As reported in European Urology by Matthew R. Smith, MD, and colleagues, the final analysis of phase III SPARTAN trial has shown significant prolongation of overall survival with apalutamide vs placebo in patients with nonmetastatic castration-resistant prostate cancer and prostate-specific antigen (PSA) doubling time of ≤ 10 months.

The previously reported primary analysis of the trial showed significant prolongation of metastasis-free survival with apalutamide (median = 40.5 months vs 16.2 months, hazard ratio [HR] = 0.28, P < .001). Overall survival data were not mature at time of analysis. The primary analysis supported the February 2018 approval of apalutamide in treatment of nonmetastatic castration-resistant prostate cancer.

Matthew R. Smith, MD

Study Details

In the double-blind trial, 1,207 patients were randomly assigned 2:1 between October 2013 and December 2016 to receive apalutamide at 240 mg/day (n = 806) or placebo (n = 401) plus ongoing androgen-deprivation therapy.

Overall Survival and Other Efficacy Outcomes

Median follow-up was 52 months. After the primary analysis endpoint was met, the study was unblinded and 76 patients (19%) still receiving placebo crossed over to receive apalutamide. The median treatment durations were 32.9 months in the apalutamide group, 11.5 months in the placebo group, and 26.1 months with apalutamide in the crossover group. Subsequent life-prolonging therapy was received by 46% patients in the apalutamide group and 84% in the placebo group, including patients who received apalutamide after crossover.

Median overall survival was 73.9 months in the apalutamide group vs 59.9 months in the placebo group (HR = 0.78, 95% confidence interval [CI] = 0.64–0.96, P = 0.016). Hazard ratios favored apalutamide in virtually all subgroups analyzed.

Apalutamide was associated with significant prolongation of time to first cytotoxic chemotherapy (median not reached in either group; HR = 0.63, 95% CI = 0.49–0.81, P = 0.0002).

Median progression-free survival-2 was 55.6 months vs 41.2 months (HR = 0.55, 95% CI = 0.46–0.66, nominal P < .0001). Updated analysis confirmed the benefit of apalutamide in reducing risk of symptomatic progression (median not reached in either group; HR = 0.57, 95% CI = 0.44–0.73, nominal P < .0001). Median times to PSA progression were 40.5 months vs 3.7 months (HR = 0.07, 95% CI = 0.06–0.09], nominal P < .0001).

Safety

Safety was consistent with previous reports. The incidence of adverse events of any grade were 97% in the apalutamide group, 94% in the placebo group, and 90% in patients in the crossover group. Exposure-adjusted serious adverse event rates per 100 patient-years were 13.7 in the apalutamide group and 22.2 in the placebo group. Adverse events led to treatment discontinuation in 15% vs 8.4% of patients. One adverse event leading to death (myocardial infarction) was considered potentially related to apalutamide treatment.

The investigators concluded, “Extension of overall survival with apalutamide compared with placebo conferred impactful benefit in patients with nonmetastatic castration-resistant prostate cancer. There was a 22% reduction in the hazard of death in the apalutamide group despite 19% crossover (placebo to apalutamide) and higher rates of subsequent therapy in the placebo group…With data presented herein, all primary and secondary study endpoints of SPARTAN were met; findings demonstrate the value of apalutamide as a treatment option for nonmetastatic castration-resistant prostate cancer.”

Dr. Smith, of Massachusetts General Hospital Cancer Center and Harvard Medical School, is the corresponding author for the European Urology article.

Disclosure: The SPARTAN study was funded by Janssen Research & Development. For full disclosures of the study authors, visit europeanurology.com.