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Development of PARP inhibitor combinations for castration resistant prostate cancer unselected for homologous recombination repair mutations.

ABSTRACT: Genetic instability is a hallmark of cancer and, with the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors, is a targetable feature of many tumors. Currently, two PARP inhibitors, olaparib and rucaparib, have received approval as monotherapy by the Food and Drug Administration for the treatment of men with castration resistant prostate cancer with selected mutations involving the homologous recombination (HR) pathway. However, it is currently debated whether an HR mutation is a prerequisite for response or if patients with HR-proficient mCRPC may also benefit from their use when combined with other targeted or immunotherapeutic agents. Several large phase III trials of PARP inhibitors with novel androgen axis inhibitors in groups of unselected patients are underway. Additionally, there are several early phase trials combining PARP inhibitors with radioligands or immunecheckpoint inhibitors. Here we discuss the currently ongoing or recently concluded trials of PARP inhibitor based combinatorial therapies in unselected patients with mCRPC, the rationale behind these trials, and how these may impact the treatment paradigm in men with mCRPC.

SUBMITTER: McFarland TR

PROVIDER: S-EPMC8340210 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionA significant proportion of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor mutations in homologous recombination (HR) repair genes, with some of these mutations associating with increased tumor susceptibility to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy. While mutations in some HR repair genes (e.g., BRCA1/2) have been associated with a more aggressive clinical course, prior studies correlating HR mutational status with treatment response to androgen receptor (AR) signaling inhibitors (ARSIs) or taxane-based chemotherapy have yielded conflicting results.MethodsWe conducted a single-center retrospective analysis to assess clinical outcomes to conventional, regulatory-approved therapies in mCRPC patients with somatic (monoallelic and biallelic) and/or germline HR repair mutations compared to patients without alterations as determined by clinical-grade next-generation sequencing assays. The primary endpoint was PSA30/PSA50 response, defined as ≥30%/≥50% prostate-specific antigen (PSA) reduction from baseline. Secondary endpoints of PSA progression-free survival (pPFS) and clinical/radiographic progression-free survival (crPFS) were estimated using Kaplan-Meier methods.ResultsA total of 90 consecutively selected patients were included in this analysis, of which 33 (37%) were identified to have HR repair gene mutations. Age, race, Gleason score, prior surgery, and receipt of prior radiation therapy were comparable between carriers and non-carriers. There was no evidence that PSA30/PSA50 differed by HR gene mutational status. Median pPFS and crPFS ranged 3-14 months across treatment modalities, but there was no evidence either differed by HR gene mutational status (all p>0.05). There was also no difference in outcomes between those with BRCA2 or PALB2 mutations (n = 17) compared to those without HR repair mutations.ConclusionHR gene mutational status was associated with comparable clinical outcomes following treatment with ARSIs or taxane-based chemotherapy. Additional prospective studies are needed to confirm these findings.

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Development of PARP inhibitor combinations for castration resistant prostate cancer unselected for homologous recombination repair mutations.

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