ASCO 2019: TITAN: Meets Dual Primary Endpoints, Apalutamide vs Placebo in Patients with Metastatic Castration-sensitive Prostate Cancer Receiving ADT 

Chicago, IL ( The Targeted Investigational Treatment Analysis of Novel Anti-Androgen (TITAN) study was a phase III, double-blind, randomized study designed to determine whether apalutamide, a selective next-generation androgen receptor inhibitor, plus ADT improves radiographic progression-free survival (rPFS) and overall survival (OS) compared with placebo plus ADT in men with metastatic castration sensitive prostate cancer (mCSPC). Kim Chi, MD from the British Columbia Cancer Agency presented the first results of this phase III trial.

Apalutamide is an androgen receptor inhibitor approved in the United States and Europe for patients with nonmetastatic castration-resistant prostate cancer.1 Direct inhibition of the androgen receptor may provide a more complete reduction of androgen signaling than ADT alone, leading to improved clinical outcomes. Key eligibility of TITAN included patients that were (i) castration sensitive, (ii) had distant metastatic disease by >= 1 lesion on bone scan, and (iii) were ECOG performance status 0 or 1. An on-study requirement was that patients had continuous ADT. Patients with prior docetaxel were permitted, as were (i) patients with ADT <= 6 months for mCSPC or <= 3 years for local disease, and (ii) patients with local treatment completed >= 1 year prior. Patients were stratified by Gleason score (<=7 vs >=8), region (North America and Europe vs other countries), and prior docetaxel use.

Dual primary endpoints were rPFS and OS. Secondary endpoints were time to (i) initiation of cytotoxic chemotherapy, (ii) pain progression, (iii) chronic opioid use, and (iv) skeletal-related event. Time-to-event endpoints were estimated by Kaplan-Meier and Cox proportional hazards methods. Patients were randomized 1:1 to apalutamide (240 mg/d) or placebo, added to ADT, in 28-day cycles. This first planned OS interim analysis took place after ~50% of expected events.

ASCO 2019 TITAN study design all comer pt pop

There were 525 patients randomized to apalutamide and 527 to placebo. The median age was 68 years, 8% had prior treatment for localized disease, and 11% had prior docetaxel. With regards to disease burden, 63% had high-volume disease and 37% had low-volume disease. At the median follow-up of 22.6 months, 66% of patients on apalutamide and 46% of patients receiving placebo remained on treatment. Apalutamide significantly improved rPFS (HR 0.48, 95% CI 0.39-0.60), with a 52% reduction in risk of death or radiographic progression. Importantly, this benefit was observed across all subgroups analyzed. Median rPFS was not reached in the apalutamide group and was 22.1 months in the placebo group. Second, apalutamide significantly improved OS (HR 0.67, 95% CI 0.51-0.89), with a 33% reduction in risk of death. Median OS was not reached in the apalutamide or placebo group.

ASCO 2019 TITAN OS APA death risk

Similarly, there was a response across most subgroups:

ASCO 2019 TITAN OS benefit

In terms of secondary endpoints, time to initiation of cytotoxic chemotherapy was significantly improved with apalutamide (HR 0.39, 95% CI, 0.27-0.56). There was no difference in time to chronic opioid use or time to skeletal-related event. Apalutamide was also favored for time to PSA progression and second progression-free survival. Rates of grade 3/4 adverse events (42% apalutamide, 41% placebo) were similar, and discontinuations due to adverse events (8% apalutamide, 5% placebo) were low. Based on these results, the independent data monitoring committee recommended unblinding to allow crossover of placebo patients to receive apalutamide.

Dr. Chi concluded his presentation of the TITAN study with several take-home messages:
  • The TITAN study met its dual primary endpoints, demonstrating significant benefits with apalutamide + ADT in an all-comer mCSPC population
  • There was a significant improvement in OS, with a 33% reduction in risk of death for apalutamide
  • There was a significant improvement in rPFS, with a 52% reduction in the risk of progression or death for apalutamide
  • Secondary and exploratory endpoints also favored apalutamide – prolonged time to cytotoxic chemotherapy (61% risk reduction), PSA progression (74% risk reduction), and second progression-free survival (34% risk reduction)
  • Treatment was tolerable and the safety profile was consistent with the known side-effects of apalutamide
Clinical Trial Information: NCT02489318
Further Related Content: Interview with Kim Chi, MD - First Results of TITAN

Presented by: Kim N. Chi, MD, FRCPC, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA

  1. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 2018;378(15):1408-1418.