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)

Background: 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.

Objective: To evaluate the safety and activity of ¹⁷⁷Lu PSMA 617 (LuPSMA-617) in combination with idronoxil suppositories (NOX66) in patients with end-stage mCRPC.

Design, setting, and participants: 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.

Intervention: 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.

Outcome measurements and statistical analysis: Adverse events (AEs), pain inventory scores, prostate-specific antigen (PSA) response, progression-free survival, and overall survival were evaluated.

Results and limitations: 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).

Conclusions: NOX66 with LuPSMA-617 is a safe and feasible therapeutic strategy in men treated with third-line therapy and beyond for mCRPC.

Patient summary: 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.