Early clinical trial data has shown that patients with cancers driven by DNA damage repair (DDR) mutations can be safely treated with the PARP inhibitor olaparib and the WEE1 inhibitor adavosertib when given sequentially rather than concurrently.
Presenting results from the Phase Ib STAR trial to the 34th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, last week, Timothy Yap, Associate Professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, said that sequential dosing with the two drugs was a strategy that was safe and well-tolerated, with promising signs of anti-tumor activity in patients with a range of different cancers.
Yap told Inside Precision Medicine that preclinical and clinical trials conducted at MD Anderson and other cancer centers had previously shown that the concurrent administration of PARP and WEE1 inhibitors effectively inhibits tumor growth and leads to patient benefit, but the regimen is poorly tolerated, with anemia, neutropenia, thrombocytopenia, diarrhea, nausea, vomiting and fatigue among the side-effects observed.
To investigate the causes of such toxicity, Yap and colleagues carried out reverse translational research, which showed that concurrent treatment with PARP and WEE1 inhibitors induces replication stress, DNA damage, and abolishes the G2 DNA damage checkpoint in both normal and malignant cells.
“What was interesting was that following cessation of monotherapy with PARP or WEE1 inhibitors, the effects of these inhibitors persist, suggesting that the sequential administration of PARP and WEE1 inhibitors could maintain efficacy while ameliorating toxicity,” said Yap. “Strikingly, while the sequential administration mirrored concurrent therapy in cancer cells that have high basal replication stress, low basal replication stress in normal cells protected them from DNA damage and toxicity, thus improving tolerability while preserving efficacy in ovarian cancer xenograft and patient-derived xenograft models.”
These results gave the rationale for the Phase Ib Sequential Trial of Agents against DNA Repair (STAR) Study, which investigated the sequential combination of olaparib and adavosertib in 13 patients (mean age 50 years, 85% women) with DDR-aberrant advanced tumors. The cohort included five patients with breast cancer, five with ovarian cancer, and one case each of prostate, gastric, and bowel cancer. Ten of the patients had received three or more previous lines of chemotherapy, and seven had cancers that progressed during prior PARP inhibitor therapy.
The patients were given the treatments at two dose levels; for dose-level 1, three patients were given oral olaparib 300 mg twice daily on days 1–5 and 15–19 along with oral adavosertib 250 mg on days 8–12 and 22–26. Dose level 2 followed the same schedule but the adavosertib dose was increased from 250 mg to 300 mg for the 10 patients in this group.
The most common grade 1 or 2 toxicities encountered were nausea, which was reported in ten patients, anemia (n=7), fatigue (n=7), vomiting (n=7), and diarrhea (n=4). There were no dose-limiting toxicities but two heavily pretreated (≥5 prior lines) patients experienced non-dose-limiting grade 3 or worse myelosuppression. One patient needed a dose reduction.
Twelve participants were evaluated for tumor response, of whom three (25.0%) had a partial response to treatment and five (41.7%) had stable disease for 4 months or longer, giving a combined disease control rate of 66.7%.
Yap said that the findings provide “early clinical proof of concept for a novel sequential approach for the combination of PARP inhibitors with WEE1 inhibitors that is potentially effective with improved toxicity.”
“It also provides the blueprint for other related DDR drugs to be potentially combined safely with good tolerability and promising efficacy for patients with cancers where the mutations have been identified.”