olaparib

Overview

Olaparib (Lynparza) is an orally available PARP1/PARP2 inhibitor with FDA approvals in germline BRCA1/2-mutated breast, ovarian, fallopian tube, primary peritoneal, and pancreatic cancers, and in HRR gene-mutated metastatic castration-resistant prostate cancer. It exploits synthetic lethality in homologous recombination-deficient (HRD) tumors. In pancreatic cancer it is approved as maintenance therapy following platinum-based first-line chemotherapy in germline BRCA1/2-mutated metastatic PDAC.

Evidence in the corpus

  • Olaparib is among the compounds included in the sarcoma PDTO functional precision-medicine screen of 92 specimens; it is listed in the drugs screened across diverse sarcoma histologies in the UCLA platform PMID:39305899.
  • In the MSK PDAC clinicogenomic cohort (n=2,336), olaparib and other PARP inhibitors (collectively “PARPi”) were received by 29 stage-IV patients; 38% (11/29) had ≥6 months on therapy. All 10 long-responders with available data had BRCA2 mutations that were biallelic (somatic LOH). However, 6/16 BRCA2-mutant tumors with biallelic loss did not benefit, indicating biallelic BRCA2 loss is necessary but not sufficient for durable PARPi benefit. One BRCA1/2 wild-type patient with a BAP1 loss-of-function fusion also derived durable benefit PMID:39753968.
  • 1 metastatic gallbladder carcinoma patient received olaparib targeting BRCA/ATM alterations (OncoKB level 3B); BRCA1/BRCA2 oncogenic mutations identified in 3 and 6 patients respectively among 233 GBC cases profiled with MSK-IMPACT PMID:36228155
  • Homologous recombination defects in ~50% of 489 HGSOC tumors (BRCA1/2 mutations, BRCA1 methylation, PTEN deletion, etc.) provide a rationale for PARP inhibitor therapy (olaparib) beyond germline BRCA carriers PMID:21720365
  • BRCA1/BRCA2 mutations in basal-like breast tumors identified as genomic basis for sensitivity to PARP inhibitor olaparib PMID:23000897
  • PARP inhibitor olaparib under investigation in combination with immune checkpoint inhibitors to exploit DNA repair deficiencies in recurrent/metastatic nasopharyngeal carcinoma (NPC) PMID:24952746
  • Biallelic inactivation of BRCA2, BRCA1, or ATM in 19.3% of 150 mCRPC patients identifies a subset that may benefit from olaparib; multiple patients on a parallel PARP-inhibitor trial who achieved clinical benefit harbored biallelic BRCA2 loss PMID:26000489
  • DNA repair deficiency (14% Fanconi-anaemia-pathway alterations, 3% BRCA1/2 alterations) in 109 resected pancreatic ductal adenocarcinomas nominates olaparib (PARP inhibitor) as a therapeutic candidate; high-CNV clusters enriched for DSB-repair lesions could serve as stratification biomarkers PMID:25855536
  • 19% of 333 primary PRAD tumors carry DNA-repair gene defects (BRCA2, BRCA1, ATM, CDK12, FANCD2, RAD51C); authors link this to TOPARP-A trial results in mCRPC and propose PARP-inhibitor strategies (e.g., olaparib) could be considered at earlier prostate cancer disease stages PMID:26544944
  • The FA-pathway/ATM biomarker that predicted longer carboplatin response in mCRPC (prad_fhcrc) was noted by the authors to dovetail with contemporaneous olaparib PARP-inhibitor responses in the same DNA-repair-deficient biomarker subset of prostate cancer. PMID:26928463
  • PALB2 somatic mutations occur in 4% of metastatic breast cancer vs 0.1% of primary breast cancer (FDR=0.006); authors propose PALB2-deficient mBC as a candidate population for PARP inhibitor (olaparib) trials PMID:28027327
  • In BRCA1/2-wild-type mCRPC cell lines and PDX models, olaparib combined with the USP10 inhibitor spautin-1 produced HSA synergy scores >10 in 22Rv1 and C4-2 cells and CI=0.76 in 22Rv1 CDX; TRMT10A is identified as a BRCA1-recruitment scaffold whose degradation via USP10 inhibition induces BRCAness and sensitizes cells to olaparib PMID:28068672
  • Cited as level 2B matched therapy for BRCA1/BRCA2 likely-inactivating mutations in 860-patient MSK-IMPACT LUAD cohort based on olaparib approval in BRCA-mutant ovarian carcinoma; no patient with BRCA1/BRCA2 truncating mutations received matched PARP-inhibitor therapy due to off-label barriers; basket trials NCT02201212 and NCT02675829 opened to address this gap PMID:28336552.
  • 22% somatic HR-gene alteration rate (BRCA2 7%, ATM 5%, CDK12 7%) and 27% combined germline+somatic DDR-gene rate in 451 prostate cancer patients identifies candidates for olaparib and platinum-based therapy (per TOPARP-A and case-series citations) PMID:28825054

Resistance mechanisms

  • Biallelic BRCA2 inactivation is necessary but not sufficient for durable PARPi benefit in PAAD; 6/16 biallelic BRCA2-mutant tumors did not benefit, suggesting additional resistance determinants beyond HRD status PMID:39753968.

Cancer types (linked)

  • PAAD — pancreatic adenocarcinoma; maintenance PARPi in germline BRCA1/2-mutated metastatic disease; biallelic BRCA2 loss necessary but insufficient for durable response.
  • Sarcoma (various histologies — included in PDTO functional screen panel)

Sources

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