Enzalutamide improves survival in chemo-naive metastatic prostate cancer

The androgen receptor–blocker enzalutamide is efficacious and safe in men with metastatic castration-resistant prostate cancer who have not received chemotherapy, according to interim results of the randomized phase III PREVAIL trial.

Patients who received enzalutamide (Xtandi) were 29% less likely to die and 81% less likely to experience radiographic progression than patients who received a placebo, researchers are reporting at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Enzalutamide also prolonged the median time to chemotherapy by 17 months and was associated with a nearly 12 times higher rate of response.

Safety results showed that the drug was well tolerated and not associated with an increase in the rate of treatment discontinuation because of adverse events.

"As a result of these observations, it is my view that enzalutamide provides a meaningful clinical benefit to men with metastatic prostate cancer," lead author Dr. Tomasz Beer, professor of medicine and deputy director of the Knight Cancer Institute at Oregon Health and Science University, Portland, commented in a press briefing before the symposium.

The PREVAIL trial’s findings would apply to roughly 50,000 men each year in the United States, he estimated. "For folks who develop metastatic prostate cancer, by and large, all of them at some point or another would be expected to have this metastatic hormone-resistant state that is represented in this study population."

The favorable interim results prompted the investigators to stop the trial early, in October 2013, and offer enzalutamide to patients in the placebo arm. The manufacturer, Medivation, plans to file with the Food and Drug Administration for a new indication for enzalutamide, which is currently approved for the treatment of castration-resistant metastatic prostate cancer in men who have received chemotherapy.

"This is a very important study from the perspective that this applies to patients who have not yet had chemotherapy, which may expand the regulatory approval of enzalutamide. And one key fact for me is that although chemotherapy is sort of held up as the benchmark for this disease, the reality is that our current data suggest that less than 50% of men with castration-resistant prostate cancer actually receive chemotherapy," noted press briefing moderator Dr. Charles J. Ryan, a professor at the University of California, San Francisco, and leader of the Genitourinary Medical Oncology Program.

"So this treatment should change the regulatory status of enzalutamide and would open up this possibility of therapy for a very large group of patients who currently have really only one or two treatment options available to them," Dr. Ryan commented.

Dr. Beer declined to directly compare the efficacy results of PREVAIL with those of Cougar 302, a similar trial of the oral antiandrogen abiraterone (Zytiga) that led to its approval in this patient population.

But he noted that the trials’ populations differed in some respects that may be important; for example, about 12% of patients in PREVAIL had visceral metastases, compared with none in Cougar 302. Also, the former study excluded patients with a history of seizure, whereas the latter excluded those with cardiac risk factors.

Should enzalutamide gain approval for this new indication, the choice between enzalutamide and abiraterone would likely be individualized, taking into account these factors as well as others such as the need to coadminister steroids and follow dietary restrictions with abiraterone, according to Dr. Beer.

"That’s a decision that every clinician and patient will make in the clinic individually ... I don’t think there is a blanket answer to that question for all patients," he said. "We have two active drugs, we are fortunate to have those, and my real hope is that the work we are currently doing on the research front as a part of the [Stand Up to Cancer] West Coast Dream Team and other such efforts will enable us to further define which patient populations benefit the most from which therapeutic approach and be able to answer this question in a scientific manner in the future."

The two drugs may be compared in a head-to-head trial and will likely be tested in sequence, in combination, and in earlier stages of the disease, he added.

In fact, Dr. Ryan, the press briefing moderator, pointed out that just last week, the U.S. cooperative group system launched a trial comparing the combination of enzalutamide and abiraterone with enzalutamide monotherapy.

PREVAIL was sponsored by Medivation and enrolled 1,717 men with metastatic prostate cancer who had experienced progression on androgen deprivation therapy but had not received chemotherapy. They had no or only mild symptoms.

The men were randomized evenly to double-blind treatment with enzalutamide (160 mg/day) or a placebo.

