Evaluation of Olaparib Efficacy Following CDK4/6 Inhibitor Therapy in BRCA-Mutated, Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: A Turkish Oncology Group (TOG) Study.

BACKGROUND

Poly(ADP-ribose) polymerase (PARP) inhibitors are established treatment options for patients with germline BRCA1/2-mutated hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer. However, evidence regarding their optimal sequencing after cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor-based therapy remains limited.

OBJECTIVE

To evaluate the real-world efficacy and safety of olaparib after prior CDK4/6 inhibitor plus endocrine therapy, with particular emphasis on treatment sequence and line of olaparib use.

PATIENTS AND

METHODS

This multicenter real-world retrospective study included patients with HR+/HER2- metastatic breast cancer harboring germline BRCA1/2 pathogenic variants who received olaparib after prior CDK4/6 inhibitor plus endocrine therapy. We retrospectively collected clinical characteristics, treatment sequence, response, survival outcomes, and olaparib-related adverse events. We evaluated progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events.

RESULTS

We included 52 patients from 28 institutions. Median age at olaparib initiation was 49.9 years [interquartile range (IQR), 40.2-59.0 years], and median follow-up was 12.84 months (95% confidence interval [CI], 10.52-15.15). The ORR was 57.7%. Median PFS was 11.0 months (95% CI 5.94-16.05), and the 12-month overall survival rate was 78.7%. Immediate post-CDK4/6 inhibitor olaparib use was associated with a numerically longer median PFS than use after intervening systemic treatment, although the difference was not statistically significant (13.4 versus 8.4 months; p = 0.088). Earlier-line olaparib use (≤ third line) was associated with longer PFS than later-line use (≥ fourth line) (17.7 versus 8.4 months; p = 0.005). No unexpected safety signals were observed.

CONCLUSIONS

Olaparib demonstrated clinically meaningful activity and manageable safety after prior CDK4/6 inhibitor therapy in patients with germline BRCA1/2-mutated HR+/HER2- metastatic breast cancer. Earlier-line olaparib use was associated with longer PFS, although this nonrandomized finding should be interpreted cautiously and requires prospective validation.