A novel strategy involves combining antibody-drug conjugates (ADCs) with PARP inhibitors. This approach could potentially overcome the need for a germline BRCA mutation, significantly broadening the patient population that could benefit from PARP inhibitor therapy in triple-negative breast cancer.

The modest benefit of PARP inhibitors in metastatic breast cancer, compared to ovarian cancer, is likely due to resistance induced by prior exposure to DNA-damaging agents like anthracyclines. This explains the clinical rationale for moving PARP inhibitors to earlier treatment settings, such as neoadjuvant or adjuvant therapy, before resistance develops.

The OlympiA study showed neoadjuvant olaparib plus durvalumab achieved an 80% pathologic complete response (pCR) rate in patients with T2N0 BRCA-mutated TNBC. This result, superior to what chemotherapy typically accomplishes, suggests a highly effective, chemotherapy-free future for this specific patient subgroup.

For de novo metastatic, PD-L1 positive TNBC patients with a BRCA mutation, experts prefer an ADC with immunotherapy over a PARP inhibitor. This choice is driven by the potential for longer-lasting responses with the ADC/IO combination, even though PARP inhibitors directly target the underlying genetic mutation.

For high-risk, HR+ patients with germline BRCA mutations, data suggest they derive less benefit from CDK4/6 inhibitors. A practical approach is to give one year of the PARP inhibitor olaparib first, followed by a CDK4/6 inhibitor, capitalizing on the delayed initiation allowance in major trials.

A nuanced approach to PARP inhibitors involves reserving combinations for BRCA2 patients with clear, aggressive clinical features like high-volume disease or liver metastases. This strategy balances potent efficacy against toxicity for a molecularly defined but clinically heterogeneous group, avoiding overtreatment of those with more indolent disease.

Recent trial data shows that patients with somatic BRCA1/2 mutations (found only in the tumor, not inherited) can achieve significant responses to PARP inhibitors. This finding supports routine tumor genomic testing to identify more candidates for this targeted therapy beyond just those with germline mutations.

In high-risk, BRCA-positive patients eligible for both, clinicians favor giving a PARP inhibitor first. The rationale is based on established survival data, shorter one-year duration, and emerging biological evidence suggesting BRCA2-mutated tumors may be resistant to CDK4/6 inhibitors due to concurrent RB gene loss.

The initial broad enthusiasm for PARP inhibitors in ovarian cancer has been refined. New data confirms a lack of overall survival improvement for patients with HRD-negative (or HR proficient) tumors, pushing clinicians toward a precision medicine approach where these drugs are reserved for patients with BRCA mutations or HRD-positive disease who are most likely to benefit.