(177)Lu-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

(177)Lu-PSMA-617 is an effective therapy for metastatic castration-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 (177)Lu-PSMA-617 with idronoxil (NOX66), a radiosensitizer, and examine potential clinical, blood-based, and imaging biomarkers. Methods: Fifty-six men with progressive mCRPC previously treated with taxane chemotherapy and novel androgen signaling inhibitor (ASI) were enrolled. Patients received up to 6 doses of (177)Lu-PSMA-617 (7.5 GBq) on day 1 in combination with a NOX66 suppository on days 1–10 of each 6-wk cycle. Cohort 1 (n = 8) received 400 mg of NOX66, cohort 2 (n = 24) received 800 mg, and cohort 3 (n = 24) received 1,200 mg. (68)Ga-PSMA and (18)F-FDG PET/CT were performed at study entry, and semiquantitative imaging analysis was undertaken. Blood samples were collected for analysis of 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: Fifty-six of the 100 men screened were enrolled (56%), with a screening 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. Ninety-six percent (54/56) of patients received at least 2 cycles of combination NOX66 and (177)Lu-PSMA-617, and 46% (26/56) completed 6 cycles. Common adverse events were anemia, fatigue, and xerostomia. Anal irritation attributable to NOX66 occurred in 38%. Forty-eight of 56 had a reduction in prostate-specific antigen (PSA) level (86%; 95% CI, 74%–94%); 34 of 56 (61%; 95% CI, 47%–74%) had a PSA reduction of at least 50%. Median PSA progression-free survival was 7.5 mo (95% CI, 5.9–9 mo), and median overall survival was 19.7 mo (95% CI, 9.5–30 mo). A higher PSMA SUV(mean) correlated with treatment response, whereas a higher PSMA tumor volume and prior treatment with ASI for less than 12 mo were associated with worse overall survival. Conclusion: NOX66 with (177)Lu-PSMA-617 is a safe and feasible strategy in men being treated with third-line therapy and beyond for mCRPC. PSMA SUV(mean), PSMA-avid tumor volume, and duration of treatment with ASI were independently associated with outcome.