TheraPb Phase 1b: First-in-Human Dose-Escalation and Optimization Study of 212Pb-ADVC001 in PSMA-Positive Metastatic Androgen Pathway Modulation-Resistant Prostate Cancer.

[212Pb]Pb-ADVC001 (212Pb-ADVC001) is a prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical therapy with high linear energy transfer derived predominantly from the alpha-emission of its 212Pb payload which, upon decay, delivers potent ionizing radiation directly to the tumor. TheraPb (NCT05720130) is a first-in-human dose-escalation and optimization study evaluating 212Pb-ADVC001 in metastatic androgen pathway modulation-resistant prostate cancer (mAPM-R, formerly metastatic castration-resistant prostate cancer). Phase 1 results, including available long-term safety and efficacy outcomes, are presented. Methods: Participants with progressive mAPM-R previously treated with ≥1 androgen-receptor pathway inhibitor and ≥1 taxane chemotherapy (unless contraindicated/declined) were enrolled. Escalating doses of 60-200 MBq 212Pb-ADVC001 were administered at prespecified intervals every 6, 4, 2, or 1 week(s) for up to 6 doses across 7 dose-schedule cohorts (interval 3 + 3 design). The primary objective was to determine the recommended phase 2 dose (RP2D) with primary endpoints of dose-limiting toxicities (DLTs) and adverse events (AEs). Secondary endpoints included prostate-specific antigen (PSA) response, overall response rate (ORR), and radiographic progression-free survival (rPFS). Results: Twenty-two participants were enrolled, with a median follow-up of 14.1 months (IQR 8.8-17.1). No DLTs were observed and the maximum tolerated dose was not reached. The most common treatment-related AEs (TRAE) were dry mouth (18/22 participants [82%], all grade 1-2) and nausea (14/22 participants [64%], all grade 1-2); there were no grade 4-5 or serious TRAEs. The selected RP2D are 160 and 200 MBq. At these dose levels, 12/15 (80%) participants had a PSA decline of ≥50% and the median rPFS from C1D1 was 11.2 months (95% CI 2.0-not estimable) as of data cutoff. ORR was 100%, with centrally confirmed objective responses in all 5 Response Evaluation Criteria in Solid Tumours (RECIST)-evaluable participants treated at the RP2D. Conclusion: 212Pb-ADVC001 was well tolerated up to 200 MBq, including at weekly dosing, and showed encouraging anti-tumor activity in pretreated mAPM-R. Two RP2D, 160 and 200 MBq, are under evaluation in phase 2.