Phase 2 expansion study of ²¹² Pb-ADVC001 in metastatic prostate cancer: The TheraPb trial.

TPS280 Background: 212 Pb-ADVC001 (ADVC001) is an alpha-emitting PSMA-targeting radioligand therapy (RLT) designed to deliver radiation at a cellular level. ADVC001 demonstrated favorable safety and promising anti-tumor activity in participants with PSMA-avid metastatic castration-resistant prostate cancer (mCRPC) enrolled in the TheraPb Phase 1b dose escalation (NCT05720130). There were no dose-limiting toxicities in Phase 1b, the maximum tolerated dose was not reached and dosimetry and pharmacokinetic (PK) studies supported proceeding to Phase 2 expansion to further evaluate the therapeutic efficacy and safety of 2 recommended dose levels of ADVC001. Methods: TheraPb Phase 2 evaluates ADVC001 using a randomized multi-dose-response design and adaptive dosing strategies to optimize clinical outcomes in three distinct indications in metastatic prostate cancer: Group 1: metastatic hormone-sensitive prostate cancer (mHSPC) with a sub-optimal PSA response defined as PSA ≥ 0.2 ng/mL despite receiving androgen deprivation therapy (ADT) and an androgen receptor pathway inhibitor (ARPi) without evidence of disease progression. Group 2: progressive mCRPC post ≥ 1 ARPi; 177 Lutetium ( 177 Lu)-PSMA-naïve and not previously treated with chemotherapy for CRPC. Group 3: progressive mCRPC with prior exposure to 177 Lu-PSMA. All participants are randomized 1:1 to receive either 160 or 200 MBq of ADVC001. Each participant receives up to 4 doses of ADVC001 as induction therapy. Additional doses may be administered as maintenance therapy for a total of up to 12 doses. ADVC001 is administered according to an adaptive dosing schedule and rules allowing for a treatment pause (‘treatment holiday’) based on response with the possibility of subsequent therapy restarts. All participants continue ADT throughout the study. Group 1 participants receive ongoing ARPi as per standard of care, and Group 2 participants also are randomized to receive ADVC001 ± concomitant ARPi. The primary objective is to determine the efficacy of ADVC001 utilizing PSA, conventional imaging and PSMA PET/CT. Assessment of tumor response is undertaken by a blinded independent central review in accordance with the Response Evaluation Criteria in Solid Tumours (RECIST v1.1) and the Prostate Cancer Clinical Trials Working Group. Secondary objectives are to assess safety including late radiation adverse events of special interest, tolerability, dosimetry and PK. Exploratory objectives are to evaluate quality of life, biomarkers and predictors for response and toxicity, and exploratory imaging. Participants are followed for up to 5 years. The TheraPb study is active at 3 clinical sites and will enroll up to 100 participants. Clinical trial information: NCT05720130 .