Abstract OT-30-01: KEYLYNK-009: A phase 2/3, open-label, randomized study of pembrolizumab plus olaparib vs pembrolizumab plus chemotherapy after induction with first-line pembrolizumab plus chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC)
Authors: Rugo Hope , Llombart-Cussac Antonio , Andre Fabrice , Robson Mark E. , Saji Shigehira , Harbeck Nadia , Schmid Peter , Cescon David , Ahn Jin Seok , Nanda Rita , Fan Li , Mejia Jaime Alberto , Karantza Vassiliki , Bardia Aditya 
Published: February 2021

Background: Combination therapy with immunotherapy + chemotherapy is a promising approach for first-line treatment of locally recurrent, inoperable TNBC or metastatic TNBC (mTNBC). However, an unmet need exists for effective and tolerable maintenance regimens in mTNBC to sustain clinical benefit after induction therapy and avoid potential toxicity or resistance to prolonged chemotherapy. The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib has shown efficacy in the maintenance setting for platinum-sensitive ovarian cancer, and the high prevalence of BRCA mutations (or “BRCAness”) in TNBC may make these tumors particularly sensitive to DNA-damaging agents. Moreover, evidence suggests that combination therapy with olaparib and the PD-1 inhibitor pembrolizumab may provide clinical benefit greater than treatment with either single-agent. KEYLYNK-009 (NCT04191135) is a phase 2/3, open-label, randomized study of pembrolizumab + olaparib or pembrolizumab + chemotherapy after induction with first-line pembrolizumab + chemotherapy in patients with locally recurrent, inoperable TNBC or mTNBC.Methods: This 2-in-1 study design will enroll ~317 patients in phase 2; if a planned efficacy boundary is met, ~615 additional patients will be enrolled in phase 3. Patients eligible for induction therapy must have measurable, locally recurrent, inoperable TNBC that cannot be treated with curative intent or mTNBC previously untreated with chemotherapy in the metastatic setting. All patients will receive up to 6 cycles of induction therapy with pembrolizumab 200 mg Q3W + chemotherapy (carboplatin AUC 2 + gemcitabine 1000 mg/m2 on days 1 and 8 Q3W). Patients eligible for postinduction treatment must achieve complete or partial response or maintain stable disease during induction after 4-6 treatment cycles, with ECOG PS 0/1 and no persistent grade &gt;1 toxicities related to induction therapy (excluding alopecia, hemoglobin ≥9.0 g/dL, grade 2 hyper-/hypothyroidism, or grade 2 hyperglycemia). These patients will be randomized 1:1 to receive pembrolizumab 200 mg Q3W + olaparib 300 mg twice daily or continue pembrolizumab + chemotherapy (same as induction regimen). Olaparib and chemotherapy may continue until progression or unacceptable toxicity; pembrolizumab may continue for ≤35 cycles (including induction), unacceptable toxicity, or progression. Phase 3 dual primary endpoints are PFS per RECIST version 1.1 by blinded independent central review and OS. Secondary endpoints are OS and PFS in patients with BRCA mutation, health-related quality of life, and safety. PFS and OS will be estimated using the Kaplan-Meier method, treatment differences will be assessed using a stratified log-rank test, and HRs and 95% CIs will be assessed using a stratified Cox proportional hazard model with Efron's method of tie handling. AEs are monitored until 30 days (90 days for serious AEs) after treatment discontinuation per NCI CTCAE version 5.0. Patient enrollment is ongoing with a total planned enrollment of 932 patients. Contact Hope S. Rugo at hope.rugo@ucsf.edu for additional information.

Citation Format: Hope Rugo, Antonio Llombart-Cussac, Fabrice Andre, Mark E. Robson, Shigehira Saji, Nadia Harbeck, Peter Schmid, David Cescon, Jin Seok Ahn, Rita Nanda, Li Fan, Jaime Alberto Mejia, Vassiliki Karantza, Aditya Bardia. KEYLYNK-009: A phase 2/3, open-label, randomized study of pembrolizumab plus olaparib vs pembrolizumab plus chemotherapy after induction with first-line pembrolizumab plus chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-30-01.