Analysis of quality-adjusted time without symptoms or toxicity (Q-TWiST) in patients with metastatic hormone-sensitive prostate cancer: From the ARASENS trial.

133 Background: Triplet combination of darolutamide (DARO; an androgen receptor inhibitor) with androgen deprivation therapy (ADT), and docetaxel significantly improved overall survival (OS; HR 0.68; 95% CI 0.57–0.80; P <0.001) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in the ARASENS trial (NCT02799602). DARO also showed benefit of intensified therapy in maximizing efficacy while minimizing toxicity. Q-TWiST is an approach that compares variation in efficacy and toxicity between treatment arms. This study assessed quality of life-adjusted survival of patients with mHSPC using DARO triplet therapy compared with doublet therapy (ADT and docetaxel). Methods: The Q-TWiST method assumes patients progress through a set of three health states. Time Without Symptoms or Toxicity (TWiST), time in RELapse or disease progression (REL), and time with TOXicity (TOX; with grade 3/4 symptoms or toxic effects) were estimated by the 53-month restricted mean using grade 3/4 adverse event (AE), OS, and time to castration-resistant prostate cancer (CRPC) data from ARASENS. Q-TWiST was calculated as the weighted sum of time spent in each health state for each treatment arm (DARO vs placebo [PBO]), adjusted by corresponding utility scores obtained from published sources. Differences in mean Q-TWiST between treatment arms were calculated for utility weights. For each health state, 95% CIs and mean standard errors (SEs) of TWiST, REL, TOX, and Q-TWiST were calculated based on 1000 bootstrap samples. Relative gain in Q-TWiST was calculated by dividing the mean Q-TWiST difference between treatment arms by the restricted mean OS of the PBO arm. Results: The full analysis set included 651 and 654 patients in the DARO and PBO arms, respectively. Patients had similar incidence of grade 3/4 AEs prior to disease progression (47.5% vs 53.2%), lower incidence of CRPC (34.6% vs 59.8%), and improved OS (deaths: 35.2% vs 46.5%) with DARO vs PBO. Significantly, patients had 6.3 months more Q-TWiST with DARO vs PBO driven by an increase in TWiST (mean 17.6 months [SE 0.9] vs 10.9 months [0.7]), and less REL (2.4 months [0.3] vs 8.7 months [0.4]); due to the long treatment duration, there was more TOX (17.2 months [0.9] vs 11.3 months [0.7]) at 53 months (all P <0.001). Partitioned Kaplan–Meier survival curves showed significantly persistent TWiST with DARO vs PBO indicating patients spent more time without grade 3/4 AEs before disease progression ( P <0.001). The DARO Q-TWiST relative gain was 16.0% (clinically important). Conclusions: In ARASENS, DARO triplet therapy provided an additional 6.3 months of OS without symptoms or toxicity and a Q-TWiST relative gain of 16.0% corresponding to higher overall quality-adjusted survival vs doublet therapy at 53 months. This highlights the benefit of the standard of care ARASENS regimen for patients with mHSPC. Clinical trial information: NCT02799602 .