LuCarbo: A phase 1a/1b trial of ¹⁷⁷ Lu-PSMA-617 (LuPSMA) with carboplatin in advanced prostate cancer.

TPS304 Background: LuPSMA is a proven life-prolonging therapy in men with metastatic castrate-resistant prostate cancer (mCRPC) who have previously received a taxane and an androgen receptor pathway inhibitor (ARPI). Despite patient selection by PSMA-PET/CT, responses are only seen in 50% of patients with PSMA-avid disease and are generally not durable. The mechanism of LuPSMA relies on delivery of beta emissions upon target engagement, thereby leading to DNA damage. Carboplatin is an inexpensive and widely available agent used as a radiosensitizer in other solid tumors and often combined with a taxane in CRPC. Given the need to improve outcomes with LuPSMA and the mechanisms of action of both agents, there is a rationale to evaluate the combination of LuPSMA with carboplatin in mCRPC. Methods: This is a single-center phase 1a/1b trial of LuPSMA and carboplatin. Patients with mCRPC who have previously received ≥1 taxane and ≥1 ARPI and have PSMA-avid disease on baseline PSMA-PET/CT are eligible. LuPSMA is given at the standard dose of 7.4GBq every 6 weeks, and carboplatin is dosed every 3 weeks, with 6 weeks constituting 1 cycle. In phase 1a, a 3+3 design is used with 3 planned dose levels of carboplatin (DL1 – AUC2; DL2 – AUC3: DL3 – AUC4); the dose-limiting toxicity (DLT) period is during cycle 1, and the recommended phase 2 dose (RP2D) will be the highest administered dose level with ≤1 DLTs out of 6 treated patients. In phase 1b, 19 patients will be enrolled at the RP2D (for a total of 25 patients treated at RP2D), and these patients will additionally undergo baseline and on-therapy research biopsies and an on-therapy PSMA-PET/CT after 2 cycles. The primary objective is to evaluate the safety of the combination and establish the RP2D; secondary objectives include overall response rate (PSA50 – reduction in PSA by ≥50% - and objective response rate, per RECIST 1.1), radiographic progression-free survival (per RECIST 1.1/PCWG3) and overall survival. Exploratory objectives include evaluation of genomic, transcriptomic, proteomic, and imaging biomarkers of response and resistance. With a sample size of 25 patients treated at RP2D, the combination will be deemed effective if 15 or more PSA50 responses are seen; the probability of concluding that the combination is effective is ≤0.1 if its true PSA50 rate is ≤45% and ≥0.9 if the true PSA50 rate is ≥70%. The study was activated in May 2024, and a total of 6 patients have been enrolled to date. Clinical trial information: NCT06303713 .