177Lu-PSMA-617 and Idronoxil in Men with End-Stage Metastatic Castration-Resistant Prostate Cancer (LuPIN): Patient Outcomes and Predictors of Treatment Response in a Phase I/II Trial

Background: 177Lutetium PSMA-617 (Lu-PSMA-617) is an effective therapy for metastatic castrate-resistant prostate cancer (mCRPC). However, treatment resistance occurs frequently and combination therapies may improve outcomes. We report the final safety and efficacy results of a phase I/II study combining Lu-PSMA-617 with idronoxil (NOX66), a radiosensitiser, and examined potential clinical, blood-based and imaging biomarkers. Methods: 56 men with progressive mCRPC previously treated with taxane chemotherapy and novel androgen signaling inhibitor (ASI) were enrolled. Patients received up to six doses of Lu-PSMA-617 (7.5Gbq) day 1 in combination with NOX66 suppository days 1-10 each 6-week cycle. Cohort 1 (n = 8) received 400mg NOX66, cohort 2 (n = 24) received 800mg and cohort 3 (n = 24) received 1200mg. 68Ga-PSMA and FDG PET/CT were performed at study entry and semi-quantitative imaging analysis was undertaken. Blood samples were collected for blood-based biomarkers including androgen receptor splice variant 7 expression. The primary outcomes were safety and tolerability; secondary outcomes included efficacy, pain scores and xerostomia. Regression analyses were performed to explore the prognostic value of baseline clinical, blood-based and imaging parameters. Results: 56/100 men screened were enrolled (56%) with a screen failure rate of 26% (26/100) for PET imaging criteria. All men had received prior treatment with ASI and docetaxel, and 95% (53/56) had received cabazitaxel. 96% (54/56) patients received ≥2 cycles of combination NOX66 and Lu-PSMA-617, and 46% (26/56) completed six cycles. Common adverse events were anaemia, fatigue and xerostomia. Anal irritation attributable to NOX66 occurred in 38%. 48/56 had a reduction in prostate-specific antigen (PSA) (86%, 95% CI 74-94), 34/56 (61%, 95% CI 47-74) had a PSA reduction ≥50% (PSA50). Median PSA progression-free survival was 7.5 months (95% CI 5.9-9) and median overall survival 19.7 months (95% CI 9.5-30). Higher PSMA SUVmean correlated with treatment response, while higher PSMA tumour volume and prior treatment with ASI for less than 12 months were associated with worse overall survival. Conclusion: NOX66 with Lu-PSMA-617 is a safe and feasible therapeutic strategy in men treated 3rd line and beyond for mCRPC. PSMA SUVmean, PSMA avid tumour volume and duration of treatment with ASI were independently associated with outcome.