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 treatment landscape for platinum-resistant ovarian cancer has rapidly evolved into a biomarker-driven paradigm. Clinicians must now test for and choose between therapies targeting distinct markers like folate receptor alpha (mirvetuximab), HER2 (T-DXd), and PD-L1 (pembrolizumab), requiring a sophisticated sequencing strategy.

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 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.

Because POLE testing often requires a send-out NGS test, the turnaround time is slow. Clinicians report they cannot wait for these results and must make treatment decisions, such as starting chemotherapy for a p53-mutant tumor, before the full molecular profile, including the crucial POLE status, is known.

To maximize the chances of successful biomarker identification from a liquid biopsy, especially when tissue is scant, the blood sample must be drawn before initiating any chemotherapy. This pre-treatment timing is critical for improving the diagnostic yield of blood-based next-generation sequencing (NGS) testing.

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.

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.