Retrospective data from the PAOLA-one trial shows a significant reduction in benefit from subsequent platinum-based therapy for patients who progressed while on a PARP inhibitor. Objective response rates dropped from 50-60% (placebo group) to 30% (PARP group).

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.

Real-world data shows that in platinum-sensitive ovarian cancer patients who have progressed on PARP inhibitors, subsequent platinum-based chemotherapy has a surprisingly low response rate of only 20%. This quantifies a significant opportunity for highly active ADCs to potentially replace platinum in this growing patient population.

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.

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.

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.

When an HRD test is inconclusive due to insufficient tumor tissue after neoadjuvant chemotherapy, it can paradoxically indicate a very strong response to treatment and high platinum sensitivity, as there is little to no residual tumor to analyze.

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.