Introduction: The Challenge of Metastatic Triple-Negative Breast Cancer
Triple-negative breast cancer (TNBC) remains the most aggressive subtype of breast cancer, characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression. Historically, the management of metastatic TNBC (mTNBC) relied heavily on cytotoxic chemotherapy. However, the landscape has shifted with the introduction of immune checkpoint inhibitors (ICIs) and poly(ADP-ribose) polymerase (PARP) inhibitors.
The KEYNOTE-355 trial established the combination of pembrolizumab, an anti-PD-1 therapy, plus chemotherapy as a standard of first-line treatment for patients with PD-L1-positive mTNBC. Despite this progress, the duration of response is often limited, and the cumulative toxicity of continuous chemotherapy poses a significant challenge to patient quality of life. The KEYLYNK-009 study was designed to address this by exploring a switch-maintenance strategy, substituting chemotherapy with the PARP inhibitor olaparib in patients who achieved clinical benefit from initial chemo-immunotherapy.
KEYLYNK-009: Trial Rationale and Design
The biological rationale for combining PARP inhibitors with ICIs is robust. PARP inhibition leads to the accumulation of DNA double-strand breaks, which can increase the tumor mutational burden and the release of DNA fragments into the cytosol. This activates the cGAS-STING pathway, enhancing interferon production and promoting an inflamed tumor microenvironment, thereby potentially sensitizing the tumor to PD-1 blockade.
KEYLYNK-009 (NCT04191135) was a randomized, open-label, Phase 2 study. The trial enrolled participants with previously untreated, locally recurrent inoperable or metastatic TNBC, regardless of PD-L1 status. The study proceeded in two phases:
Induction Phase
All participants received first-line induction therapy consisting of pembrolizumab (200 mg every 3 weeks) plus platinum-based chemotherapy (carboplatin and gemcitabine).
Randomization Phase
Participants who achieved a complete response (CR), partial response (PR), or stable disease (SD) after induction (per RECIST v1.1) were randomized 1:1 to receive either:
1. Pembrolizumab (200 mg Q3W) plus olaparib (300 mg BID).
2. Continued pembrolizumab plus chemotherapy (carboplatin plus gemcitabine).
The primary endpoints were progression-free survival (PFS) and overall survival (OS) in the randomized population.
Primary Efficacy Outcomes: PFS and OS Analysis
A total of 460 participants entered the induction phase, of whom 271 (58.9%) derived clinical benefit and were randomized to the maintenance/continuation phase. The results, recently published in Clinical Cancer Research, indicated that the study did not meet its primary endpoints of superior PFS or OS for the pembrolizumab plus olaparib combination.
In the intention-to-treat randomized population, the median PFS was 5.5 months for the pembrolizumab plus olaparib group compared to 5.6 months for the pembrolizumab plus chemotherapy group. The hazard ratio (HR) was 0.98 (95% CI, 0.72–1.33; P=0.4556), indicating no statistically significant difference between the two arms.
Similarly, the OS analysis showed no significant advantage for the olaparib combination. The median OS was 25.1 months in the pembrolizumab plus olaparib arm versus 23.4 months in the chemotherapy arm (HR, 0.95; 95% CI, 0.64–1.40). While the numerical median OS was slightly higher in the olaparib group, the confidence intervals heavily overlapped, precluding a definitive claim of superiority.
The BRCA Mutation Subgroup: A Signal of Benefit
One of the most clinically relevant findings from the KEYLYNK-009 trial emerged from the subgroup analysis of patients with tumor BRCA1 or BRCA2 mutations (tBRCAm). PARP inhibitors are specifically indicated for patients with germline BRCA mutations due to the principle of synthetic lethality.
In participants with tBRCAm, the hazard ratios for both PFS and OS favored the pembrolizumab plus olaparib arm:
– PFS HR: 0.70 (95% CI, 0.33–1.48)
– OS HR: 0.81 (95% CI, 0.28–2.37)
Although the small sample size in this subgroup limited the statistical power and resulted in wide confidence intervals, the trend suggests that for BRCA-mutated TNBC, the switch to a PARP inhibitor as maintenance may provide a more effective, less toxic alternative to continued chemotherapy.
Safety and Tolerability Profile
A secondary goal of the switch-maintenance strategy is to reduce the burden of treatment-related adverse events (TRAEs) associated with long-term chemotherapy. The safety data from KEYLYNK-009 were encouraging in this regard.
TRAEs occurred in 84.4% of participants in the pembrolizumab plus olaparib group compared to 96.2% in the pembrolizumab plus chemotherapy group. Grade 3 or higher TRAEs were also lower in the olaparib arm. The specific profile of adverse events differed as expected: the chemotherapy arm saw higher rates of myelosuppression (neutropenia, thrombocytopenia), while the olaparib arm was associated with more manageable gastrointestinal symptoms and anemia. No new safety signals were identified for the combination of pembrolizumab and olaparib.
Clinical Context and Expert Interpretation
While the KEYLYNK-009 study was technically a negative trial regarding its primary endpoints, it provides essential data for clinical decision-making. The finding that pembrolizumab plus olaparib yielded “similar” efficacy to continued chemotherapy is notable. In the palliative setting of mTNBC, maintaining clinical benefit while minimizing toxicity is a primary objective.
The trial confirms that for the general population of TNBC (PD-L1 unselected), switching to olaparib maintenance does not provide a survival advantage over the current standard of care. However, the data for the BRCA-mutated subgroup align with the OlympiAD and EMBRACA trials, which demonstrated the efficacy of PARP inhibitor monotherapy in this population. KEYLYNK-009 extends this by suggesting that olaparib can be successfully integrated into an immunotherapy-based maintenance framework.
Study limitations include its open-label design and the fact that the chemotherapy arm was limited to platinum-based agents, which may have performed better than other non-platinum agents in a TNBC population, potentially narrowing the gap between the two arms.
Conclusion: Implications for Clinical Practice
The KEYLYNK-009 trial demonstrates that pembrolizumab plus olaparib is a feasible maintenance strategy for patients with mTNBC who have responded to induction therapy. While it did not surpass the efficacy of continued chemotherapy in the overall population, it offered comparable survival outcomes with a more favorable toxicity profile.
For clinicians, the most significant takeaway is the potential for a chemotherapy-free window in patients with BRCA mutations. Future research should focus on identifying further biomarkers beyond BRCA mutation—such as homologous recombination deficiency (HRD) scores—that might predict which patients are most likely to benefit from this PARP inhibitor and immunotherapy combination.
Funding and ClinicalTrials.gov
This study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and AstraZeneca. The trial is registered at ClinicalTrials.gov as NCT04191135.
References
1. Rugo HS, Cescon DW, Robson ME, et al. KEYLYNK-009: Pembrolizumab Plus Olaparib in Locally Recurrent Inoperable or Metastatic Triple-Negative Breast Cancer and Clinical Benefit From First-Line Pembrolizumab Plus Chemotherapy. Clin Cancer Res. 2025; doi: 10.1158/1078-0432.CCR-25-1818.
2. Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817-1828.
3. Robson M, Im SA, Senkus E, et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017;377(6):523-533.