In ovarian cancer trials, many patients in the placebo group later receive a PARP inhibitor. This crossover "pollutes" the data, making it difficult to prove a statistically significant overall survival benefit for frontline PARP maintenance, despite its clear effectiveness.

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 OlympiA study showed neoadjuvant olaparib plus durvalumab achieved an 80% pathologic complete response (pCR) rate in patients with T2N0 BRCA-mutated TNBC. This result, superior to what chemotherapy typically accomplishes, suggests a highly effective, chemotherapy-free future for this specific patient subgroup.

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.

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.

The combination of olaparib and radium-223 improves progression-free survival in an unselected patient population. The mechanism isn't reliant on pre-existing BRCA mutations. Instead, radium (an alpha-emitter) induces DNA breaks, and olaparib prevents the PARP enzyme from repairing this new damage, thus sensitizing the tumor to the radiopharmaceutical.

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.

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.