With a median follow-up of about 20 months, enzalutamide was associated with better overall survival (hazard ratio, 0.71; P less than .0001) and better radiographic progression-free survival (HR, 0.19; P less than .0001). In post hoc analyses, the findings were much the same in the small subset of patients who had visceral metastases, according to Dr. Beer.

The response rate was 59% with enzalutamide (20% complete response; 39% partial response), compared with just 5% with placebo (P less than .0001).

Enzalutamide also delayed the median time to receipt of chemotherapy – "a pragmatic measure of real-world treatment effect," he noted – from 11 to 28 months (HR, 0.35; P less than .0001).

The rate of grade 3 or worse adverse events was 43% with enzalutamide and 37% with placebo. The most common toxicities of any grade were fatigue, back pain, constipation, and arthralgia. The rate of treatment discontinuation from adverse events was identical at 6% in each arm.

Two patients (0.1%) – one in each study arm – experienced seizure, which has been a concern with enzalutamide; both were subsequently determined to have a history of seizure unknown to their enrolling physician, which would have excluded them from the trial.

"What that tells us is that with appropriate patient selection, this clinical trial demonstrates that the drug can be administered very safely from the perspective of seizure risk," Dr. Beer said. "In point of fact, in patients who didn’t have a prior history of seizures, there were no seizures at all in this trial."

Dr. Beer disclosed that he receives research funding from Cougar Biotechnology, Janssen Biotech, Astellas Pharma, and Medivation. The trial was sponsored by Medivation.

The androgen receptor–blocker enzalutamide is efficacious and safe in men with metastatic castration-resistant prostate cancer who have not received chemotherapy, according to interim results of the randomized phase III PREVAIL trial.

Patients who received enzalutamide (Xtandi) were 29% less likely to die and 81% less likely to experience radiographic progression than patients who received a placebo, researchers are reporting at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Enzalutamide also prolonged the median time to chemotherapy by 17 months and was associated with a nearly 12 times higher rate of response.

Safety results showed that the drug was well tolerated and not associated with an increase in the rate of treatment discontinuation because of adverse events.

"As a result of these observations, it is my view that enzalutamide provides a meaningful clinical benefit to men with metastatic prostate cancer," lead author Dr. Tomasz Beer, professor of medicine and deputy director of the Knight Cancer Institute at Oregon Health and Science University, Portland, commented in a press briefing before the symposium.

The PREVAIL trial’s findings would apply to roughly 50,000 men each year in the United States, he estimated. "For folks who develop metastatic prostate cancer, by and large, all of them at some point or another would be expected to have this metastatic hormone-resistant state that is represented in this study population."

The favorable interim results prompted the investigators to stop the trial early, in October 2013, and offer enzalutamide to patients in the placebo arm. The manufacturer, Medivation, plans to file with the Food and Drug Administration for a new indication for enzalutamide, which is currently approved for the treatment of castration-resistant metastatic prostate cancer in men who have received chemotherapy.

"This is a very important study from the perspective that this applies to patients who have not yet had chemotherapy, which may expand the regulatory approval of enzalutamide. And one key fact for me is that although chemotherapy is sort of held up as the benchmark for this disease, the reality is that our current data suggest that less than 50% of men with castration-resistant prostate cancer actually receive chemotherapy," noted press briefing moderator Dr. Charles J. Ryan, a professor at the University of California, San Francisco, and leader of the Genitourinary Medical Oncology Program.

"So this treatment should change the regulatory status of enzalutamide and would open up this possibility of therapy for a very large group of patients who currently have really only one or two treatment options available to them," Dr. Ryan commented.

Dr. Beer declined to directly compare the efficacy results of PREVAIL with those of Cougar 302, a similar trial of the oral antiandrogen abiraterone (Zytiga) that led to its approval in this patient population.

But he noted that the trials’ populations differed in some respects that may be important; for example, about 12% of patients in PREVAIL had visceral metastases, compared with none in Cougar 302. Also, the former study excluded patients with a history of seizure, whereas the latter excluded those with cardiac risk factors.

