Olaparib in Non-Small Cell Lung Cancer (NSCLC)
Olaparib is not currently FDA-approved or recommended by clinical guidelines for the treatment of non-small cell lung cancer (NSCLC). While PARP inhibitors like olaparib have established roles in other cancers with homologous recombination deficiency (HRD), particularly those with BRCA mutations, there is insufficient evidence to support their routine use in NSCLC.
Current Evidence for Olaparib in NSCLC
The PIN trial (Olaparib Maintenance versus Placebo Monotherapy in Patients with Advanced Non-Small Cell Lung Cancer) showed a trend toward improved progression-free survival (PFS) with olaparib maintenance therapy in chemosensitive NSCLC patients, but this did not reach statistical significance at the primary analysis (HR 0.83,80% CI upper limit 1.03) 1
When adjusted for smoking status and histology, the PIN trial showed a marginally significant improvement in PFS (HR 0.73,80% CI upper limit 0.91, p=0.11), suggesting potential benefit in specific molecular subgroups with homologous recombination deficiency 1
Preclinical studies have demonstrated that NSCLC cells with deficiencies in homologous recombination genes (BRCA1, BRCA2, ATM) are hypersensitive to PARP inhibitors like olaparib 2
Recent research using a Genomic Scarring Score (GSS) suggests that approximately 28.7% of early-stage NSCLC patients have high GSS, which may predict response to PARP inhibitors in preclinical models 3
FDA-Approved Indications for Olaparib
Olaparib is currently FDA-approved for:
Metastatic castration-resistant prostate cancer (mCRPC) with deleterious or suspected deleterious germline or somatic HRR gene mutations who have progressed following prior treatment with enzalutamide or abiraterone 4
Ovarian cancer with BRCA mutations (maintenance therapy and treatment settings) 4
Pancreatic cancer with germline BRCA mutations as maintenance therapy after response to platinum-based chemotherapy 4
Breast cancer with germline BRCA mutations 4
Clinical Trial Results in Lung Cancer
The GOAL trial evaluated the combination of gefitinib plus olaparib versus gefitinib alone in EGFR-mutant NSCLC and found no significant benefit with the addition of olaparib (median PFS 12.8 vs. 10.9 months, HR 1.38, p=0.124) 5
The STOMP trial assessed olaparib as maintenance therapy in small cell lung cancer (SCLC) and found no significant improvement in PFS compared to placebo (HR 0.76,90% CI 0.57-1.02, p=0.125) 6
Potential Future Applications
Emerging research suggests that biomarkers beyond BRCA mutations, such as the Genomic Scarring Score, may help identify NSCLC patients who could benefit from PARP inhibitors 3
Patients with specific homologous recombination repair gene mutations (BRCA1/2, ATM) may represent a subgroup of NSCLC patients who could potentially benefit from PARP inhibitors, but this requires further validation in clinical trials 1, 2
Safety Considerations
Common adverse events with olaparib include anemia, fatigue, nausea, vomiting, and anorexia 1, 5, 6
In the PIN trial, 97% of patients in the olaparib arm experienced adverse events, with fatigue (65%), nausea (55%), and anemia (48%) being most common 1
Clinical Implications
Despite promising preclinical data, there is currently insufficient clinical evidence to support the use of olaparib in NSCLC outside of clinical trials 1, 5
Patients with NSCLC and known homologous recombination deficiencies (particularly BRCA1/2 mutations) may be candidates for clinical trials evaluating PARP inhibitors 2, 3
Future research should focus on identifying biomarkers that can predict response to PARP inhibitors in NSCLC patients, such as the Genomic Scarring Score or specific genetic mutations 3