Overall survival and quality of life with [ ¹⁷⁷ Lu] Lu-PSMA-617 plus enzalutamide versus enzalutamide alone in poor-risk, metastatic, castration-resistant prostate cancer in ENZA-p (ANZUP 1901).

17 Background: Interim analysis of ENZA-p with median follow-up 20 months showed improved PSA-progression-free survival (PFS) and depth of PSA-response with the addition of [ 177 Lu]Lu-PSMA-617 (LuPSMA) to enzalutamide (enza) as first-line treatment of poor-risk, metastatic, castration-resistant prostate cancer (mCRPC). Here we report effects on overall survival (OS) and health-related quality of life (HRQL) with longer follow-up. Methods: We randomly assigned 162 participants (pts) to enza 160 mg daily alone, or in combination with (2 or 4 doses) LuPSMA 7.5 GBq. Eligible pts had mCRPC not previously treated with chemotherapy or an androgen receptor pathway inhibitor for mCRPC, 68 Ga-PSMA PET-avid disease, and at least 2 risk factors for early disease progression on enza-alone. HRQL was to be rated with the EORTC core quality-of-life questionnaire every 6 weeks until radiological progression. Deterioration-free survival was from random assignment until the earliest of death, clinical progression, discontinuation of study treatment, or a worsening of 10 points or more from baseline in physical function, or in overall health and quality of life (OHQL). HRQL scores were analyzed with repeated measures modelling to calculate group means and differences. HRQL scores range from 0 (lowest possible) to 100 (highest possible). Time to event data were analysed with the Kaplan-Meier method, stratified log rank test, and stratified Cox-proportional hazards regression. Analyses of these secondary endpoints were specified a priori and are by intention to treat. P-values and confidence intervals are 2-sided without adjustment for multiple comparisons. Results: A total of 96 deaths were reported after a median follow-up of 34 months (IQR 29-39): 53 among those assigned enza-alone and 43 among those assigned enza+LuPSMA. OS was longer in the enza +LuPSMA group than the enza-alone group (median months 34 vs 26; HR 0.55, 95% CI 0.36 to 0.84; p=0.005). 30 of 79(38%) in the enza-alone arm received subsequent LuPSMA off trial. HRQL was rated by 154 of 162 pts (95%). Deterioration-free survival rates at 12 months, and stratified log-rank p-values favored enza+LuPSMA for both OHQL (40% v 13%; p <0.001), and for physical function (38% v 17%; p <0.001). Mean scores for pain until progression favoured the enza+LuPSMA group over the enza-alone group (difference 7.2, 95% CI 1.6 to 13; p=0.01). Mean scores for fatigue until progression favoured the enza+LuPSMA group over the enza-alone group (difference 5.9, 95% CI 1.1 to 10.7; p=0.02). The frequency of self-rated xerostomia was lower in the enza-alone group (74% vs. 57%; p=0.04). Conclusions: The addition of LuPSMA to enzalutamide in poor risk mCRPC improved overall survival, scores for both pain and fatigue, and deterioration-free survival for both physical function and for OHQL. Clinical trial information: NCT04419402 .