Enzalutamide Bests Bicalutamide in Two CRPC Studies

Celestia S. Higano, MD

Enzalutamide (Xtandi) significantly improved progression-free survival (PFS), PSA kinetics, and quality of life (QoL) compared with bicalutamide in men with castration-resistant prostate cancer (CRPC), according to findings from the TERRAIN and STRIVE trials presented during the late-breaking abstract session at the 2015 American Urological Association (AUA) Annual Meeting.

In the STRIVE trial of men with M0 and M1 CRPC, the median PFS was 19.4 months with enzalutamide and 5.7 months with bicalutamide (hazard ratio [HR] = 0.24; 95% CI, 0.18-0.32; P <.0001). In the phase II TERRAIN study of men with M1 CRPC, the median PFS was 15.7 months with enzalutamide compared with 5.8 months with bicalutamide (HR = 0.44; 95% CI, 0.34-0.57; P <.0001). In the two studies, the benefits of enzalutamide were seen in PSA kinetics and Functional Assessment of Cancer Treatment-Prostate (FACT-P) scores.

"Results from the STRIVE trial are of key interest to the medical community as they mark the second head-to-head trial of enzalutamide versus bicalutamide," STRIVE co-principal investigator Celestia S. Higano, MD, professor, medicine and urology, University of Washington, said in a statement. Results from the TERRAIN trial were presented earlier this year, at the 2015 European Association of Urology (EAU) Congress.

In the STRIVE trial, 396 men with CRPC were evenly randomized to enzalutamide (n = 198) or bicalutamide (n = 198). The median age of patients was 73 years and 35% were M0 (n = 139). Overall, 70 patients with M0 disease and 128 with M1 CRPC were treated with enzalutamide. The median baseline PSA level was 12 ng/mL.

Specifically in those with M1 disease (n = 257), the median PFS was 16.5 months for those treated with enzalutamide and 5.5 months with bicalutamide (HR = 0.24; 95% CI, 0.17-0.34; P <.0001). In those with M0 CRPC, the median PFS was not yet reached with enzalutamide versus 8.6 months with bicalutamide (HR = 0.24; 95% CI, 0.14-0.42; P <.0001).

The median duration of treatment was 14.7 months with enzalutamide and 8.4 months with bicalutamide. The median time to PSA progression in patients with M0 disease treated with enzalutamide was not reached compared with 11.1 months in the bicalutamide arm (HR = 0.18). In the M1 arm, PSA progression was seen at 24.9 months with enzalutamide versus 5.7 months with bicalutamide (HR = 0.19).

Overall, 29.4% of patients treated with enzalutamide experienced a serious adverse event compared with 28.3% with bicalutamide. Grade 3 or higher cardiac toxicity was seen in 5.1% versus 4.0% for enzalutamide and bicalutamide, respectively. There was one seizure in the enzalutamide-treated patients compared with none in the bicalutamide arm.

"The analyses from STRIVE are in line with previous data from the TERRAIN trial demonstrating that patients treated with enzalutamide have improved clinical outcomes versus the common practice of adding bicalutamide to a luteinizing hormone-releasing hormone therapy," Higano said.

In the TERRAIN study, 375 patients with asymptomatic or minimally symptomatic M1 CRPC were randomized to enzalutamide at 160 mg/day (n = 184) or bicalutamide at 50 mg/day (n = 191). The median PSA was 21 ng/mL, 74% of patients had an ECOG score of 0, and the median FACT-P total score was 121.

Median time on treatment was 11.7 and 5.8 months in the enzalutamide and bicalutamide arms, respectively. The median time to PSA progression was 19.4 versus 5.8 months for enzalutamide and bicalutamide, respectively (HR = 0.28; P .<0001).

A PSA response of ≥50% was achieved in 82.1% of patients in the enzalutamide arm compared with 20.9% with bicalutamide. A more than 90% PSA response was seen in over half the patients treated with enzalutamide (56%) versus 5.2% with bicalutamide. The HR for time to ≥50% decline was 7.0 (95% CI, 4.8-10.2) and the HR for ≥90% was 13.9 (95% CI, 7.2-26.8).

