Apalutamide Prolongs Survival in Metastatic Castration-Sensitive Prostate Cancer: Findings of TITAN Trial

Introduction

Recent evidence shows that adding chemotherapy or abiraterone to androgen deprivation therapy (ADT) yields more beneficial outcomes in high-risk or high-volume disease than ADT alone. However, in addition to patient preference, age-related comorbidities as well as the toxicity (of chemotherapy) and adverse effects due to hormonal excess (hyperaldosteronism-related and prednisone use-related adverse effects of abiraterone) limit their use in clinical practice. In this context, the concept of maximum androgen blockade using apalutamide which targets the core androgen-driven process of metastatic castration-sensitive prostate cancer was explored in this study. Efficacy in terms of survival outcomes and safety after adding apalutamide to ADT in patients with metastatic, castration-sensitive prostate cancer (PCa) is not known.

Aim

The Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) evaluated the effects of apalutamide on the radiographic progression-free survival and overall survival outcomes when added to ADT in men with metastatic castration-sensitive PCa. This trial also assessed the safety profile in these men.

Method

Study Design

• Multinational, randomized, double-blind, placebo-controlled phase 3 trial
• Patients with metastatic castration-sensitive PCa having a score of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance-status scale
• The cohort was randomized to receive either apalutamide at a dose of 240 mg orally once daily or placebo in addition to ADT.

Endpoints

• Radiographic progression-free survival defined as time from randomization to first imaging-based documentation of progressive disease or death, whichever occurred first.
• Overall survival (OS) measured as the interval from randomization to death from any cause
• Adverse events (AEs)

Results

• A total of 1052 men with a mean age of 68 years were assessed
• Apalutamide group comprised of 525 patients and placebo group included 527 patients
• Prostatectomy or radiotherapy was performed in 16.4%
• Prior docetaxel therapy was received by 10.7%
• Across both randomized arms, 62.7% patients had high volume disease
• The apalutamide group had significantly higher proportion of patients with radiographic progression-free survival as well as overall survival outcomes at 24 months as shown in figure 1.

• Apalutamide group had a 52% lower risk of radiographic progression and 33% lower risk of death than the placebo group, hazard ratios (HR) of 0.48; 95% confidence interval (CI) 0.39-0.60; p<0.001 and 0.67; 95% CI 0.51-0.89; p=0.005 respectively
• Time to cytotoxic chemotherapy was significantly longer with apalutamide + ADT versus ADT + placebo with 61% lower risk associated with apalutamide + ADT than ADT + placebo (HR 0.39, 95% CI 0.27 – 0.56, p < 0.001)
• The incidence of grade 3 or 4 events was similar across the groups (42.2% vs 40.8%) as was the incidence of serious AEs between the groups (19.8% vs 20.3%)
• Events reported in ≥10% of patients in either group or events of grade ≥3 reported in ≥10 patients in either group were hot flushes, fatigue, hypertension, back pain, arthralgia, pain in arm or leg, pruritus, weight gain, anaemia, constipation, asthenia, bone pain, generalized rash, raised serum alkaline phosphatase and urinary retention.
• Adverse events of special interest were rash, fall, fracture, hypothyroidism and seizure.
• AE-related discontinuation rates were 8% in the study group and 5.3% in placebo

Conclusion

• Addition of enzalutamide to androgen deprivation therapy (ADT) significantly prolonged the overall survival and radiographic progression-free survival outcomes as compared to placebo plus ADT in patients with metastatic castration-sensitive prostate cancer.
• Treatment with apalutamide was safe and did not increase the incidence of adverse events as compared to placebo plus ADT.

N Engl J Med. 2019 Jul 4;381(1):13-24. Doi: 10.1056/NEJMoa1903307.