{"entity":{"id":"idea-rlt-plus-parp-inhibitor","kind":"idea","name":"Adding a PARP inhibitor to PSMA radioligand therapy","aka":[],"tldr":"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.\n\nThe 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%.\n\nA 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.","asOf":"2026-09-22","links":[{"label":"LuPARP: Phase 1 trial of 177Lu-PSMA-617 and olaparib in mCRPC (JCO, 2023)","url":"https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.5005"},{"label":"177Lu-PSMA-617 Therapy and Olaparib in Patients With mCRPC (LuPARP) (ClinicalTrials.gov, NCT03874884)","url":"https://clinicaltrials.gov/study/NCT03874884"},{"label":"Recent Advances in Radioligand Therapy: LuPARP recommended phase 2 dose results","url":"https://nuclide-hema.healthbooktimes.org/article/154290-recent-advances-in-radioligand-therapy"},{"label":"FPI-2265 and Olaparib for Patients With mCRPC (ClinicalTrials.gov, NCT06909825)","url":"https://clinicaltrials.gov/study/NCT06909825"}],"tags":["combination therapy","PARP","prostate"],"related":["radionuclide-parp-combination","pluvicto","olaparib","fpi-2265","sandhu-shahneen","prostate-mcrpc","lu-177","ac-225"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"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.","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","cost":"medium","horizonYears":5},"route":"/ideas/idea-rlt-plus-parp-inhibitor/","neighbours":{"technology":[{"id":"radionuclide-parp-combination","kind":"technology","name":"Radioligand plus DNA-repair inhibitor combinations","route":"/technologies/radionuclide-parp-combination/"}],"drug":[{"id":"fpi-2265","kind":"drug","name":"FPI-2265","route":"/drugs/fpi-2265/"},{"id":"pluvicto","kind":"drug","name":"Lutetium-177 vipivotide tetraxetan","route":"/drugs/pluvicto/"},{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"}],"person":[{"id":"sandhu-shahneen","kind":"person","name":"Shahneen Sandhu","route":"/people/sandhu-shahneen/"}],"indication":[{"id":"prostate-mcrpc","kind":"indication","name":"Metastatic castration-resistant prostate cancer","route":"/indications/prostate-mcrpc/"}],"isotope":[{"id":"ac-225","kind":"isotope","name":"Actinium-225","route":"/isotopes/ac-225/"},{"id":"lu-177","kind":"isotope","name":"Lutetium-177","route":"/isotopes/lu-177/"}]}}