For first-line metastatic triple-negative breast cancer, determining PD-L1 status is the most critical first step, even in BRCA-positive patients. An immunotherapy-based regimen is preferred for PD-L1 positive cases to pursue the potential for a durable, complete response, deferring PARP inhibitors.
Although the KeyLink 009 study did not show superiority for olaparib/pembrolizumab maintenance and was halted, it successfully generated crucial safety data for this combination. This information is now valuable for designing trials in other settings, such as post-neoadjuvant therapy for early-stage BRCA-positive breast cancer.
For TNBC patients with newly discovered, asymptomatic brain metastases, the practical approach is to start systemic therapy immediately while planning for CNS-directed treatment. This contrasts with strict clinical trial protocols that require CNS treatment and stabilization first, which can dangerously delay systemic control of extracranial disease.
The belief that immune-related adverse events (irAEs) predict better response to immunotherapy is likely confounded by survival bias. Patients must remain on treatment long enough to both respond and develop an irAE. This extended duration creates a correlation that may not be causal.
Using local therapy to treat isolated progressive sites while continuing systemic treatment is promising for ER-positive disease to prolong a well-tolerated therapy. However, this approach is far less applicable in triple-negative breast cancer due to its typically shorter treatment durations and more aggressive, widespread progression patterns.
Clinicians should be cautious not to conflate the remarkable CNS activity of trastuzumab deruxtecan (T-DXd) in HER2-positive disease with that of other ADCs, like TROP2-ADCs, in HER2-low or negative settings. Data is emerging for TROP2-ADCs, but their CNS activity is expected to be much more modest.