Phase I/II Trial of the Combination of 177Lutetium Prostate specific Membrane Antigen 617 and Idronoxil (NOX66) in Men with End-stage Metastatic Castration-resistant Prostate Cancer (LuPIN)

Trials of lutetium prostate specific membrane antigen (PSMA) in men with metastatic castration-resistant prostate cancer (mCRPC) have demonstrated good safety and efficacy, but combination strategies may improve outcomes. Idronoxil is a synthetic flavonoid derivative with radiosensitising properties. To evaluate the safety and activity of 177Lu PSMA 617 (LuPSMA-617) in combination with idronoxil suppositories (NOX66) in patients with end-stage mCRPC. Thirty-two men with progressive mCRPC previously treated with taxane-based chemotherapy (91% treated with both docetaxel and cabazitaxel) and abiraterone and/or enzalutamide were enrolled in this phase I dose escalation study with phase II dose expansion. Screening with 68Ga PSMA and 18F-fludeoxyglucose positron emission tomography (PET)/computed tomography (CT) was performed. Men received up to six cycles of LuPSMA-617 (7.5 GBq) on day 1, with escalating doses of NOX66 on days 1–10 of a 6-wk cycle. Cohort 1 (n = 8) received 400 mg and cohort 2 (n = 24) 800 mg of NOX66. Adverse events (AEs), pain inventory scores, prostate-specific antigen (PSA) response, progression-free survival, and overall survival were evaluated. Fifty-six men were screened and 32 (57%) were enrolled with a screen failure rate of 21% for PET imaging criteria. Dosing was as follows: 97% (31/32) received two or more doses and 47% (15/32) completed six doses. Common AEs included xerostomia, fatigue, and anaemia. Anal irritation attributable to NOX66 occurred in 28%. PSA responses were as follows: 91% (29/32) had any PSA response (median –74%; 95% confidence interval [CI] 76–97) and 62.5% (20/32) had a PSA fall of >50% (95% CI 45–77). The median PSA progression-free survival was 6.1 mo (95% CI 2.8–9.2) and median overall survival was 17.1 mo (95% CI 6.5–27.1). NOX66 with LuPSMA-617 is a safe and feasible therapeutic strategy in men treated with third-line therapy and beyond for mCRPC. Addition of NOX66 to 177Lu prostate-specific membrane antigen 617 is safe, and further studies are needed to assess its potential to augment the anticancer effects of LuPSMA-617. •This phase I/II study demonstrates that lutetium prostate-specific membrane antigen with idronoxil is safe and well tolerated in heavily pretreated metastatic castration-resistant prostate cancer.•The most common adverse events were low-grade xerostomia, fatigue, and anaemia.•The prostate-specific antigen response rate of ≥50% was 63% and median overall survival was 17.1 mo (95% confid