Olaparib maintenance has favourable safety profile in TNBC

In patients with previously untreated, locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC), maintenance olaparib/pembrolizumab shows similar efficacy outcomes compared with chemotherapy/pembrolizumab but with a more favourable safety profile, the results from KEYLYNK-009 demonstrated.

Patients with previously untreated, locally recurrent inoperable or metastatic TNBC can benefit from treatment with pembrolizumab (plus chemotherapy), as results from the phase 3 KEYNOTE-355 study (NCT02819518) showed [1]. There is a need for tolerable and effective regimens in this setting that maintain the clinical benefits after induction therapy. In pre-clinical tumour models, PARP inhibitors activated the STING pathway, upregulated PD-L1 expression, and showed synergistic antitumor activity when combined with anti-PD-(L)1 antibodies, regardless of BRCA status [2]. In addition, phase 1 trials with anti-PD-(L)1 antibodies plus PARP inhibitors have demonstrated tolerable safety and promising antitumor activity in patients with advanced TNBC [3,4].

The phase 2 KEYLYNK-009 study (NCT04191135) evaluated the efficacy and safety of maintenance pembrolizumab plus olaparib versus pembrolizumab plus chemotherapy for patients with locally recurrent inoperable or metastatic TNBC who had clinical benefit from induction with first-line pembrolizumab plus platinum-based chemotherapy. The trial enrolled 460 patients with locally recurrent inoperable or metastatic TNBC not previously treated in the metastatic setting. Participants were treated with platinum-based chemotherapy plus pembrolizumab for 4–6 cycles (induction); those who had benefit from induction therapy (response or stable disease, n=27) were 1:1 randomised to post-induction therapy with olaparib plus pembrolizumab or chemotherapy plus pembrolizumab. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Prof. Hope Rugo (UCSF Helen Diller Family Comprehensive Cancer Center, CA, USA) presented the results [5].

At a median follow-up of 17 months, median PFS (from randomisation) was almost identical in both treatment groups: 5.5 months for participants treated with olaparib/pembrolizumab and 5.6 months for participants treated with chemotherapy/pembrolizumab (HR 0.98; 95% CI 0.72–1.33; P=0.4556). In addition, no difference in median OS was observed between the groups. In a subgroup analysis, a positive trend for PFS was observed for patients with BRCA-mutated tumours when treated with olaparib/pembrolizumab (HR 0.70; 95% CI 0.33-1.48).

A lower incidence of treatment-related adverse events was reported in participants receiving olaparib/pembrolizumab versus chemotherapy/pembrolizumab.

“Stopping chemotherapy in patients responding to induction therapy with chemotherapy/pembrolizumab and treating them with maintenance olaparib/pembrolizumab shows similar efficacy outcomes compared with continued chemotherapy/pembrolizumab, but with a more favourable safety profile,” concluded Prof. Rugo.

1. Cortes J, et al. N Engl J Med 2022;387:217-226.
2. Wang Z, et al. Sci Rep. 2019;9:1853.
3. Domchek SM, et al. Lancet Oncol. 2020;21:1155-1164.
4. Vinayak S, et al. JAMA Oncol. 2019;5:1132-1140.
5. Rugo HS, et al. Pembrolizumab plus olaparib vs pembrolizumab plus chemotherapy after induction with pembrolizumab plus chemotherapy for locally recurrent inoperable or metastatic TNBC: randomized, open-label, phase 2 KEYLYNK-009 study. Abstract GS01-05, SABCS 2023, 5–9 December, San Antonio, TX, USA.

 

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Posted on 11 January 202425 March 2024