Olaparib and adavosertib work best when used sequentially to treat DNA damage response mutations in advanced tumors

Patients with cancers caused by certain mutations that occur in response to DNA damage can be safely treated with two drugs, olaparib and adavosertib, when given sequentially rather than at the same time.

Presenting the results of the Phase Ib STAR clinical trial at the 34th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapy in Barcelona, ​​Spain, Timothy A. Yap, Associate Professor of Research Cancer Therapy at The University of Texas MD Anderson Cancer Center, Texas, USA, explains that the sequential use of two drugs was a strategy that was safe and well tolerated, with promising signs of antitumor activity in patients with different types of cancer.

“These are early clinical findings for 13 patients and will need to be further investigated in more patients,” he said.

Genetic mutations that result in an abnormal DNA damage response (“DNA damage response” or “DDR”) include BRCA1, BRCA2 (both involved in breast, ovary, prostate, and pancreatic cancer), PALB2 (breast, ovarian and pancreatic cancer), ATM (breast, ovarian and prostate cancer), ARID1A (breast, lung, endometrial, bladder and bowel cancer) and CCNE1 (breast, lung, bowel, endometrial and glioblastoma cancer). These mutations are sensitive to anticancer drugs that prevent two enzymes called PARP and WEE1 from helping damaged cancer cells repair themselves. However, when the PARP inhibitor, olaparib, and the 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 administering two drugs back-to-back did not cause these problems.

“Based on these compelling preclinical data, we initiated the STAR trial, which is investigating the sequential use of olaparib and adavosertib in patients with BRCA1, BRCA2, PALB2, ATM, ARID1A, and CCNE1 mutations,” said Dr. Yap. “We were also interested in evaluating whether this combination was effective in patients with cancer resistant to platinum and PARP inhibitor chemotherapy; these are immediate areas of clinical unmet need. What is promising is that we have seen patient benefits, including long-lasting radiographic responses, in these patients with highly resistant cancers. This suggests that this is a promising rational therapeutic combination for such patients.”

Two men and eleven women, with an average age of 50, took part in the study between April 2020 and November 2021. Five had breast cancer, five ovarian cancer, one patient had prostate cancer, one had gastric cancer, and one had intestinal cancer. Ten patients had received three or more prior lines of chemotherapy, and cancer continued to grow in seven patients previously treated with PARP inhibitors.

Three of 13 patients received olaparib 300 mg orally twice daily for the first five days and again from days 15 to 19, alternating with adavosertib 250 mg orally once daily from days 8 to 12 and from days 22 to 26. This was a dose level (DL) of 1. The remaining ten patients received 300 mg of olaparib twice daily from days one to five and from days 15 to 19 and 300 mg of adavasertib orally once daily from days 8 to 12 and from days 22 to 26. This was DL 2. Both DL 1 and 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 sequential administration of a PARP inhibitor olaparib and the WEE1 inhibitor adavosertib was safe and well tolerated even when patients were treated long-term. Importantly, we also saw promising early clinical activity in patients with DNA damage response-refractory cancers, including those resistant to platinum chemotherapy and PARP inhibitors,” said Dr. Yap.

Three of the 12 patients available for evaluation had a partial response, in which their tumors shrank by 30% or more, or the level of a cancer biomarker called CA125 in their blood samples dropped by at least 50%. Of these, partial responses were observed in a patient with BRCA2 estrogen receptor-positive breast cancer for six months and in a patient with PARP inhibitor-resistant ovarian cancer with BRCA2 mutations for ten months. Five other patients had stable disease, in which their cancer did not grow or shrink for four or more months.

The most common side effects were mild nausea, anemia, fatigue, vomiting, and diarrhea. Only two patients had to reduce the dose.

“This trial provides early clinical proof of concept for this new sequential approach to the combination of PARP inhibitors with WEE1 inhibitors. It also provides a blueprint for other relevant DNA damage response drugs that can be potentially safely combined with good tolerability and promising efficacy for cancer patients where the mutations have been identified. These clinical results support our preclinical results published in Cancer cellwhich we seamlessly translated into this clinical trial,” said Dr. Yap.

The recommended dose for the phase II clinical trial was established as the dose used for DL2. The researchers plan to enroll in the study patients with BRCA1/2 tumors that are inherently resistant to PARP inhibition and patients with DDR-mutated tumors with acquired resistance to PARP inhibition.

Professor Ruth Plummer of the University of Newcastle, UK, is Chair of the 34th EORTC-NCI-AACR Symposium and was not involved in the study. She said: “This study shows the value of exploring different dosing schedules to see if they can improve the tolerability of drugs targeting cancers driven by an abnormal DNA damage response. It is encouraging to see signs of activity, particularly in patients resistant to PARP inhibition. As this is a small study, we look forward to the results of the phase II trial.”

Courtesy of the European Organization for Research and Treatment of Cancer