Final Analysis Confirms Superior OS Benefit with ERLEADA® in Metastatic Castrate Sensitive Prostate Cancer

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 248,530 new cases of prostate cancer will be diagnosed in 2021 and 34,130 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second generation anti-androgen agents, which include ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide), ERLEADA® (Apalutamide) and NUBEQA® (Darolutamide). Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis.

ERLEADA® (Apalutamide) is an orally administered Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. ERLEADA® inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription. ERLEADA® is presently approved for the treatment of patients with metastatic Castration Sensitive Prostate Cancer (CSPC) and non-metastatic Castration Resistant Prostate Cancer (CRPC).

TITAN (Targeted Investigational Treatment Analysis of Novel Anti-androgen) is an international, randomized, placebo-controlled, double-blind, Phase III trial, conducted to determine whether treatment with ERLEADA® would result in longer radiographic Progression Free Survival (PFS) and Overall Survival (OS) than placebo, with an acceptable Safety profile and Health-Related Quality of Life, among patients with metastatic CSPC, who were receiving concomitant ADT. In this study a 1052 patients were randomly assigned 1:1 to receive ERLEADA® plus ADT (N=525) or placebo plus ADT (N=527). Patients received ERLEADA® 240 mg orally once daily, in addition to continuous ADT. The median age was 68 years and eligible patients had adenocarcinoma of the prostate with distant metastatic disease and were castration sensitive (patients were not receiving ADT at the time of disease progression). Previous treatment for prostate cancer was limited to no more than 6 cycles of Docetaxel, with no evidence of progression during treatment. A total of 16% of the patients had undergone prostatectomy or received radiotherapy for localized disease, and 11% had received previous Docetaxel therapy and 63% had high-volume disease. The co-Primary end points were OS and radiographic PFS (rPFS).

At the first interim analysis, with a median follow up of 22.7 months, ERLEADA® significantly improved dual Primary end points of OS (HR for death=0.67; P=0.005) and rPFS (HR for radiologic progression or death=0.48; P<0.001; Chi et al. NEJM. 2019). When this data was reported, OS information was from the first planned interim analysis, whereas rPFS data was final. TITAN study was then unblinded, allowing patients without progression who were still receiving placebo, to cross over to ERLEADA®. The authors in this publication reported the final analysis of efficacy and safety results from TITAN study.

At a median follow up was 44.0 months, the previous efficacy data was confirmed even after 39.5% of patients in the placebo group crossed over to receive ERLEADA®. Median treatment durations were 39.3 months with ERLEADA® in the ERLEADA® group, 20.2 months with placebo in the placebo group, and 15.4 months with ERLEADA® in placebo-treated patients who crossed over. In the intention-to-treat population, including patients who crossed over from the placebo group, the median Overall Survival was Not Reached in the ERLEADA® group versus 52.2 months in the placebo group (HR=0.65, P < 0.0001). The OS was superior in the ERLEADA® group compared with the placebo group despite crossover and the 4-year survival rates were 65% with ERLEADA® versus 52% with placebo. When the analysis was adjusted for crossover, the Hazard Ratio further improved to 0.52 (P<0.0001). At final analysis, cytotoxic chemotherapy had been initiated in 13.1% of ERLEADA®-treated patients versus 23.9% of placebo-treated patients (HR=0.47, P<0.0001). Secondary endpoints including second PFS (PFS2) was also in favor of ERLEADA®, and Health-Related Quality of Life (HRQoL) was maintained in the ERLEADA® group throughout the study and was not different from the placebo group. Safety was consistent with previous reports.

The authors concluded that with close to 4 years of follow up, the final analysis of the TITAN study demonstrated that among patients with metastatic Castrate Sensitive Prostate Cancer, ERLEADA® plus ADT provided an improvement in Overall Survival with a 35% reduction in risk of death, which further increased to 48% reduction, after adjusting for patients who had crossed over from placebo to ERLEADA®. Further, ERLEADA® also delayed castration resistance, and maintained Quality of Life.

Apalutamide in Patients with Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. Chi KN, Chowdhury S, Bjartell A, et al. J Clin Oncol. 2021 Apr 29;JCO2003488. doi: 10.1200/JCO.20.03488. Online ahead of print.