Olaparib and adavosertib can be safely used to treat patients with cancers that are driven by certain mutations occurring in response to DNA damage if they are given in sequence rather than concurrently, according to a novel study published by Yap et al in the European Journal of Cancer. The findings were also presented at the 34th European Organisation for Research and Treatment of Cancer (EORTC)–National Cancer Institute (NCI)–American Association for Cancer Research (AACR) Symposium on Molecular Targets and Cancer Therapeutics (Abstract 9).

In the phase Ib STAR clinical trial, researchers found that sequential dosing with the two drugs was a strategy that may be safe and well-tolerated, with promising signs of antitumor activity in patients with a range of different cancers.

“These are early clinical findings for 13 patients and will need to be investigated further in a larger population of patients,” said first study author Timothy A. Yap, MBBS, PhD, FRCP, Associate Professor in the Department of Investigational Cancer Therapeutics and the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, Medical Director of the Institute for Applied Cancer Science, and Associate Director of Translational Research at the Institute for Personalized Cancer Therapy.

Study Background

Genetic mutations that led to abnormal responses to DNA damage included BRCA1, BRCA2 (both associated with breast, ovarian, prostate, and pancreatic cancers), PALB2 (associated with breast, ovarian, and pancreatic cancers), ATM (associated with breast, ovarian, and prostate cancers), ARID1A (associated with breast, lung, endometrial, bladder, and bowel cancers), and CCNE1 (associated with breast, lung, bowel, endometrial, and glioblastoma cancers). These mutations were sensitive to anticancer drugs that stopped two enzymes—PARP and WEE1—from helping damaged cancer cells repair themselves. However, when the PARP inhibitor olaparib and WEE1 inhibitor adavosertib were given together to patients with these mutations, they caused serious side effects. Dr. Yap and his colleagues found evidence in cancer cells and mice that giving the two drugs one after the other did not cause these side effects.

“Based on these compelling preclinical data, we started the STAR study investigating sequential olaparib and adavosertib [in] patients with BRCA1, BRCA2, PALB2, ATM, ARID1A, and CCNE1 alterations,” said Dr. Yap. “We were also interested to assess if this combination was effective in patients who had cancers that were resistant to platinum chemotherapy and PARP inhibitors; these are urgent areas of clinical unmet need. Promisingly, we observed patient benefit, including durable responses as assessed by radiology, in these patients with highly resistant cancers. This suggests that this is a promising rational therapeutic combination for such patients.”

Research Methods and Results

A total of 13 patients, with a mean age of 50 years, enrolled in the study between April 2020 and November 2021. There were five cases of breast cancer, five of ovarian cancer, one of prostate cancer, one of gastric cancer, and one of bowel cancer. Ten of the patients had received three or more previous lines of chemotherapy, and cancer had continued growing in seven patients who had been treated previously with a PARP inhibitor.

Of the 13 patients, 3 received 300-mg doses of olaparib orally twice daily for the first 5 days, and again from days 15 to 19, alternating with 250-mg doses of adavosertib orally once daily from days 8 to 12 and days 22 to 26. This was dose level 1. The remaining 10 patients received 300-mg doses of olaparib orally twice daily from days 1 to 5 and days 15 to 19, and 300-mg doses of adavosertib orally once daily from days 8 to 12 and days 22 to 26. This was dose level 2. Both dose level 1 and dose level 2 were given every 28 days in the absence of disease progression or unacceptable side effects.

“Our clinical data showed for the first time that the sequential administration of the PARP inhibitor olaparib and the WEE1 inhibitor adavosertib was safe and well-tolerated, even with prolonged treatment of patients. Importantly, we also observed promising early clinical activity in patients with very advanced DNA damage response–aberrant cancers, including those who were platinum chemotherapy– and PARP inhibitor–resistant,” noted Dr. Yap.

Of 12 patients available for evaluation, 3 had a partial response—with tumors shrinking by at least 30% or CA125 levels falling by at least 50%. Of these, one patient with BRCA2-mutated estrogen receptor–positive breast cancer responded for 6 months, and one patient with PARP inhibitor–resistant BRCA2-mutated ovarian cancer for 10 months. Five other patients had stable disease for 4 or more months.

The most common side effects were mild nausea, anemia, fatigue, vomiting, and diarrhea. The dose had to be reduced in only two patients.

“This trial provides early clinical proof of concept for this novel sequential approach for the combination of PARP inhibitors with WEE1 inhibitors. It also provides the blueprint for other related DNA damage response drugs to be potentially combined safely with good tolerability and promising efficacy for patients with cancers where the mutations have been identified. These clinical findings validate our preclinical findings published in Cancer Cell, which we translated seamlessly into this clinical trial,” Dr. Yap concluded.

“This study shows the value of exploring different dosing schedules to see if they can improve the tolerability of drugs aimed at cancers driven by abnormal responses to DNA damage. It is encouraging to see signs of activity, particularly in patients who are resistant to PARP inhibition. As this is a small study, we look forward to results from the phase II trial with interest,” said Ruth Plummer, MD, PhD, Professor of Experimental Cancer Medicine at Newcastle University and Chair of the 34th EORTC–NCI–AACR Symposium on Molecular Targets and Cancer Therapeutics, who was not involved in the study.

The recommended dose for a phase II clinical trial was established as that used for dose level 2. The researchers plan to include patients with BRCA1/BRCA2 tumors, which are intrinsically resistant to PARP inhibition, and patients with DNA damage response–mutated tumors with acquired resistance to PARP inhibition in the trial.

Disclosure: For full disclosures of the study authors, visit ejcancer.com.