Should enzalutamide gain approval for this new indication, the choice between enzalutamide and abiraterone would likely be individualized, taking into account these factors as well as others such as the need to coadminister steroids and follow dietary restrictions with abiraterone, according to Dr. Beer.

"That’s a decision that every clinician and patient will make in the clinic individually ... I don’t think there is a blanket answer to that question for all patients," he said. "We have two active drugs, we are fortunate to have those, and my real hope is that the work we are currently doing on the research front as a part of the [Stand Up to Cancer] West Coast Dream Team and other such efforts will enable us to further define which patient populations benefit the most from which therapeutic approach and be able to answer this question in a scientific manner in the future."

The two drugs may be compared in a head-to-head trial and will likely be tested in sequence, in combination, and in earlier stages of the disease, he added.

In fact, Dr. Ryan, the press briefing moderator, pointed out that just last week, the U.S. cooperative group system launched a trial comparing the combination of enzalutamide and abiraterone with enzalutamide monotherapy.

PREVAIL was sponsored by Medivation and enrolled 1,717 men with metastatic prostate cancer who had experienced progression on androgen deprivation therapy but had not received chemotherapy. They had no or only mild symptoms.

The men were randomized evenly to double-blind treatment with enzalutamide (160 mg/day) or a placebo.

With a median follow-up of about 20 months, enzalutamide was associated with better overall survival (hazard ratio, 0.71; P less than .0001) and better radiographic progression-free survival (HR, 0.19; P less than .0001). In post hoc analyses, the findings were much the same in the small subset of patients who had visceral metastases, according to Dr. Beer.

The response rate was 59% with enzalutamide (20% complete response; 39% partial response), compared with just 5% with placebo (P less than .0001).

Enzalutamide also delayed the median time to receipt of chemotherapy – "a pragmatic measure of real-world treatment effect," he noted – from 11 to 28 months (HR, 0.35; P less than .0001).

The rate of grade 3 or worse adverse events was 43% with enzalutamide and 37% with placebo. The most common toxicities of any grade were fatigue, back pain, constipation, and arthralgia. The rate of treatment discontinuation from adverse events was identical at 6% in each arm.

Two patients (0.1%) – one in each study arm – experienced seizure, which has been a concern with enzalutamide; both were subsequently determined to have a history of seizure unknown to their enrolling physician, which would have excluded them from the trial.

"What that tells us is that with appropriate patient selection, this clinical trial demonstrates that the drug can be administered very safely from the perspective of seizure risk," Dr. Beer said. "In point of fact, in patients who didn’t have a prior history of seizures, there were no seizures at all in this trial."

Dr. Beer disclosed that he receives research funding from Cougar Biotechnology, Janssen Biotech, Astellas Pharma, and Medivation. The trial was sponsored by Medivation.

The androgen receptor–blocker enzalutamide is efficacious and safe in men with metastatic castration-resistant prostate cancer who have not received chemotherapy, according to interim results of the randomized phase III PREVAIL trial.

Patients who received enzalutamide (Xtandi) were 29% less likely to die and 81% less likely to experience radiographic progression than patients who received a placebo, researchers are reporting at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Enzalutamide also prolonged the median time to chemotherapy by 17 months and was associated with a nearly 12 times higher rate of response.

Safety results showed that the drug was well tolerated and not associated with an increase in the rate of treatment discontinuation because of adverse events.

"As a result of these observations, it is my view that enzalutamide provides a meaningful clinical benefit to men with metastatic prostate cancer," lead author Dr. Tomasz Beer, professor of medicine and deputy director of the Knight Cancer Institute at Oregon Health and Science University, Portland, commented in a press briefing before the symposium.

The PREVAIL trial’s findings would apply to roughly 50,000 men each year in the United States, he estimated. "For folks who develop metastatic prostate cancer, by and large, all of them at some point or another would be expected to have this metastatic hormone-resistant state that is represented in this study population."

The favorable interim results prompted the investigators to stop the trial early, in October 2013, and offer enzalutamide to patients in the placebo arm. The manufacturer, Medivation, plans to file with the Food and Drug Administration for a new indication for enzalutamide, which is currently approved for the treatment of castration-resistant metastatic prostate cancer in men who have received chemotherapy.

