers Symposium.

Patients in the open-label phase III trial had received one or two prior anti-angiogenic therapies, usually one of the tyrosine kinase inhibitors that target signaling through the vascular endothelial growth factor receptor.

In all, 821 patients were randomized to nivolumab (Opdivo), an antibody to the cell surface receptor programmed death 1 (PD-1), or everolimus (Afinitor), an inhibitor of the mammalian target of rapamycin that is considered a standard of care in this setting.

Previously reported results showed that the trial met its primary endpoint, with an overall survival favoring nivolumab among the entire trial population (hazard ratio, 0.73; P = .0018) (N Engl J Med. 2015;373:1803-13), ultimately resulting in FDA approval of the drug. Nivolumab also yielded a better response rate, fewer grade 3 and 4 adverse events, and improved quality of life.

Findings of the new subgroup analysis showed that compared with everolimus, nivolumab was associated with a roughly 20%-50% reduced risk of death across patients stratified by disease characteristics and prior therapies, reported lead author Dr. Robert J. Motzer of Memorial Sloan Kettering Cancer Center, New York.

“Consistent with the benefit observed in the overall population of CheckMate 025, nivolumab demonstrated an overall survival and objective response benefit across all key subgroups we examined … Nivolumab is a new standard of care for patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy, and we think it’s a good choice as a second-line agent,” he said at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

In the same session, investigators reported findings of a subgroup analysis of the METEOR trial, which compared cabozantinib (Cometriq), an oral multitargeted tyrosine kinase inhibitor, with everolimus in a similar patient population. Those data were much the same, showing a consistent progression-free survival benefit of cabozantinib across subgroups.

Weighing results of the two trials, session chair Dr. Toni K. Choueiri, director of the Kidney Cancer Center at the Dana-Farber Cancer Institute, Boston, asked, “For patients who progress on a first-line VEGFR TKI, let’s say sunitinib, is your agent of choice nivolumab or cabozantinib?”

“My treatment of choice in that patient would be nivolumab, [because of] the survival benefit, the tolerability, the durability of responses that we see when the responses do occur,” Dr. Motzer replied. “I also am attracted by a change in mechanism. A change in mechanism of action to a different type of drug is what I prefer.”

This choice would remain the same even if the METEOR trial eventually shows an overall survival benefit of cabozantinib, he added.

“Obviously, we have a number of different options here. I don’t think that there is any one right answer … Neither of these drugs has been compared to the other. Neither of them has been compared to axitinib. So it’s really an individual decision. It’s going to be a patient’s decision. It’s going to be a physician’s decision,” he said. “Hopefully, as we get more experience, more data, more trials, we’ll have more evidence to base our decision on.”

A session attendee asked, “Where do we go from here? What will the approval of cabozantinib and the use of cabozantinib mean for the development of the combination of everolimus and lenvatinib, which we’ve been working on?”

“We have a number of drugs that are coming into the armamentarium that are hopefully going to get approved. Nivolumab has been approved. Cabozantinib I anticipate will be approved. I don’t know about lenvatinib –we’ll have to see,” Dr. Motzer said, adding that axitinib is also in the mix.

“We would need some comparative trials. For lenvatinib, what we’d like to see is that going into the first-line setting perhaps combined with a checkpoint inhibitor. We are currently doing a study at our center with lenvatinib and pembrolizumab. I think that will be a great combination,” he added. “So you’re right, it’s a time where suddenly this year, we may have three new drugs for kidney cancer, and we need to sort that out. We have lots of good options for our patients now.”

Results of the CheckMate 025 subgroup analysis showed a lower risk of death with nivolumab compared with everolimus among patients whether their Memorial Sloan Kettering Cancer Center (MSKCC) risk score was favorable (hazard ratio, 0.80), intermediate (hazard ratio, 0.81), or poor (hazard ratio, 0.48).

Benefit was consistent in patients with bone metastases (hazard ratio, 0.72) and liver metastases (hazard ratio, 0.81).

Nivolumab was likewise superior to everolimus in the roughly 60% of patients who had previously received sunitinib (hazard ratio, 0.81) and in the roughly 30% who had previously received pazopanib (hazard ratio, 0.60).

And benefit was essentially the same whether patients had been on first-line therapy for less than 6 months, a poor prognostic marker (hazard ratio, 0.76), or for longer than that (hazard ratio, 0.78).

There was also an overall survival advantage in favor of nivolumab when patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score, number of sites of metastases, and number of prior anti-angiogenic therapies.

The previously published results showed an advantage in favor of nivolumab regardless of programmed death–ligand 1 (PD-L1) expression, Dr. Motzer noted.

The benefit in terms of overall response rate was also consistently in favor of nivolumab over everolimus across these diverse patient subgroups.

Dr. Motzer disclosed that he has a consulting or advisory role with Eisai, Novartis, and Pfizer; that he receives travel expenses from Bristol-Myers Squibb; and that his institution receives research funding from Bristol-Myers Squibb, Eisai, Genentech/Roche, GlaxoSmithKline, Novartis, and Pfizer. The trial was sponsored in part by Bristol-Myers Squibb in collaboration with Ono Pharmaceutical Co. Ltd.

