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.
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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.
Lutetium faces criticism for its fixed 6-cycle regimen, which may be suboptimal as the PSMA target diminishes with ADT. However, this critique is rarely applied to other drugs like PARP inhibitors, which are given until progression. This highlights a double standard and the tension between using a fixed regimen for regulatory approval versus finding the optimal dose in practice.
When a patient has a BRCA2 mutation, clinicians on the panel view it as such a dominant predictive biomarker that they would prioritize a PARP inhibitor-based triplet regimen. This single genetic finding often outweighs other clinical factors or even the potential addition of docetaxel in treatment decisions.
The DESTINY-Breast11 trial showed a neoadjuvant regimen of TDXD followed by THP achieved a 67.3% pathologic complete response (pCR) rate in high-risk HER2+ breast cancer. This is the highest pCR rate seen in a registrational trial, signaling a potential new standard of care.
In metastatic breast cancer, approximately one-third of patients are unable to proceed to a second line of therapy due to disease progression or declining performance status. This high attrition rate argues for using the most effective agents, such as ADCs, in the first-line setting.
In a subset analysis of the high-risk MONARCH-E trial, an inferred Oncotype score did not identify which patients benefited from the CDK4/6 inhibitor abemaciclib. This indicates that while such scores assess prognostic risk and guide chemotherapy decisions, they are not predictive biomarkers for selecting patients for this targeted therapy.
The FDA is predicted to approve new PARP inhibitors from trials like AMPLITUDE only for BRCA-mutated patients, restricting use to where data is strongest. This contrasts with the EMA's potential for broader approvals or denials. This highlights the diverging regulatory philosophies that create different drug access landscapes in the US and Europe.
Three 2025 trials (AMPLITUDE, PSMA-addition, CAPItello) introduced personalized therapy for metastatic hormone-sensitive prostate cancer. However, significant benefits were confined to narrow subgroups, like BRCA-mutated patients. This suggests future success depends on even more stringent patient selection, not broader application of targeted agents.
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.
Data from the MONARCH-E and NATALY trials show that the benefit of adjuvant CDK4/6 inhibitors like abemaciclib and ribociclib persists and even increases after patients complete their 2-3 year treatment course. This sustained "carryover effect" suggests a lasting impact on disease biology rather than just temporary suppression.