As reported in the Journal of Clinical Oncology by Kim N. Chi, MD, of BC Cancer and Vancouver Prostate Centre, and colleagues, the final overall survival analysis of the phase III TITAN trial showed significant benefit of 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 the crossover to apalutamide that occurred among patients initially randomly assigned to the placebo group.¹

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 double-blind trial, 1,052 patients were randomly assigned to receive apalutamide at 240 mg/d (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.

For the apalutamide vs placebo groups, at baseline, the median patient age was 69 years (range = 45–94 years) vs 68 years (range = 43–90 years), and Gleason score was < 7 in 7.8% vs 7.4%, 7 in 25.3% vs 24.7%, and > 7 in 66.9% vs 67.9%. The Eastern Cooperative Oncology Group performance status was 0 (62.5% vs 66.0%) or 1 in all but one patient (placebo group). High-volume disease was present in 61.9% vs 63.6%; 11.0% vs 10.4% had received prior docetaxel; and 17.9% vs 15.0% had undergone prior therapy for localized disease. Median prostate-specific antigen (PSA) level was 5.97 µg/mL (range = 0–2,682 µg/mL) vs 4.02 µg/mL (range = 0–2,229 µg/mL). Metastatic stage at initial diagnosis was M0 in 16.2% vs 11.2%, M1 in 78.3% vs 83.7%, and MX in 5.5% vs 5.1%. Mean Brief Pain Inventory–Short Form pain score was 0 (no pain) in 37.7% vs 38.0%, 1 to 3 (mild pain) in 37.1% vs 39.3%, 4 to 7 (moderate pain) in 18.7% vs 18.0%, and 8 to 10 (severe pain) in 2.3% vs 2.1%.

Overall Survival

At the prespecified event-based final analysis clinical cutoff in September 2020, 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 the placebo patients who crossed over.

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

A total of 257 patients given apalutamide (49.0%) and 358 patients given placebo (67.9%) discontinued study treatment, the most common reason being progressive disease. Among 247 patients treated with apalutamide and 345 patients given placebo who discontinued study treatment and remained alive, 36.0% vs 50.1% received first subsequent life-prolonging therapy for prostate cancer. Among 138 and 261 who were alive and discontinued therapy because of progressive disease, 54.3% vs 57.9% received first subsequent life-prolonging therapy, most commonly docetaxel (26.8% vs 27.2%) and abiraterone acetate plus prednisone (14.5% vs 21.5%). Among 109 and 84 patients who were alive and discontinued study treatment for reasons other than disease progression, 12.8% vs 26.2% received first subsequent life-prolonging therapy.

Secondary Endpoints and Other Outcome Measures

At final analysis, cytotoxic chemotherapy had been initiated in 13.1% of patients given apalutamide vs 23.9% of patients given placebo (HR = 0.47, 95% CI = 0.35–0.63, P < .0001), with the median time to cytotoxic chemotherapy not reached in either group (95% CI = not reached to not reached in either group). PSA disease progression occurred in 26.3% vs 65.3% of patients (HR = 0.27, 95% CI = 0.22–0.33, P < .0001), with the median time to PSA disease progression not reached (95% CI = not reached to not reached) vs 12.9 months (95% CI = 10.2–14.8 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 the median second progression-free survival (defined as the time from random assignment to disease progression on first subsequent therapy or death) not reached (95% CI = not reached to not reached) vs 44.0 months (95% CI = 38.9 months to not reached). Castration resistance occurred in 36.4% vs 71.2% of patients (HR = 0.34, 95% CI = 0.29–0.41, P < .0001), with the median time to castration resistance not reached (95% CI = not reached to not reached) vs 11.4 months (95% CI = 10.1–14.7 months).

Numeric benefit with apalutamide was observed for the 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 based on total FACT-P score was maintained in the apalutamide group, with no substantial differences in change from baseline observed between treatment groups. Health-related quality of life in specific domains measured by FACT-P subscales were also maintained throughout follow-up in the apalutamide group.

Safety

The safety of apalutamide treatment 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. Adverse events led to discontinuation of treatment in 11.8% of the apalutamide group, 6.0% of the placebo group excluding patients who crossed over to apalutamide, and 7.7% of patients who crossed over to apalutamide. No treatment-related deaths were reported.

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].” 

DISCLOSURE: The study was supported by Janssen Research & Development. Dr. Chi has received honoraria from Astellas Pharma, AstraZeneca, Bayer, Janssen, Merck, and Roche; has served as a consultant or advisor to Amgen, Astellas Pharma, AstraZeneca, Bayer, Constellation Pharmaceuticals, Daiichi Sankyo, ESSA, Janssen, Merck, Point Biopharma, Roche, and Sanofi; and has received institutional research funding from Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, ESSA, Janssen, Merck, Novartis, Pfizer, Roche, and Sanofi.

REFERENCE

1. Chi KN, Chowdhury S, Bjartell A, et al: Apalutamide in patients with metastatic castration-sensitive prostate cancer: Final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol 39:2294-2303, 2021.