Adding a PARP inhibitor to PSMA radioligand therapy

Lutetium-177-PSMA-617 kills cells mainly by causing single-strand breaks in DNA, which the cell can often repair using PARP-dependent base excision repair. PARP inhibitors such as olaparib block this repair pathway, and preclinical work has shown this can convert what would have been a survivable single-strand break into a lethal double-strand break, radiosensitising tumour cells.

The combination has been tested clinically in the LuPARP phase 1 trial (NCT03874884, Peter MacCallum Cancer Centre), which enrolled patients with metastatic castration-resistant prostate cancer who had progressed on an androgen receptor pathway inhibitor. Across ten dose-escalation cohorts of olaparib schedules combined with a fixed 7.4 GBq dose of 177Lu-PSMA-617 every six weeks for up to six cycles, no dose-limiting toxicities were reported; common adverse events were low-grade xerostomia, nausea and fatigue, with transient grade 1-3 cytopenias. Reported activity was promising: a PSA50 response rate of 62% and PSA90 of 48% were seen in an interim 29-patient analysis, and at the recommended phase 2 dose (an intermittent olaparib schedule starting four days before each lutetium cycle), the median radiographic progression-free survival was 12.8 months with a PSA90 response rate of 55%.

A second, alpha-emitter version of this combination is now in trial: FPI-2265 (225Ac-PSMA-I&T) plus olaparib (NCT06909825) is testing whether the same DNA-repair rationale extends to alpha-particle radioligand therapy. Neither the beta nor the alpha combination has yet been tested in a randomised trial against radioligand therapy alone, so the magnitude of any added benefit over 177Lu-PSMA-617 or 225Ac-PSMA-I&T monotherapy is not yet established.