177Lu-PSMA-617 (Pluvicto) with olaparib

LuPARP (NCT03874884) is a phase 1 dose-escalation and dose-expansion trial run by Sandhu, Joshua, Emmett and colleagues (Peter MacCallum Cancer Centre and collaborators) combining 177Lu-PSMA-617 (7.4 GBq every 6 weeks, up to 6 cycles) with olaparib at doses from 50 mg to 300 mg twice daily, given on varying schedules relative to the radioligand infusion. The rationale is mechanistic: 177Lu-PSMA-617 causes single-strand DNA breaks that are normally repaired through PARP-dependent base-excision repair, and PARP inhibition is intended to convert these into lethal double-strand breaks, radiosensitising the tumour irrespective of BRCA or other homologous-recombination-repair status.

Across the 48 enrolled patients with mCRPC previously treated with an androgen-receptor pathway inhibitor and docetaxel, no dose-limiting toxicities were reported and the recommended phase 2 dose was set at olaparib 300 mg twice daily on days -4 to 18 of each 6-week cycle. In the overall cohort, the PSA50 response rate was 66% and PSA90 was 44%, with an objective response rate of 78% by RECIST v1.1 (comparable to, and in the PSA90 measure slightly higher than, the single-agent benchmarks from TheraP and VISION). Hematologic grade 3 toxicity was low (anaemia, neutropenia and thrombocytopenia each in the single digits of percent) and no patient discontinued for toxicity.

This is dose-finding, single-arm evidence in a heavily pre-treated population, not a randomised comparison, so it cannot show whether adding olaparib improves survival or response over 177Lu-PSMA-617 alone; a randomised phase 2 component was being planned as of the 2023 report. Trials of 225Ac-PSMA-I&T plus olaparib (e.g. NCT06909825) are testing the same radiosensitisation idea with an alpha emitter.