The introduction of ADCs into frontline ovarian cancer treatment creates a new challenge: conflicting biomarkers. A patient's tumor might be positive for both HER2 (an ADC target) and a BRCA mutation (a PARP inhibitor target), forcing clinicians to choose between two effective targeted therapies without clear guidance.

The traditional six-month timeframe for defining platinum sensitivity is being challenged. A growing theory suggests that tumors progressing while on a PARP inhibitor have a distinct biology that responds poorly to subsequent platinum, indicating a potential need to move directly to therapies like ADCs.

The traditional practice of classifying recurrent ovarian cancer as 'platinum-sensitive' or 'platinum-resistant' based on a six-month treatment-free interval is rapidly becoming obsolete. The introduction of maintenance therapies like PARP inhibitors is changing tumor biology and response patterns, suggesting this simple time-based distinction no longer adequately reflects the clinical reality.

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 selection between PARP inhibitors like olaparib and niraparib is not one-size-fits-all. It's a personalized decision based on patient preference for dosing frequency (once vs. twice daily), tolerance for side effects like hypertension, and potential drug-drug interactions.

The development of PARP-1 selective inhibitors like seriparib signals a shift in drug innovation. Instead of only chasing higher efficacy, these new agents aim for a more favorable toxicity profile (less GI toxicity, fewer dose discontinuations) to improve patient quality of life and treatment adherence.

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.

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.