BACKGROUND

Quantitative parameters derived from gallium-68 [Ga]Ga-prostate-specific membrane antigen (PSMA)-11 PET-CT (PSMA-PET-CT) such as whole-body standardised uptake value (SUV)mean and total tumour volume (PSMA-TTV) have shown prognostic value for response to lutetium-177 [Lu]Lu-PSMA-617 monotherapy in patients with prostate cancer. Adding [Lu]Lu-PSMA-617 to enzalutamide improved overall survival compared with enzalutamide in patients with metastatic castration-resistant prostate cancer in the ENZA-p trial. This prespecified substudy of ENZA-p evaluated baseline PSMA-PET quantitative parameters as predictive and prognostic biomarkers for enzalutamide plus [Lu]Lu-PSMA-617 and enzalutamide monotherapy.

METHODS

ENZA-p was an open-label, randomised, phase 2 trial done in 15 hospitals in Australia. Participants were aged 18 years or older with progressive metastatic castration-resistant prostate cancer who had not previously been treated with docetaxel or androgen receptor pathway inhibitors (abiraterone permitted) for metastatic castration-resistant prostate cancer, had [Ga]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. Patients were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to either enzalutamide 160 mg daily (oral) or enzalutamide 160 mg daily plus adaptive-dosed (two or four doses) intravenous [Lu]Lu-PSMA-617 7·5 GBq every 6-8 weeks. The primary endpoint was prostate-specific antigen (PSA) progression-free survival, which has been reported previously. All participants underwent baseline [Ga]Ga-PSMA-11 PET-CT to assess eligibility (SUVmax >15 at a single site and SUVmax >10 at all larger tumour sites). PSMA-PET parameters were quantified with semi-automated software to derive PSMA-TTV and SUVmean and correlated with overall and PSA progression-free survival in a prespecified analysis, with the primary endpoint of this substudy being overall survival. Thresholds were based on SUVmean highest quartile (Q4 vs Q1-3) and PSMA-TTV median at baseline. We used the Kaplan-Meier method and Cox regression models and analysed patients on a treatment received basis. The trial is registered with ClinicalTrials.gov, NCT04419402, and follow-up is complete.

FINDINGS

Between Aug 17, 2020, and July 26, 2022, 162 participants were randomly assigned to enzalutamide (n=79) or enzalutamide plus [Lu]Lu-PSMA-617 (n=83). This substudy included the 160 of the 162 randomly assigned patients who received study treatment (79 in the enzalutamide group and 81 in the enzalutamide plus [Lu]Lu-PSMA-617 group). Median follow-up at the final data cutoff (July 31, 2024) was 34 months (IQR 29-39), with 96 overall survival events (53 with enzalutamide and 43 with enzalutamide plus [Lu]Lu-PSMA-617). Baseline median SUVmean was 7·7 (IQR 6·5-9·8) and median PSMA-TTV was 234 mL (76-687). Median overall survival for PSMA-TTV below or above the median in the enzalutamide group was 39 months (95% CI 31-not estimable) versus 20 months (13-24; HR 0·23 [95% CI 0·13-0·42], log-rank p<0·0001). The corresponding median overall survival for PSMA-TTV below or above the median in the enzalutamide plus [Lu]Lu-PSMA-617 group was 35 months (95% CI 32-37) versus 28 months (26-34; HR 0·66 [0·36-1·21], log-rank p=0·18). The test for interaction between PSMA-TTV and treatment group for overall survival was p=0·0078. Median overall survival for SUVmean Q4 versus Q1-3 in the enzalutamide group was 29 months (95% CI 17-39) versus 25 months (21-31; HR 0·84 [0·44-1·60], log-rank p=0·59). For enzalutamide plus [Lu]Lu-PSMA-617, median overall survival for SUVmean Q4 versus Q1-3 was 32 months (95% CI 21-not estimable) versus 34 months (27-35; HR 0·80 [0·38-1·68], log-rank p=0·56). The test for interaction between SUVmean (Q4 vs Q1-3) and treatment group for overall survival was p=0·88.

INTERPRETATION

Baseline PSMA-TTV is prognostic for overall survival and predictive for a beneficial effect on overall survival with the addition of [Lu]Lu-PSMA-617 to enzalutamide as first-line treatment for high-risk metastatic castration-resistant prostate cancer. By contrast, PSMA SUVmean was not prognostic for PSA progression-free survival or overall survival when [Lu]Lu-PSMA-617 was administered with enzalutamide.

FUNDING

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