"This is a very important study from the perspective that this applies to patients who have not yet had chemotherapy, which may expand the regulatory approval of enzalutamide. And one key fact for me is that although chemotherapy is sort of held up as the benchmark for this disease, the reality is that our current data suggest that less than 50% of men with castration-resistant prostate cancer actually receive chemotherapy," noted press briefing moderator Dr. Charles J. Ryan, a professor at the University of California, San Francisco, and leader of the Genitourinary Medical Oncology Program.

"So this treatment should change the regulatory status of enzalutamide and would open up this possibility of therapy for a very large group of patients who currently have really only one or two treatment options available to them," Dr. Ryan commented.

Dr. Beer declined to directly compare the efficacy results of PREVAIL with those of Cougar 302, a similar trial of the oral antiandrogen abiraterone (Zytiga) that led to its approval in this patient population.

But he noted that the trials’ populations differed in some respects that may be important; for example, about 12% of patients in PREVAIL had visceral metastases, compared with none in Cougar 302. Also, the former study excluded patients with a history of seizure, whereas the latter excluded those with cardiac risk factors.

Should enzalutamide gain approval for this new indication, the choice between enzalutamide and abiraterone would likely be individualized, taking into account these factors as well as others such as the need to coadminister steroids and follow dietary restrictions with abiraterone, according to Dr. Beer.

"That’s a decision that every clinician and patient will make in the clinic individually ... I don’t think there is a blanket answer to that question for all patients," he said. "We have two active drugs, we are fortunate to have those, and my real hope is that the work we are currently doing on the research front as a part of the [Stand Up to Cancer] West Coast Dream Team and other such efforts will enable us to further define which patient populations benefit the most from which therapeutic approach and be able to answer this question in a scientific manner in the future."

The two drugs may be compared in a head-to-head trial and will likely be tested in sequence, in combination, and in earlier stages of the disease, he added.

In fact, Dr. Ryan, the press briefing moderator, pointed out that just last week, the U.S. cooperative group system launched a trial comparing the combination of enzalutamide and abiraterone with enzalutamide monotherapy.

PREVAIL was sponsored by Medivation and enrolled 1,717 men with metastatic prostate cancer who had experienced progression on androgen deprivation therapy but had not received chemotherapy. They had no or only mild symptoms.

The men were randomized evenly to double-blind treatment with enzalutamide (160 mg/day) or a placebo.

With a median follow-up of about 20 months, enzalutamide was associated with better overall survival (hazard ratio, 0.71; P less than .0001) and better radiographic progression-free survival (HR, 0.19; P less than .0001). In post hoc analyses, the findings were much the same in the small subset of patients who had visceral metastases, according to Dr. Beer.

The response rate was 59% with enzalutamide (20% complete response; 39% partial response), compared with just 5% with placebo (P less than .0001).

Enzalutamide also delayed the median time to receipt of chemotherapy – "a pragmatic measure of real-world treatment effect," he noted – from 11 to 28 months (HR, 0.35; P less than .0001).

The rate of grade 3 or worse adverse events was 43% with enzalutamide and 37% with placebo. The most common toxicities of any grade were fatigue, back pain, constipation, and arthralgia. The rate of treatment discontinuation from adverse events was identical at 6% in each arm.

Two patients (0.1%) – one in each study arm – experienced seizure, which has been a concern with enzalutamide; both were subsequently determined to have a history of seizure unknown to their enrolling physician, which would have excluded them from the trial.

"What that tells us is that with appropriate patient selection, this clinical trial demonstrates that the drug can be administered very safely from the perspective of seizure risk," Dr. Beer said. "In point of fact, in patients who didn’t have a prior history of seizures, there were no seizures at all in this trial."

Dr. Beer disclosed that he receives research funding from Cougar Biotechnology, Janssen Biotech, Astellas Pharma, and Medivation. The trial was sponsored by Medivation.