Overall survival and quality of life with [Lu]Lu-PSMA-617 plus enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer (ENZA-p): secondary outcomes from a multicentre, open-label, randomised, phase 2 trial.

Background

Interim analysis of the ENZA-p trial showed improved prostate-specific antigen (PSA) progression-free survival with the addition of lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 to enzalutamide as first-line treatment of metastatic castration-resistant prostate cancer. Here, we report the secondary endpoints of overall survival and health-related quality of life (HRQOL) with longer follow-up.

Methods

ENZA-p was a multicentre, open-label, randomised, phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older who had not previously been treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga PSMA-PET-CT-positive disease, an Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, early docetaxel, and previous treatment with abiraterone. Treatment was oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks. The primary endpoint was prostate-specific antigen (PSA) progression-free survival, which has been previously reported. Overall survival, defined as the interval from the date of randomisation to date of death from any cause, or the date last known alive, and HRQOL were key secondary endpoints. HRQOL was assessed with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the Patient Disease and Treatment Assessment Form. For HRQOL analyses, deterioration-free survival was measured from randomisation until the earliest occurrence 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 QOL. Analyses of these secondary endpoints were prespecified and are by intention to treat. The trial is registered with ClinicalTrials.gov, NCT04419402, and follow-up is complete.

Findings

Between Aug 17, 2020, and July 26, 2022, 79 patients were randomly assigned to enzalutamide and 83 to enzalutamide plus [177Lu]Lu-PSMA-617. 96 deaths was reported after a median follow-up of 34 months (IQR 29-39): 53 (67%) in the enzalutamide group and 43 (52%) in the enzalutamide plus [177Lu]Lu-PSMA-617 group. Overall survival was longer in the enzalutamide plus [177Lu]Lu-PSMA-617 group than the enzalutamide group (median 34 months [95% CI 30-37] vs 26 months [23-31]; HR 0·55 [95% CI 0·36-0·84], log-rank p=0·0053). HRQOL was rated by 154 (95%) of 162 participants. Deterioration-free survival at 12 months and stratified log-rank p values favoured enzalutamide plus [177Lu]Lu-PSMA-617 for both physical function (median 10·64 months [95% CI 7·66-12·42] vs 3·42 months [3·19-7·89]; HR 0·51 [95% CI 0·36-0·72], log-rank p<0·0001) and overall health and QOL (8·71 months [6·41-11·56] vs 3·32 months [3·09-5·26]; HR 0·47 [95% CI 0·33-0·67], log-rank p=0·0001). Mean scores for pain until progression favoured enzalutamide plus [177Lu]Lu-PSMA-617 over enzalutamide (difference 7·3 [95% CI 1·6-12·9]; p=0·012). Mean scores for fatigue until progression favoured enzalutamide plus [177Lu]Lu-PSMA-617 over enzalutamide (difference 5·9 [95% CI 1·1-10·7]; p=0·016). The frequency of self-rated xerostomia was lower in the enzalutamide group than in the enzalutamide plus [177Lu]Lu-PSMA-617 group (43 [57%] of 75 vs 58 [74%] of 78; p=0·039), and scores were not significantly different between groups for all other domains. Grade 3-5 adverse events occurred in 35 (44%) of 79 patients in the enzalutamide group and 37 (46%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group. No deaths were attributed to study treatment in either group.

Interpretation

The addition of [177Lu] Lu-PSMA-617 to enzalutamide was associated with improved survival and some aspects of HRQOL in patients with high-risk metastatic castration-resistant prostate cancer. Our findings warrant phase 3 evaluation of adaptive-dosed [177Lu] Lu-PSMA-617 in combination with androgen receptor pathway inhibitors in people with metastatic prostate cancer.

Funding

The Prostate Cancer Research Alliance initiative (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, RoyMorgan, AdAcAp (a Novartis company), and Astellas.