FACT-P score deteriorated at 13.8 months for patients treated with enzalutamide compared with 8.5 months with bicalutamide (HR = 0.63; 95% CI, 0.46-0.88). FACT-P total score response was seen in 33% of patients treated with enzalutamide and 22% with bicalutamide.

"The results of the TERRAIN trial, if confirmed, have the potential to impact the treatment landscape of metastatic castration-resistant prostate cancer," co-principle investigator Axel Heidenreich, MD, PhD, professor and director, Department of Urology, University hospital, Aachen, Germany, said when the first analysis of the study was presented at the EAU Congress.

Overall, serious adverse events were seen in 31.1% of patients treated with enzalutamide compared with 23.3% in the bicalutamide arm. The most frequently observed adverse events with enzalutamide versus bicalutamide were fatigue (27.9% vs 20.1%), back pain (19.1% vs 18.0%), hot flush (14.8% vs 11.1%), hypertension (14.2% vs 7.4%), diarrhea (11.5% vs 9.0%), weight decrease (10.9% vs 7.9%), and pain in extremities (10.9% vs 5.3%).

Grade 3 or higher cardiac toxicity was observed in 5.5% versus 2.1% of patients in the enzalutamide and bicalutamide arms, respectively. Two seizures were reported in the enzalutamide arm versus one in the bicalutamide-treated patients.

"TERRAIN was truly head-to-head trial saying, 'OK, let's see which one is better,'" TERRAIN co-principal investigator Neal D. Shore, MD, Carolina Urologic Research Center, said in an interview with OncLive. "We started this trial before the PREVAIL trial, which clearly showed the benefits of enzalutamide prior to chemotherapy, had been completed."

Findings from the phase III PREVAIL trial were the basis for an expansion of the enzalutamide label in September 2014. The therapy is FDA approved for men with mCRPC, regardless of prior treatment with chemotherapy. The antiandrogen was initially approved for chemotherapy-pretreated men with metastatic CRPC in August 2012.

In the PREVAIL study, 1717 men with a median age of 71 years received treatment with enzalutamide (n = 872) or placebo (n = 845). Enzalutamide was administered at 160 mg daily. The median time on treatment was 16.6 months with enzalutamide versus 4.6 months with placebo.

The median overall survival was 32.4 months with enzalutamide versus 30.2 months with placebo (HR = 0.71; P <.0001). The median radiographic PFS was not yet reached in the enzalutamide arm compared with 3.9 months with placebo (HR = 0.19; P <.0001). The overall response rate was 58.8% versus 5%, for enzalutamide and placebo, respectively (P <.0001).

The large phase III PROSPER trial is assessing the efficacy of enzalutamide in patients with M0 CRPC. The study was initiated in December 2013 with the goal of enrolling approximately 1560 patients. In the study, patients are randomized in a 2:1 ratio between enzalutamide at 160 mg/day and placebo. The primary endpoint of the study is metastasis-free survival (NCT02003924).

References:

1. Shore ND, Heidenreich A, Villers A, et al. TERRAIN Trial: Prostate-specific Antigen Kinetics and Quality of Life Results of Enzalutamide versus Bicalutamide in Metastatic Castration-resistant Prostate Cancer. Presented at: 2015 AUA Annual Meeting; 2015 15-19; New Orleans, LA. Abstract PII-LBA4.
2. Penson D, Armstrong AJ, Concepcion R, et al. A Multicenter Phase 2 Study of Enzalutamide (ENZA) versus Bicalutamide (BIC) in Men with Nonmetastatic (M0) or Metastatic (M1) Castration-Resistant Prostate Cancer (CRPC): the STRIVE Trial. Presented at: 2015 AUA Annual Meeting; 2015 15-19; New Orleans, LA. Abstract PII-LBA10.
3. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014; 371:424-433.

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