Enzalutamide added to androgen-deprivation therapy provides clinically meaningful benefits to men with metastatic castration-resistant prostate cancer.
—Andrew J. Armstrong, MD, ScM, FACP
Three separate studies of treatments for prostate cancer reported at the 2014 ASCO Annual Meeting in Chicago showed excellent, intermediate, and disappointing results. An update of the previously reported PREVAIL trial (see March 1 issue of The ASCO Post, page 1) was overwhelmingly positive for the androgen receptor antagonist enzalutamide (Xtandi). A second study showed that the androgen-synthesis inhibitor orteronel improved radiographic progression-free survival but failed to improve overall survival, while a third study of the monoclonal antibody cixutumumab was negative.
Enzalutamide a ‘Home Run’
“In the PREVAIL trial, treatment with enzalutamide significantly delayed radiographic progression-free survival, significantly reduced the risk of death by nearly 30%, delayed the time to initiation of cytotoxic chemotherapy, and improved quality of life on the FACT-P. Enzalutamide added to androgen-deprivation therapy provides clinically meaningful benefits to men with metastatic castration-resistant prostate cancer,” said Andrew J. Armstrong, MD, ScM, FACP, Associate Professor of Medicine at Duke Cancer Institute, Duke University, Durham, North Carolina.1 Results of PREVAIL were published online in The New England Journal of Medicine to coincide with Dr. Armstrong’s presentation.2
Enzalutamide is already approved by the U.S. Food and Drug Administration (FDA) for postdocetaxel treatment of metastatic castration-resistant prostate cancer. These favorable data show that the drug is effective in the predocetaxel setting, and may pave the way for approval of that indication. Abiraterone (Zytiga), another drug that targets the androgen receptor, is now FDA-approved for treatment before and after chemotherapy in metastatic castration-resistant prostate cancer.
The double-blind, phase III PREVAIL study randomly assigned 1,717 men with metastatic castration-resistant prostate cancer not previously treated with chemotherapy to receive enzalutamide at 160 mg/d or placebo. Enzalutamide was significantly superior to placebo for the co–primary endpoints of radiographic progression-free survival and overall survival and for all secondary endpoints as well.
The median duration of enzalutamide treatment was 16.6 months vs 4.6 months for those receiving placebo. At data cutoff, 42% of men were still on enzalutamide. Compared with placebo, enzalutamide reduced the risk of death or radiographic progression-free survival by 81% (hazard ratio [HR] = 0.19; P < .0001).
The 12-month rate of radiographic progression-free survival was 65% for enzalutamide vs 14% for placebo (P < .001). At data cutoff, enzalutamide reduced the risk of death by 29% (hazard ratio [HR] = 0.71; P < .0001); 626 patients (72%) treated with enzalutamide were alive vs 532 patients (63%) in the placebo group.
Dr. Armstrong presented updated overall survival data, factoring in 116 additional deaths and an additional 4 months of follow-up. At 26 months of follow-up, median survival has not yet been reached for enzalutamide vs 31 months for placebo.
Enzalutamide significantly delayed the time to initiation of chemotherapy, achieved significantly superior prostate-specific antigen (PSA) response, time to PSA progression, objective soft-tissue response, and time to first skeletal-related event (P < .001 for all comparisons with placebo).
Dr. Armstrong presented the quality-of-life results for the first time at the Annual Meeting. “These men had compromised quality of life at baseline,” he noted. “Many had poor prognostic features.” Nearly 40% of the enzalutamide group showed [quality-of-life] response vs 22.9% of placebo patients. All quality-of-life domains on the FACT-P showed greater improvement for enzalutamide vs placebo.
Treatment with enzalutamide was associated with fatigue and hot flushes, as well as a slightly increased risk of falls. Grade 3 or greater hypertension was reported in 6% of the enzalutamide group vs 2.3% of the placebo patients. The risk of cardiovascular events was similar in both groups of patients. One seizure occurred in each of the two arms.
Orteronel Improves Progression-Free Survival
Orteronel plus prednisone significantly improved radiographic progression-free survival in men with chemotherapy-naive castration-resistant prostate cancer in the large, international, phase III ELM-PC 4 study.3 However, orteronel failed to improve the primary endpoint of overall survival.
Lead author Ronald de Wit, MD, PhD, is Professor in the Department of Medical Oncology at Erasmus University Medical Center, Rotterdam, the Netherlands, said that the ELM-PC 5 trial of orteronel also showed improved radiographic progression-free survival but no improvement in overall survival; in a subset analysis of that subsequent trial, it appeared that survival was improved in the non-Europe/North America population, whereas no regional differences in overall survival were seen in the results he reported for ELM-PC 4.
Orteronel is an investigational, nonsteroidal, reversible, selective inhibitor of 17, 20-lyase, whose activity is upregulated in castration-resistant prostate cancer, Dr. de Wit explained.
