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.

Clinicians should view HRD scores as a spectrum rather than a simple positive/negative result. For a patient with a score near the arbitrary cutoff and an excellent clinical response to platinum, oncologists may advocate for insurance coverage of PARP inhibitors.

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.

A strong response to neoadjuvant chemotherapy can eliminate viable tumor cells, making subsequent HRD testing impossible. It is critical to obtain an adequate biopsy for molecular testing before initiating systemic therapy to guide future maintenance decisions.

If multiple attempts at HRD biomarker testing are indeterminate, a strong clinical response to platinum-based neoadjuvant chemotherapy can serve as a surrogate for HRD positivity. This clinical observation can support the decision to treat the patient as HRD-positive and offer a PARP inhibitor.

Tissue may become insufficient or necrotic after neoadjuvant chemotherapy, leading to failed molecular tests. Securing tissue for comprehensive biomarker analysis at the initial diagnosis is crucial to guide treatment decisions, including PARP inhibitor eligibility.

For HRD-positive ovarian cancer, a strong initial response to platinum chemotherapy may justify using a PARP inhibitor alone for maintenance. A weaker response, however, suggests adding bevacizumab for a potentially greater benefit, using clinical response as a key decision-making tool.

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.