Data from the final analysis of the international, phase III PREVAIL study show that enzalutamide (XTANDI) added to androgen deprivation therapy at the time of progression provides meaningful clinical benefit for men with chemotherapy-naïve metastatic castrate-resistant prostate cancer, including those with visceral disease.
Editor's note: This article has been updated since its original publication to include additional study data and commentary from the author/presenter.
Orlando, FL-Data from the final analysis of the international, phase III PREVAIL study show that enzalutamide (XTANDI) added to androgen deprivation therapy (ADT) at the time of progression provides meaningful clinical benefit for men with chemotherapy-naïve metastatic castrate-resistant prostate cancer (mCRPC), including those with visceral disease.
“In 2009, enzalutamide was demonstrated in the AFFIRM trial to improve radiographic progression-free survival and overall survival in men with mCRPC previously treated with chemotherapy. PREVAIL investigated this oral androgen receptor inhibitor in the pre-chemotherapy setting,” said first author Christopher Evans, MD, who presented the results at the AUA annual meeting in Orlando, FL.
“It is important to note that PREVAIL is distinguished from other trials of treatments for chemotherapy-naïve mCRPC patients by its inclusion of men with visceral metastases, and that the results show enzalutamide had significant benefit for patients with either visceral or nonvisceral disease.”
PREVAIL randomized 1,717 men at 207 centers 1:1 to treatment with oral enzalutamide, 160 mg/day or placebo while continuing ADT. Steroids were allowed, but not required.
Eligible patients had absent or mild symptoms, 12% of the study population had visceral disease (lung and/or liver metastases), and more than half of nonvisceral patients had soft tissue metastases, predominantly lymph node disease. Baseline median PSA in the nonvisceral and visceral subgroups was 51.0 ng/mL and 80.0 ng/mL, respectively.
Results of a pre-planned interim analysis conducted at the time of 540 deaths showed a statistically significant benefit of enzalutamide versus placebo in the co-primary endpoints of overall survival and radiographic progression-free survival. Based on those findings, PREVAIL was halted and unblinded, and control patients were offered enzalutamide.
At the time of the final analysis, which was planned at 765 deaths and conducted at a median follow-up of about 22 months, enzalutamide significantly reduced the risk of radiographic disease progression by 81% compared to placebo and relative risk of death by 29%. Estimated median overall survival was improved by 2 months with enzalutamide compared to placebo in the intent-to-treat (ITT) population (32.4 vs. 30.2 months), which was statistically significant (p<.0001).
“Median time to death was not yet reached in the nonvisceral subgroup, while enzalutamide had a treatment benefit of 5 months among men with visceral disease,” said Dr. Evans, PREVAIL investigator and professor and chair of urology at the University of California, Davis, School of Medicine, Sacramento.
Analyses of secondary endpoints showed the median time to initiation of cytotoxic chemotherapy in the enzalutamide and control groups was 28 and 10.8 months, respectively, for the ITT population; 28.4 and 11.6 months, respectively, for the nonvisceral subgroup; and 22.6 and 6.6 months, respectively, for those with visceral disease. In the nonvisceral subgroup, the proportion of men requiring at least one subsequent life-extending therapy was 40% in the enzalutamide group and 70% among the controls.
Enzalutamide’s benefit was highly statistically significant (p<.001) in all of the aforementioned analyses except overall survival in the nonvisceral group, which was not yet reached, and there were also highly statistically significant differences favoring enzalutamide over placebo in the nonvisceral subgroup analyses of time to PSA progression, time to Functional Assessment of Cancer Therapy-Prostate total score decline, and PSA response rates.
Adverse events in PREVAIL include treatment and disease-related events, and those that might be associated with enzalutamide were similar in the nonvisceral and visceral subgroups. However, discontinuation due to adverse events and adverse events leading to death were more common in the visceral subgroup, possibly reflecting their more advanced disease. The most common adverse events manifested by at least 20% of patients on enzalutamide and at least 2% of controls were fatigue, back pain, constipation, arthralgia, hypertension, and cardiac events. Single patients in the enzalutamide and placebo arms experienced a seizure.
“The PREVAIL safety data validated the favorable tolerability profile established for enzalutamide previously in post-chemotherapy mCRPC patients,” Dr. Evans told Urology Times. “In early experience with enzalutamide, there was some question about a potential association between enzalutamide and seizures. That does not appear to be an issue based on these data, although PREVAIL excluded patients with a history of seizures.”
Focusing on the subgroup of patients with nonvisceral disease, Dr. Evans pointed out that with a 28-month median time to initiation of chemotherapy, there is a long window of opportunity for urologists to become involved in treating chemotherapy-naïve mCRPC patients with enzalutamide, if and when it becomes FDA-approved for this indication. However, he noted that while 45% of the PREVAIL principal investigators were urologists globally, urologists accounted for only 2% of investigators in the U.S.
“The outcomes data speak to the potential for urologists to manage chemotherapy-naïve mCRPC patients, but the information about the investigators show that in the U.S., urologists are not embracing this role,” said Dr. Evans.
“Urologists are administering ADT and understand treatment affecting the androgen axis. However, those interested in treating patients whose disease has progressed must be qualified, dedicated, and willing to invest the time. They need to know the indications for stopping and starting treatment along with the contraindications, monitoring protocols, and how to manage treatment toxicity, and they need to have the infrastructure to provide this care.”
Astellas Pharma and Medivation announced on May 6 the FDA’s acceptance for filing the supplemental new drug application to extend the indication for enzalutamide capsules for the treatment of men with mCRPC who have not received chemotherapy. The application received priority review designation with a stated Prescription Drug User Fee Act review date of Sept. 18, 2014. Enzalutamide is currently approved for the treatment of patients with mCRPC who have previously received docetaxel (Taxotere) chemotherapy.
Dr. Evans has a research agreement and material transfer agreement with Astellas Pharma/Medivation and is also a consultant, clinical trial investigator, and speaker for both companies. Several of his co-authors are consultants/advisers for and/or have another relationship with Astellas Pharma and/or Medivation.UT
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