Predictive and prognostic value of baseline PSMA-PET total tumor volume and SUV mean within ENZA-p, a randomized phase II trial of enzalutamide versus enzalutamide plus [ ¹⁷⁷ Lu] Lu-PSMA-617 (ANZUP1901).

5011 Background: [ 68 Ga]Ga-PSMA-11 PET (PSMA-PET) standardized uptake value (SUV)mean and total tumor volume (PSMA-TTV) have been respectively identified as predictive and prognostic of response to [ 177 Lu]Lu-PSMA-617 (LuPSMA) monotherapy. The addition of LuPSMA to enzalutamide (enza + LuPSMA) improved overall survival (OS) compared to enza-alone in mCRPC in the ENZA-p trial. This pre-specified sub-study of ENZA-p evaluated baseline PSMA-PET quantitative parameters as predictive and prognostic biomarkers for enza+ LuPSMA and enza-alone. Methods: ENZA-p is an open-label, randomized, phase 2 trial. Participants (pts) with mCRPC not previously treated with chemotherapy or AR antagonist (abiraterone permitted) and [ 68 Ga]Ga-PSMA-avid disease were randomized (1:1) to either enza-alone or enza + LuPSMA using adaptive-dosed [ 177 ]Lu LuPSMA-617 7.5 GBq for (2 or 4 doses). All pts had a baseline [ 68 Ga]Ga-PSMA-11 PET/CT to assess eligibility (SUVmax >14 at a single site and SUVmax >10 at all larger tumor sites). PSMA-PET were quantified with semi-automated software to derive PSMA-TTV and SUVmean. The pre-specified tertiary study objective was to evaluate associations between quantitative parameters on the baseline PSMA-PET and both PSA progression-free survival (PSA-PFS) and OS. Prespecified cut-points 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. Results: This sub-study included the 160 of 162 randomized pts who received study treatment. Median follow-up was 34 months with 96 OS events. Baseline PSMA-PET SUVmean Q4 was 9.8 and median PSMA-TTV was 234 mL. Median OS for PSMA-TTV above or below the median for enza-alone were 20 vs 39 months respectively (p<0.001). The corresponding median OS for enza + LuPSMA were 28 vs 35 months (p=0.18). The test for interaction between PSMA-TTV and treatment arm for OS was p=0.008. Median OS for SUVmean Q4 vs Q1-3 for enza alone were 29 vs 25 months (p=0.59). For enza + LuPSMA median OS for SUVmean Q4 vs Q1-3 were 32 vs 34 months (p=0.56). The test for interaction between SUVmean (Q4 vs Q1-3) and treatment for OS was p=0.88. Results for PSA-PFS are also tabulated below. Conclusions: Baseline PSMA-TTV was prognostic of shorter OS with enza-alone, but not with the addition of LuPSMA-617. In contrast to LuPSMA-617 monotherapy, PSMA SUVmean was neither predictive nor prognostic of improved OS, nor of PSA-PFS when LuPSMA-617 was given together with enza as first line treatment for mCRPC. Clinical trial information: NCT04419402 . Treatment Arm SUVmean Q4 SUVmean Q1-3 P Interaction PSMATTV>234mls PSMATTV<234mls p Interaction Enza-alone OS 29mo 25mo 0.59 0.88 20mo 39mo 0.001 0.008 Enza+LuPSMA OS 32mo 34mo 0.56 28mo 35mo 0.18 Enza-alone PSA-PFS 7.8mo 5mo 0.55 0.17 3mo 11mo 0.001 0.017 Enza+LuPSMA PSA-PFS 15mo 13mo 0.22 11mo 15mo 0.11