Experts are cautious about using ADCs as long-term frontline maintenance therapy in ovarian cancer. Unlike oral PARPs, prolonged administration of these potent chemotherapies could cause cumulative toxicities, especially bone marrow suppression, potentially rendering patients unable to tolerate essential treatments upon relapse.

The widespread use of PARP inhibitors has altered tumor biology in platinum-sensitive ovarian cancer. A recent meta-analysis of heavily pretreated patients, 97% of whom had prior PARP inhibitor exposure, revealed an objective response rate to subsequent therapy of only 17%—far lower than historical expectations, highlighting a critical unmet clinical need.

The risk of developing myeloid neoplasms from PARP inhibitors in the frontline ovarian cancer setting is very low, around 1%. However, it is critical to adhere to the recommended 2-3 year treatment duration and then stop the therapy to avoid unnecessary long-term risk.

While the risk of secondary leukemia (MDS/AML) from PARP inhibitors is low (0.5-1.5%) in the frontline setting, it escalates dramatically to 8-11% in heavily pretreated patients or those receiving therapy for more than two years, highlighting a significant long-term safety concern.

While retreating with a PARP inhibitor after a long progression-free interval is a viable strategy for patients with BRCA mutations, experts express caution and hesitancy in applying the same approach to patients who are HRD-deficient but BRCA wild-type, partly due to changing FDA labels.

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.

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.

Giving adjuvant olaparib to BRCA-mutated patients who have already achieved a pathologic complete response (pCR) from neoadjuvant platinum-based chemotherapy is discouraged. Their prognosis is already excellent, so adding a PARP inhibitor offers little potential benefit while exposing them to unnecessary risks of toxicity, such as MDS/AML.