SAN FRANCISCO – The immune checkpoint inhibitor nivolumab has a consistent survival benefit over everolimus among diverse patients with previously treated advanced clear-cell renal cell carcinoma, finds a subgroup analysis of the CheckMate 025 trial reported at the 2016 Genitourinary Cancers Symposium.

Patients in the open-label phase III trial had received one or two prior anti-angiogenic therapies, usually one of the tyrosine kinase inhibitors that target signaling through the vascular endothelial growth factor receptor.

In all, 821 patients were randomized to nivolumab (Opdivo), an antibody to the cell surface receptor programmed death 1 (PD-1), or everolimus (Afinitor), an inhibitor of the mammalian target of rapamycin that is considered a standard of care in this setting.

Previously reported results showed that the trial met its primary endpoint, with an overall survival favoring nivolumab among the entire trial population (hazard ratio, 0.73; P = .0018) (N Engl J Med. 2015;373:1803-13), ultimately resulting in FDA approval of the drug. Nivolumab also yielded a better response rate, fewer grade 3 and 4 adverse events, and improved quality of life.

Findings of the new subgroup analysis showed that compared with everolimus, nivolumab was associated with a roughly 20%-50% reduced risk of death across patients stratified by disease characteristics and prior therapies, reported lead author Dr. Robert J. Motzer of Memorial Sloan Kettering Cancer Center, New York.

“Consistent with the benefit observed in the overall population of CheckMate 025, nivolumab demonstrated an overall survival and objective response benefit across all key subgroups we examined … Nivolumab is a new standard of care for patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy, and we think it’s a good choice as a second-line agent,” he said at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

In the same session, investigators reported findings of a subgroup analysis of the METEOR trial, which compared cabozantinib (Cometriq), an oral multitargeted tyrosine kinase inhibitor, with everolimus in a similar patient population. Those data were much the same, showing a consistent progression-free survival benefit of cabozantinib across subgroups.

Weighing results of the two trials, session chair Dr. Toni K. Choueiri, director of the Kidney Cancer Center at the Dana-Farber Cancer Institute, Boston, asked, “For patients who progress on a first-line VEGFR TKI, let’s say sunitinib, is your agent of choice nivolumab or cabozantinib?”

“My treatment of choice in that patient would be nivolumab, [because of] the survival benefit, the tolerability, the durability of responses that we see when the responses do occur,” Dr. Motzer replied. “I also am attracted by a change in mechanism. A change in mechanism of action to a different type of drug is what I prefer.”

This choice would remain the same even if the METEOR trial eventually shows an overall survival benefit of cabozantinib, he added.

“Obviously, we have a number of different options here. I don’t think that there is any one right answer … Neither of these drugs has been compared to the other. Neither of them has been compared to axitinib. So it’s really an individual decision. It’s going to be a patient’s decision. It’s going to be a physician’s decision,” he said. “Hopefully, as we get more experience, more data, more trials, we’ll have more evidence to base our decision on.”

A session attendee asked, “Where do we go from here? What will the approval of cabozantinib and the use of cabozantinib mean for the development of the combination of everolimus and lenvatinib, which we’ve been working on?”

“We have a number of drugs that are coming into the armamentarium that are hopefully going to get approved. Nivolumab has been approved. Cabozantinib I anticipate will be approved. I don’t know about lenvatinib –we’ll have to see,” Dr. Motzer said, adding that axitinib is also in the mix.

“We would need some comparative trials. For lenvatinib, what we’d like to see is that going into the first-line setting perhaps combined with a checkpoint inhibitor. We are currently doing a study at our center with lenvatinib and pembrolizumab. I think that will be a great combination,” he added. “So you’re right, it’s a time where suddenly this year, we may have three new drugs for kidney cancer, and we need to sort that out. We have lots of good options for our patients now.”

Results of the CheckMate 025 subgroup analysis showed a lower risk of death with nivolumab compared with everolimus among patients whether their Memorial Sloan Kettering Cancer Center (MSKCC) risk score was favorable (hazard ratio, 0.80), intermediate (hazard ratio, 0.81), or poor (hazard ratio, 0.48).

Benefit was consistent in patients with bone metastases (hazard ratio, 0.72) and liver metastases (hazard ratio, 0.81).

Nivolumab was likewise superior to everolimus in the roughly 60% of patients who had previously received sunitinib (hazard ratio, 0.81) and in the roughly 30% who had previously received pazopanib (hazard ratio, 0.60).

And benefit was essentially the same whether patients had been on first-line therapy for less than 6 months, a poor prognostic marker (hazard ratio, 0.76), or for longer than that (hazard ratio, 0.78).

There was also an overall survival advantage in favor of nivolumab when patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score, number of sites of metastases, and number of prior anti-angiogenic therapies.

The previously published results showed an advantage in favor of nivolumab regardless of programmed death–ligand 1 (PD-L1) expression, Dr. Motzer noted.

The benefit in terms of overall response rate was also consistently in favor of nivolumab over everolimus across these diverse patient subgroups.

Dr. Motzer disclosed that he has a consulting or advisory role with Eisai, Novartis, and Pfizer; that he receives travel expenses from Bristol-Myers Squibb; and that his institution receives research funding from Bristol-Myers Squibb, Eisai, Genentech/Roche, GlaxoSmithKline, Novartis, and Pfizer. The trial was sponsored in part by Bristol-Myers Squibb in collaboration with Ono Pharmaceutical Co. Ltd.