Pembrolizumab plus olaparib does not extend survival in triple-negative breast cancer
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Key takeaways:
- Researchers observed no significant PFS or OS benefit with pembrolizumab-olaparib vs. pembrolizumab-chemotherapy.
- Patients with BRCA mutation had improved PFS with pembrolizumab-olaparib.
Pembrolizumab plus olaparib did not improve outcomes among patients with locally recurrent inoperable or metastatic triple-negative breast cancer, according to study results presented at San Antonio Breast Cancer Symposium.
However, patients with BRCA mutations did achieve longer PFS and OS with pembrolizumab (Keytruda, Merck) plus olaparib (Lynparza, AstraZeneca), suggesting a potential maintenance strategy for that subgroup, researchers concluded.
Rationale and methods
As Healio previously reported , results of the KEYNOTE-355 trial showed the addition of pembrolizumab to first-line chemotherapy significantly extended PFS and OS among patients with PD-L1-positive metastatic triple-negative breast cancer.
However, a need remains for safe and effective treatments after induction to sustain the clinical benefit.
“The [poly(ADP)-ribose polymerase (PARP)] inhibitor olaparib is an established maintenance therapy for multiple platinum-sensitive tumor types, and prior data suggest that PARP inhibitors combined with PD-1/PD-L1 inhibitors could provide an improved therapeutic effect,” Hope S. Rugo, MD, professor of medicine and director of breast oncology and clinical trials education at UCSF Helen Diller Comprehensive Cancer Center, and colleagues wrote.
The randomized phase 2 KEYLYNK-009 included 271 patients with locally recurrent inoperable or metastatic triple-negative breast cancer.
All patients derived clinical benefit from first-line treatment with pembrolizumab — an anti-PD-1 therapy — plus platinum-based chemotherapy. All patients also had measurable, locally recurrent inoperable or metastatic disease not previously treated with chemotherapy in the metastatic setting.
Study participants underwent induction therapy for up to six cycles of pembrolizumab dosed at 200 mg plus carboplatin area under the curve 2 combined with 1,000 mg/m² gemcitabine on days 1 and 8 every 3 weeks.
Researchers then assigned patients who achieved complete response, partial response or stable disease after four to six treatment cycles to either 200 mg pembrolizumab once every 3 weeks plus 300 mg twice daily olaparib (n = 135), or to pembrolizumab plus chemotherapy (n = 136).
Treatment with olaparib or chemotherapy continued until disease progression or unacceptable toxicity. Treatment with pembrolizumab continued for up to 35 cycles, or until disease progression or unacceptable toxicity.
Researchers stratified patients based on induction response, tumor PD-L1 status and tumor genomic status.
PFS by blinded independent review committee and OS served as dual primary endpoints. Secondary endpoints included PFS and OS from randomization among patients with PD-L1 combined positive score (CPS) 10, PFS and OS among those with BRCA mutations, and safety.
Findings
Median follow-up was 17.2 months.
Results showed no significant improvement in PFS (median, 5.5 months vs. 5.6 months; HR = 0.98; 95% CI, 0.72-1.33) or OS (median, 25.1 months vs. 23.4 months; HR = 0.95; 95% CI, 0.64-1.4) with pembrolizumab-olaparib vs. pembrolizumab-chemotherapy in the intention-to-treat population.
Researchers observed a numerical PFS improvement with pembrolizumab-olaparib among those with BRCA mutations (median, 12.4 months vs. 8.4 months; HR = 0.7; 95% CI, 0.33-1.48) but not among those with PD-L1 CPS ≥ 10 (median, 5.7 months for both; HR = 0.92; 95% CI, 0.59-1.43).
The OS difference between pembrolizumab-olaparib and pembrolizumab-chemotherapy did not reach statistical significance for those with PD-L1 CPS ≥10 (median not reached in either group; HR = 0.97; 95% CI, 0.53-1.76) or those with BRCA mutations (median, not reached vs. 23.4 months; HR = 0.81; 95% CI, 0.28-2.37).
No new safety signals emerged.
Treatment-related adverse events occurred in 84.4% of patients assigned pembrolizumab-olaparib and 96.2% of those assigned pembrolizumab-chemotherapy. Treatment-related grade 3 or higher adverse events occurred among 32.6% in the pembrolizumab-olaparib group — leading to no deaths — and 68.4% in the pembrolizumab-chemotherapy group, leading to two deaths (1.5%).
Twelve patients (8.9%) assigned pembrolizumab-olaparib and 26 (19.5%) assigned pembrolizumab-chemotherapy discontinued therapy due to treatment-related adverse events.
Further data are required to confirm the potential benefits of pembrolizumab plus olaparib for patients with BRCA mutations, Rugo and colleagues wrote.
Perspective
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The KEYLINK-009 trial compared chemotherapy plus pembrolizumab — standard therapy as approved from the KEYNOTE-355 trial — followed by maintenance therapy with pembrolizumab plus either chemotherapy or a PARP inhibitor. The results showed no significant improvement in PFS or OS with pembrolizumab-olaparib vs. pembrolizumab-chemotherapy. They did show a potential benefit among patients with BRCA mutations. The study didn’t have sufficient statistical power in that subset, but perhaps there may be a benefit for that group. There clearly was less toxicity in the olaparib arm compared with chemotherapy.
This may set the stage for a future studies that omit chemotherapy after four to six cycles to minimize side effects, although the impact of PARP inhibitors would remain unclear — presumably this would be important for those with BRCA (and possibly PALB2) germline mutations, as well as somatic alterations involved in DNA repair, but the small numbers of these subsets would present challenges in the statistical design and feasibility of such trials.
References:
Cortes J, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2202809.
Rugo H, et al. Abstract GS01-05. Presented at: San Antonio Breast Cancer Symposium; Dec. 5-9, 2023; San Antonio.
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Rugo H, et al. Abstract GS01-05. Presented at: San Antonio Breast Cancer Symposium; Dec. 5-9, 2023; San Antonio.
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