The ELM-PC 4 trial enrolled 1,560 men from 43 different countries who had chemotherapy-naive metastatic castration-resistant prostate cancer that was asymptomatic without opioid use and randomly assigned them 1:1 to orteronel at 400 mg twice daily plus prednisone at 5 mg twice daily or to placebo plus prednisone. The co–primary endpoint was radiographic progression-free survival and overall survival. Key secondary endpoints were PSA response, change in circulating tumor cell levels, and time to disease progression.
Baseline characteristics were well balanced between the two arms. This was not a well population, he noted. One out of five patients discontinued treatment with orteronel by 12 weeks, and adverse events were higher with orteronel. Thirty percent of treatment discontinuations were due to adverse events, with fatigue as the most common reason. Other side effects reported more frequently with orteronel were gastrointestinal (nausea, vomiting, and diarrhea), fatigue, asthenia, cardiac disorders, and increased lipase and amylase levels.
At an interim analysis, orteronel plus prednisone reduced the risk of radiographic progression-free survival or death by 30% compared to placebo and prednisone (P < .001). The final overall survival analysis, presented by Dr. de Wit, showed radiographic progression-free survival of 13.8 months for orteronel plus prednisone vs 8.7 months for prednisone alone, for an absolute difference of 5 months, which was statistically significant (P < .0001). Overall survival was 31.4 months for the orteronel group vs 29.5 months for placebo recipients.
The addition of cixutumumab—an investigational monoclonal antibody directed at insulin-like growth factor type 1 receptor (IGF-1R)—to androgen-deprivation therapy with biculatamide and luteinizing hormone–releasing hormone agonist failed to meet the primary endpoint of undetectable PSA response (ie, ≤ 0.2 ng/nL) compared with androgen-deprivation therapy alone in the randomized Southwest Oncology Group (SWOG) S0925 study of 211 men with metastatic hormone-sensitive prostate cancer.4
At 28 weeks, 40% of those in the cixutumumab group and 32.4% of those in the androgen-deprivation therapy group achieved undetectable PSA. The main adverse effect seen with cixutumumab was hyperglycemia. The rates of grades 1, 2, and 3 hyperglycemia in the cixutumumab arm were 27.7%, 14.9%, and 7.9%, respectively; in the androgen-deprivation arm, those rates were 7.7%, 0%, and 0%.
Circulating tumor cell counts declined in almost all patients, and those counts correlated with stratified PSA response, but no correlation was observed between IGF-1R biomarkers and undetectable PSA rate.
Patients will be followed for survival, said lead author of the phase II trial, Evan Ya-Wen Yu, MD, a medical oncologist at the Seattle Cancer Care Alliance. ■
Disclosure: Dr. Armstrong has served as a consultant or advisory for Amgen, Astellas/Medivation, Bristol-Myers Squibb, Dendreon, Janssen, and Sanofi, has received honoraria from Dendreon, Pfizer, and Sanofi, and has received research funding from Active Biotech, Dendreon, Janssen, Medivation, Novartis, Pfizer, and Sanofi. Dr. de Wit has served as a consultant or advisor for and has received honoraria from Millennium. Dr. Yu has received research funding from ImClone Systems and Veridex. For full disclosures of all study authors, visit abstracts.asco.org.
Editor's note: On June 19, 2014, Takeda Pharmaceutical Company announced that it has voluntarily decided to end the development program for orteronel for prostate cancer. The decision follows the results of two phase III clinical trials in metastatic castration-resistant prostate cancer. The studies found while orteronel plus prednisone could extend the time patients lived before their cancer progressed, it did not extend overall survival in these patients. After careful consideration of the data from these trials, the company has determined that the drug has not demonstrated a clinical profile sufficient to move forward in metastatic castration-resistant prostate cancer, given the availability of other therapies.
1. Armstrong AJ, Tombal B, Sternberg CN, et al: Primary, secondary, and quality of life endpoint results from PREVAIL. ASCO Annual Meeting. Abstract 5007. Presented June 1, 2014.
2. Beer TM, Armstrong AJ, Rathkopf DE, et al: Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. June 1, 2014 (early release online).
3. de Wit R, Fizazi K, Jinga V, et al: Phase 3, randomized, placebo-controlled trial of orteronel (TAK-700) plus prednisone in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (ELM-PC 4 trial). ASCO Annual Meeting. Abstract 5008. Presented June 1, 2014.
4. Yu EY, Tangen CM, Higano CS, et al: SWOG S0925: A randomized phase 2 study of androgen deprivation combined with cixutumumab versus androgen deprivation alone in patients with new metastatic hormone-sensitive prostate cancer. ASCO Annual Meeting. Abstract 5006. Presented June 1, 2014.
Despite the availability of hormonal therapy for the treatment of metastatic prostate cancer and the high response rates for these agents, most patients eventually experience progression to castration-resistant disease.
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