The latest National Comprehensive Cancer Network (NCCN) small cell lung cancer (SCLC) guidelines do not provide any recommendations for the use of olaparib or other poly(ADP-ribose) polymerase (PARP) inhibitors based on breast cancer gene 1 or 2 (BRCA1/2) germline or somatic mutations in SCLC. Available guideline summaries describe standard systemic therapy approaches (platinum-etoposide-based regimens, immunotherapy, lurbinectedin, topotecan, etc.) and do not list PARP inhibitors as recommended or biomarker-directed options for SCLC. [1]

Published reviews describe a biologic rationale for PARP inhibition in SCLC), including high PARP1 expression and increased DNA damage response pathway activity, along with preclinical studies showing greater sensitivity to olaparib compared with other lung cancer subtypes; however, these findings are not specific to BRCA2-mutated disease. Early clinical trials of PARP inhibitors in SCLC have generally shown limited activity as monotherapy, including a maintenance trial of olaparib that did not improve progression-free survival; these studies were conducted in unselected SCLC populations and did not report outcomes specifically for BRCA2-mutated tumors. Greater activity has been reported with combination regimens such as olaparib plus temozolomide, but these data are also from non-BRCA-selected cohorts. Overall, available clinical evidence reflects modest activity in unselected SCLC, and does not provide mutation-specific efficacy data for BRCA2 somatic-positive SCLC. [2], [3]

The completed phase 2 SUKSES-B trial (NCT03009682) evaluated single-agent olaparib in patients with relapsed SCLC who had homologous recombination (HR) pathway gene alterations. Eligibility included mutations in BRCA1 or BRCA2, ATM deficiency, MRE11A mutation, or other HR-pathway genes such as BLM, NBN, RAD50, RAD51-family genes, RAD52, RAD54L, RECQL-family genes, RPA1, and WRN. Published peer-reviewed results for the olaparib monotherapy arm included 15 patients with HR-pathway mutations and demonstrated limited activity, with an objective response rate of 6.7% (one partial response), a disease control rate of 33.3%, and a median progression-free survival of approximately 1.3 months. Although BRCA1/2 mutations were part of the inclusion criteria, outcomes were reported only for the overall HR-mutant cohort, and the publication did not provide results specifically for BRCA2-mutated patients or identify the mutation status of the single responder. Therefore, while the SUKSES-B trial enrolled patients with BRCA2 mutations, the published data show limited overall activity of olaparib monotherapy and do not provide mutation-specific evidence. [4], [5]

As mentioned earlier, several clinical trials have evaluated olaparib in SCLC, either as monotherapy or in combination with other agents, but the available data are generally not specific to BRCA2 somatic mutations and are largely derived from unselected or broadly biomarker-selected populations. In a randomized maintenance trial, olaparib monotherapy did not improve progression-free survival (PFS) or overall survival (OS) compared with placebo in patients who responded to first-line chemotherapy or chemoradiotherapy, with toxicity consistent with previous studies. Olaparib combined with the immune checkpoint inhibitor durvalumab showed modest activity, with a 12-week disease control rate of 28.9% and an objective response rate (ORR) of 10.5%, but no correlation with PD-L1 expression, tumor mutational burden, or other mutations was observed, and the small number of responders limits generalizability. More promising activity was observed with olaparib plus temozolomide, achieving an ORR of 41.7%, median PFS of 4.2 months, and median OS of 8.5 months, with co-clinical patient-derived xenograft studies suggesting that response may correlate with tumor gene expression profiles rather than single-gene mutations such as BRCA2. Overall, these studies indicate that single-agent olaparib has limited efficacy in unselected SCLC, and while combination strategies may increase response, there is no clinical evidence specifically supporting efficacy in BRCA2 somatic–positive SCLC, limiting the applicability of these results to that subgroup. [6], [7], [8]