Association of prostate-specific antigen (PSA) response and overall survival (OS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) from the phase 3 ARASENS trial.
Authors: Saad Fred , Hussain Maha H. A. , Tombal Bertrand F. , Fizazi Karim , Sternberg Cora N. , Crawford E. David , Thiele Silke , Li Rui , Kuss Iris , Joensuu Heikki , Smith Matthew Raymond 
Published: June 2022

5078 Background: Reductions in PSA level have been associated with improved OS in patients (pts) with mHSPC. In ARASENS (NCT02799602), darolutamide (DARO) + androgen-deprivation therapy (ADT) in combination with docetaxel significantly reduced the risk of death by 32.5% (hazard ratio [HR] 0.675; 95% confidence interval [CI] 0.568–0.801; P< 0.0001) vs ADT + docetaxel in pts with mHSPC. We report the association between PSA response and OS from ARASENS. Methods: Pts with mHSPC were randomized 1:1 to DARO 600 mg twice daily or matching PBO + ADT and docetaxel. Serum PSA was measured at screening and every 12 weeks. Exploratory analyses included time to PSA progression (≥25% increase from PSA nadir [lowest or at study entry] and PSA increase ≥2 ng/mL ≥12 weeks from nadir [both confirmed by a second value ≥3 weeks later]) and undetectable PSA (< 0.2 ng/mL for 2 samples ≥3 weeks apart) at 24, 36, and 52 weeks and any time during treatment. Comparisons between treatment groups were performed using the Cochran-Mantel Haenszel test stratified by randomization stratification factors (metastatic spread according to TNM classification and alkaline phosphatase levels at study entry). Post hoc landmark analyses evaluated the association between undetectable PSA at weeks 24 and 36 and OS for the overall population. Results: Of 1306 randomized pts, 1305 were included in the full analysis set (DARO 651; PBO 654), both with ADT and docetaxel. Median (range) PSA levels at study entry were 30.3 (0.0–9219.0) and 24.2 (0.0–11,947.0) ng/mL, respectively. DARO significantly prolonged time to PSA progression (HR 0.255; 95% CI 0.208–0.313; P< 0.0001). Undetectable PSA was achieved in more pts receiving DARO (48.7%) vs PBO (23.9%) at 24 weeks, and the rate continued to increase at 36 and 52 weeks in the DARO group to 57.1% and 60.2%, respectively, vs minimal change in the PBO group (25.1% and 26.1%). Undetectable PSA levels at any time were achieved in 67.3% in the DARO group and 28.6% in the PBO group. A treatment difference in undetectable PSA based on non-overlapping 95% CIs was observed at all time points. For the overall population, OS was improved for pts who achieved undetectable PSA levels vs those who did not at 24 weeks (HR 0.398; 95% CI 0.321–0.493) and 36 weeks (HR 0.351; 95% CI 0.284–0.434). Additional baseline and safety data by PSA level will be reported. Conclusions: The combination of DARO + ADT and docetaxel significantly prolonged the time to PSA progression and more pts receiving DARO vs PBO achieved undetectable PSA levels, reflecting strong PSA response over time. In pts with mHSPC, achievement of undetectable PSA at 24 and 36 weeks was associated with improved OS, with risk of death reduced by 60% and 65%, respectively, vs those who did not achieve undetectable PSA at 24 and 36 weeks. Clinical trial information: NCT02799602.