As reported in the Journal of Clinical Oncology by Kim N. Chi, MD, and colleagues, the final overall survival analysis of the phase III TITAN trial showed significant benefit with apalutamide plus androgen-deprivation therapy vs placebo plus androgen-deprivation therapy in patients with metastatic castration-sensitive prostate cancer, both without and with adjustment for significant crossover to apalutamide from the placebo group.

The first interim analysis of the trial (median follow-up = 22.7 months) showed superior overall and radiographic progression-free survival with the addition of apalutamide to ongoing androgen-deprivation therapy and supported the September 2019 approval of apalutamide in this setting.

Kim N. Chi, MD

Study Details

In the trial, 1,052 patients were randomly assigned to receive apalutamide at 240 mg per day (n = 525) or placebo (n = 527) in addition to ongoing androgen-deprivation therapy. After study unblinding in January 2019, patients in the placebo group were permitted to cross over to receive apalutamide. P values for secondary and other endpoints are nominal P values.

Overall Survival

Median follow-up was 44.0 months. A total of 208 patients in the placebo group (39.5%) crossed over to receive apalutamide. Median treatment durations were 39.3 months with apalutamide in the apalutamide group, 20.2 months with placebo in the placebo group, and 15.4 months with apalutamide in placebo-treated patients who crossed over.

In the intention-to-treat population, including the crossover patients as part of the placebo group, median overall survival was not reached (95% confidence interval [CI] = not reached–not reached) in the apalutamide group vs 52.2 months (95% CI = 41.9 months–not reached) in the placebo group (hazard ratio [HR] = 0.65, 95% CI = 0.53–0.79, P < .0001); 4-year rates were 65.1% vs 51.8%. In inverse probability censoring weighted analysis adjusting for crossover from placebo to apalutamide, median overall survival was not reached with apalutamide vs 39.8 months with placebo (HR = 0.52, 95% CI = 0.42–0.64, P < .0001).

Secondary Endpoints and Other Outcome Measures

At final analysis, cytotoxic chemotherapy had been initiated in 13.1% of apalutamide-treated patients vs 23.9% of placebo-treated patients (HR = 0.47, 95% CI = 0.35–0.63, P < .0001), with median time to cytotoxic chemotherapy not reached in either group. Prostate-specific antigen (PSA) progression occurred in 26.3% vs 65.3% of patients (HR = 0.27, 95% CI = 0.22–0.33, P < .0001), with a median time to PSA progression of not reached vs 12.9 months. A second progression-free survival event occurred in 33.0% vs 46.7% of patients (HR = 0.62, 95% CI = 0.51–0.75, P < .0001), with median progression-free survival-2 being not reached vs 44.0 months. Castration resistance occurred in 36.4% vs 71.2% of patients (HR = 0.34, 95% CI = 0.29–0.41, P < .0001), with median time to castration resistance being not reached vs 11.4 months.

Numeric benefit with apalutamide was observed for time to pain progression (median = not reached vs not reached, HR = 0.87, 95% CI = 0.70–1.08, P = .197), time to chronic opioid use (median = not reached vs not reached, HR = 0.79, 95% CI = 0.58–1.09, P = .156), and time to skeletal-related event (median = not reached vs not reached, HR = 0.86, 95% CI = 0.62–1.19, P = .361).

Assessment with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) instrument showed that favorable baseline health-related quality of life (HRQoL) based on total FACT-P score was maintained in the apalutamide group, with no substantial differences in change from baseline observed between treatment groups. HRQoL in specific domains measured by FACT-P subscales were also maintained throughout follow-up in the apalutamide group.

Safety

The safety profile of apalutamide was consistent with previous reports. Exposure-adjusted rates of adverse events of interest—consisting of any-grade skin rash, fracture, falls, ischemic heart disease, ischemic cerebrovascular disorders, and seizure—were 40.0, 22.4, and 41.9 per 100 patient-years in the apalutamide, placebo, and crossover groups, respectively. Grade 3 or 4 adverse events of interest occurred in 7.6%, 2.7%, and 6.5% of the three groups, respectively. The incidence of first any-grade skin rash event was higher in apalutamide-treated vs placebo-treated patients, reaching a plateau after approximately 6 months. The most common treatment-related adverse events with apalutamide were rash and fatigue. No treatment-related deaths were reported. Three patients in the crossover group had COVID-19 adverse events; all resolved, and none led to treatment discontinuation or death.

The investigators concluded, “The final analysis of TITAN confirmed that, despite crossover, apalutamide plus [androgen-deprivation therapy] improved overall survival, delayed castration resistance, maintained health-related quality of life, and had a consistent safety profile in a broad population of patients with metastatic castration-sensitive prostate cancer.”

Dr. Chi, of the Clinical Trials Unit, BC Cancer and Vancouver Prostate Centre, Vancouver Centre, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Janssen Research & Development. For full disclosures of the study authors, visit ascopubs.org.