Phase Ib Dose Expansion and Translational Analyses of Olaparib in Combination with Capivasertib in Recurrent Endometrial, Triple-Negative Breast, and Ovarian Cancer

Shannon N. Westin, Marilyne Labrie, Jennifer K. Litton, Aurora Blucher, Yong Fang, Christopher P. Vellano, Joseph R. Marszalek, Ningping Feng, Xiao Yan Ma, Allison Creason, Bryan Fellman, Ying Yuan, Sanghoon Lee, Tae Beom Kim, Jinsong Liu, Anca Chelariu-Raicu, Tsun Hsuan Chen, Nashwa Kabil, Pamela T. Soliman, Michael FrumovitzKatheleen M. Schmeler, Amir Jazaeri, Karen H. Lu, Rashmi Murthy, Larissa A. Meyer, Charlotte C. Sun, Anil K. Sood, Robert L. Coleman, Gordon B. Mills

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Purpose: On the basis of strong preclinical rationale, we sought to confirm recommended phase II dose (RP2D) for olaparib, a PARP inhibitor, combined with the AKT inhibitor capivasertib and assess molecular markers of response and resistance. Patients and Methods: We performed a safety lead-in followed by expansion in endometrial, triple-negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300 mg orally twice daily and capivasertib orally twice daily on a 4-day on 3-day off schedule was evaluated. Two dose levels (DL) of capivasertib were planned: 400 mg (DL1) and 320 mg (DL-1). Patients underwent biopsies at baseline and 28 days. Results: A total of 38 patients were enrolled. Seven (18%) had germline BRCA1/2 mutations. The first 2 patients on DL1 experienced dose-limiting toxicities (DLT) of diarrhea and vomiting. No DLTs were observed on DL-1 (n 6); therefore, DL1 was reexplored (n 6) with no DLTs, confirming DL1 as RP2D. Most common treatment-related grade 3/4 adverse events were anemia (23.7%) and leukopenia (10.5%). Of 32 evaluable subjects, 6 (19%) had partial response (PR); PR rate was 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlations between response and immune activity, cell-cycle alterations, and DNA damage response. Therapy resistance was associated with receptor tyrosine kinase and RAS-MAPK pathway activity, metabolism, and epigenetics. Conclusions: The combination of olaparib and capivasertib is associated to no serious adverse events and demonstrates durable activity in ovarian, endometrial, and breast cancers, with promising responses in endometrial cancer. Importantly, tumor samples acquired pre- and on-therapy can help predict patient benefit. _2021 American Association for Cancer Research.

Original languageEnglish (US)
Pages (from-to)6354-6365
Number of pages12
JournalClinical Cancer Research
Volume27
Issue number23
DOIs
StatePublished - Dec 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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