A phase II trial, KEYLYNK-009, evaluated the efficacy of a maintenance strategy involving checkpoint blockade and a PARP inhibitor in unselected patients with triple-negative breast cancer (TNBC). The trial aimed to determine whether adding pembrolizumab plus olaparib or continuing pembrolizumab plus chemotherapy after first-line therapy could improve survival outcomes in patients with locally recurrent inoperable or metastatic TNBC. While the combination therapy demonstrated a good safety profile, the results did not show significant improvements in progression-free survival (PFS) or overall survival (OS) compared to the pembrolizumab plus chemotherapy arm.
With a median follow-up of 17 months, both PFS and OS were essentially the same in both treatment arms. The median PFS for the pembrolizumab plus olaparib arm was 5.5 months, while the pembrolizumab plus chemotherapy arm had a median PFS of 5.6 months. The median OS for the pembrolizumab plus olaparib arm was 25.1 months, whereas the pembrolizumab plus chemotherapy arm had a median OS of 23.4 months. These findings suggested that the maintenance strategy did not provide additional benefits beyond induction chemotherapy.
The study also conducted a subgroup analysis based on the presence of a BRCA mutation. Interestingly, a trend toward a more favorable PFS was observed in the subgroup with a BRCA mutation who received the chemotherapy-free strategy. These patients had a median PFS of 12.4 months compared to 8.4 months in the pembrolizumab plus chemotherapy arm. However, the study highlighted that this finding would require confirmation in larger trials before it can be considered an effective strategy for patients with germline BRCA mutations.
Safety Profile
The trial indicated that the maintenance therapy with pembrolizumab and olaparib had a better safety profile compared to the pembrolizumab and chemotherapy arm. Patients in the combination therapy arm experienced fewer treatment-related adverse events (TRAEs) and fewer grade ≥3 TRAEs. The incidence of immune-mediated adverse events was also low in both treatment arms. The lower incidence of TRAEs in patients receiving pembrolizumab and olaparib was deemed clinically significant. Additionally, the data suggested that dropping chemotherapy and continuing with pembrolizumab after a good response or stable disease did not impact outcomes, supporting the notion that pembrolizumab alone could be used for maintenance therapy.
Implications and Future Directions
The KEYLYNK-009 study provides reassurance that clinicians can safely choose between a PARP inhibitor or continuing chemotherapy as add-ons to pembrolizumab for maintenance therapy in TNBC. The slightly better side effect profile observed with olaparib suggests that it could be a preferable option. However, future studies should explore the possibility of using pembrolizumab alone for maintenance therapy after a response to induction therapy with pembrolizumab and chemotherapy. Although not yet a standard of care, dropping chemotherapy in favor of pembrolizumab alone is a practice followed in clinical settings.
The maintenance strategy involving checkpoint blockade and a PARP inhibitor did not significantly improve survival outcomes in unselected patients with TNBC. The study emphasized the importance of considering the duration of induction chemotherapy when interpreting the results. While the combination therapy did not show significant benefits in terms of PFS and OS, the trial presented valuable findings regarding the safety profile of different maintenance therapies and the potential use of pembrolizumab alone for maintenance in certain patient subgroups. Further research is needed to validate these findings and expand the options for maintenance therapy in TNBC.
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