# Adding a PARP inhibitor to PSMA radioligand therapy

Source: https://nuclide.cc/ideas/idea-rlt-plus-parp-inhibitor/  
Nuclide record `idea-rlt-plus-parp-inhibitor` (Idea). Data CC BY-NC 4.0, attribute "Data from Nuclide (nuclide.cc)"; commercial use needs a licence.

## TL;DR

A drug that blocks a cell's DNA-repair enzyme (PARP) is being added to PSMA-targeted radioactive treatment, on the theory that if a cell can't repair the small cuts radiation makes to its DNA, those cuts become fatal breaks that kill the cancer cell.

## Summary

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-22
- Tags: combination therapy; PARP; prostate
- Hypothesis: Adding the PARP inhibitor olaparib to lutetium-177-PSMA-617 will increase the objective response rate in metastatic castration-resistant prostate cancer compared with radioligand therapy alone, by converting radiation-induced DNA single-strand breaks into lethal double-strand breaks, without added toxicity that prevents patients completing a full course of treatment.
- Rationale: 177Lu-PSMA-617 predominantly causes DNA single-strand breaks repaired via PARP-dependent base excision repair; PARP inhibition is mechanistically expected to radiosensitise tumour cells by blocking this repair. The LuPARP phase 1 trial found the combination tolerable across ten olaparib dosing schedules with no dose-limiting toxicities, and reported PSA50 62% and PSA90 48% in an interim analysis of heavily pretreated patients, with median radiographic progression-free survival of 12.8 months at the recommended phase 2 dose — figures that compare favourably with historical 177Lu-PSMA-617 monotherapy series, though this was a single-arm study without a concurrent comparator.
- Proposed test: LuPARP (NCT03874884) has already generated phase 1 safety and preliminary activity data in a single-arm design; the next step is a randomised phase 2/3 trial of 177Lu-PSMA-617 with or without olaparib in metastatic castration-resistant prostate cancer, powered on radiographic progression-free survival, alongside the ongoing alpha-emitter analogue trial of FPI-2265 plus olaparib (NCT06909825).
- Maturity: early-clinical
- Actor: research

## Sources

- LuPARP: Phase 1 trial of 177Lu-PSMA-617 and olaparib in mCRPC (JCO, 2023): https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.5005
- 177Lu-PSMA-617 Therapy and Olaparib in Patients With mCRPC (LuPARP) (ClinicalTrials.gov, NCT03874884): https://clinicaltrials.gov/study/NCT03874884
- Recent Advances in Radioligand Therapy: LuPARP recommended phase 2 dose results: https://nuclide-hema.healthbooktimes.org/article/154290-recent-advances-in-radioligand-therapy
- FPI-2265 and Olaparib for Patients With mCRPC (ClinicalTrials.gov, NCT06909825): https://clinicaltrials.gov/study/NCT06909825

## Connected records

- technologies: [Radioligand plus DNA-repair inhibitor combinations](https://nuclide.cc/technologies/radionuclide-parp-combination/)
- drugs: [FPI-2265](https://nuclide.cc/drugs/fpi-2265/), [Lutetium-177 vipivotide tetraxetan](https://nuclide.cc/drugs/pluvicto/), [Olaparib](https://nuclide.cc/drugs/olaparib/)
- people: [Shahneen Sandhu](https://nuclide.cc/people/sandhu-shahneen/)
- indications: [Metastatic castration-resistant prostate cancer](https://nuclide.cc/indications/prostate-mcrpc/)
- isotopes: [Actinium-225](https://nuclide.cc/isotopes/ac-225/), [Lutetium-177](https://nuclide.cc/isotopes/lu-177/)

---
JSON: https://nuclide.cc/api/v1/entities/idea-rlt-plus-parp-inhibitor.json