First Trial to Combine Olaparib and Capivasertib Shows Antitumor Activity

Results of a recently published phase 1 trial showed a novel combination of 2 precision medicines to be effective against a variety of advanced cancers.^1,2

The combination of olaparib, a poly ADP ribose polymerase (PARP) inhibitor, and capivasertib, an AKT inhibitor, was evaluated in patients with advanced solid tumors to determine the safety, tolerability, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity within the patient population.¹

The trial is the first to combine PARP and AKT inhibitors; investigators focused on treating tumors with germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without somatic DNA damage response (DDR) and/or PI3K/AKT pathway alterations.

The investigator-initiated phase 1b clinical trial enrolled 64 patients with advanced solid tumors from 4 major cancer centers in the United Kingdom into 1 of 2 cohorts: dose-escalation (20 patients) or dose-expansion (44 patients). Tumor types included ovarian, breast, pancreatic, cervical, endometrial, bladder, and colorectal, among others. The first and second most common tumor types were ovarian (39%) and advanced breast cancer (28%), respectively.

Of 56 evaluable patients in the study, 19 (34%) had RECIST PRs and/or tumor marker response; 14 (25%) patients achieved RECIST PRs, 12 confirmed and 2 unconfirmed; 11 (20%) patients had RECIST stable disease (SD) for at least 4 months (SD ), resulting in a clinical benefit rate (CBR) of 44.6% (95% confidence interval, 31.3-58.5).

Investigators asserted that the trial results support further study of the combination of olaparib and capivasertib in treating patients with BRCA1/2- and non-BRCA1/2-mutant cancers.

"Our study establishes the potential of a combination of two precision medicines for patients whose tumours have stopped responding to existing drugs. The combination of olaparib and capivasertib works by attacking two fundamental weaknesses in cancer, and could potentially be used to treat patients with several common tumors,” said lead author Johann de Bono, professor of experimental cancer medicine at The Institute of Cancer Research, London, and consultant medical oncologist at The Royal Marsden NHS Foundation Trust. “I look forward to seeing the possible benefit of the combination tested in later-stage trials.”

References:

1. Yap TA, Kristeleit R, Michalarea V, et al. Phase 1 trial of the PARP inhibitor plaparib and AKT Inhibitor capivasertib in patients with BRCA1/2- and non-BRCA1/2-mutant cancers. Cancer Discovery. October 2020. doi: 10.1158/2159-8290.CD-20-0163.
2. Combining two precision medicines can treat drug-resistant cancers. News Release. ScienceDaily; September 14, 2020. Accessed November 16, 2020. https://www.sciencedaily.com/releases/2020/09/200914194027.htm.