Association of early PSMA upregulation with duration of response to enzalutamide with or without [177Lu]Lu-PSMA-617 in poor-risk, metastatic, castration-resistant prostate cancer: Findings from the randomised, phase 2, ENZA-p trial (ANZUP 1901)

<title>Abstract</title> <bold>Background </bold>Prostate-specific membrane antigen (PSMA) receptor expression alters in response to androgen receptor blockade in metastatic castrate resistant prostate cancer (mCRPC). The ENZA-p trial (ANZUP 1901) demonstrated that the addition of [¹⁷⁷Lu]Lu-PSMA-617 to enzalutamide improved overall survival (OS) in mCRPC. In this preplanned imaging substudy, we evaluated the frequency and clinical significance of early changes in PSMA-PET standardised uptake value (SUV) mean with enzalutamide ± [¹⁷⁷Lu]Lu-PSMA-617. <bold>Materials and Methods</bold> Participants in ENZA-p had mCRPC not previously treated with chemotherapy or AR antagonist (abiraterone permitted), [⁶⁸Ga]Ga-PSMA-avid disease, and at least two risk factors for early progression on enzalutamide alone. Participants were randomised (1:1) to either enzalutamide 160 mg daily or enzalutamide 160 mg daily plus adaptive-dosed [¹⁷⁷Lu]Lu-PSMA-617 7.5 GBq (2 or 4 doses). Participants underwent a ⁶⁸Ga-PSMA-PET/CT at baseline and day 15 after commencing enzalutamide, with [¹⁷⁷Lu]Lu-PSMA-617 administered subsequently in the experimental arm. All ⁶⁸Ga-PSMA-PET/CT were analysed with semi-automated software to derive PSMA SUVmean. The study investigated the relationship between early change in SUVmean and the following clinical outcomes: 50% PSA decline (PSA-50), PSA progression-free survival (PSA-PFS), and OS. <bold>Results</bold> We randomised 162 pts from Aug 2020 to Jul 2022, all of whom underwent baseline imaging. Of the treated participants 96% (154 out of 160) received a PSMA PET/CT at day 15 after commencing enzalutamide. The median age was 71 years (interquartile range, IQR: 65-76), with 53% having received prior docetaxel and 14% prior abiraterone. An increase in SUVmean at day 15, regardless of magnitude was recorded in 105 out of 154 (68%). Among these participants, the median increase in SUVmean was 13% (IQR: 6.0% - 22%). The median PSA-PFS in pts with increasing SUVmean by treatment arm was 5.8 months vs 13.1 months for enzalutamide monotherapy vs enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617 respectively (Log-rank p &lt; 0.001). By contrast, in those with decreasing SUVmean, median PSA-PFS was 12.5 vs 13.3 months for enzalutamide monotherapy vs enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617 (Log-rank p = 0.5). The p-value for an interaction between early increase or decrease in SUVmean and treatment arm for PSA-PFS was p=0.055. <bold>Conclusions</bold> An early increase in PSMA SUVmean is common with first line enzalutamide in mCRPC, and predictive for shorter PSA-PFS with enzalutamide alone. The addition of [¹⁷⁷Lu]Lu-PSMA-617 to enzalutamide mitigated the shorter PSA-PFS in those with early increase in PSMA SUVmean.