Wee1 Inhibitor Promising in p53-Mutated Ovarian Cancers

Wee1 Inhibitor Promising in p53-Mutated Ovarian Cancers

Treatment with the Wee1 inhibitor AZD1775 plus carboplatin showed encouraging antitumor activity in patients with p53-mutated ovarian cancer that is refractory or resistant to standard first-line therapy, according to the results of a phase II study presented Tuesday, June 2, during the Development Therapeutics—Clinical Pharmacology and Experimental Therapeutics Oral Abstract Session (Abstract 2507).

Study presenter Suzanne Leijen, MD, PhD, of the Netherlands Cancer Institute, Amsterdam, Netherlands, explained that most p53-deficient tumors lack a functional G1 checkpoint and instead rely on the G2 checkpoint for DNA repair. Therefore, abrogation of the G2 checkpoint by a Wee1 inhibitor might sensitize p53-deficient tumors to DNA-damaging anticancer agents.

“Patients with ovarian cancer that is resistant or refractory within 3 months to first-line therapy generally have a poor prognosis, and no satisfying therapies are available after first-line treatment fails,” Dr. Leijen told the ASCO Daily News. “Improvement of therapy is, therefore, very much needed.”

The study included 23 patients of which 22 patients had p53-mutated ovarian cancer. The one patient without a p53 mutation was excluded from the efficacy analysis but included in the safety analysis. All patients had disease that was refractory or resistant to standard first-line therapy of carboplatin plus paclitaxel, and patients were re-exposed to carboplatin plus five twice-daily doses of 225 mg of AZD1775 during a 21-day cycle. The primary objectives of the trial were to evaluate antitumor activity, safety, and tolerability of the drug.

The overall response rate was 41%, with a median time to progression of 4.5 months.

The most commonly occurring adverse events were fatigue (87%), nausea (78%), diarrhea (70%), vomiting (48%), and bone marrow toxicity, including thrombocytopenia (70%), neutropenia (48%), and anemia (61%).

“This study was a proof-of-principle study, to prove the concept of sensitizing p53-deficient tumors to DNA-damaging agents,” Dr. Leijen said. “It is expected that patients with solid tumors other than ovarian cancer, but that are also p53 deficient, will benefit from the addition of Wee1 inhibitor AZD1775 to their treatment regimen. Additional studies will be needed to prove this.”

In his discussion of the results, Ryan Bruce Corcoran, MD, PhD, of Massachusetts General Hospital, said that the study included a good population to assess this therapy and set a high bar for efficacy because there was a low likelihood that patients for whom platinum therapy had just failed would respond to carboplatin alone.

Dr. Corcoran compared this study with the AURELIA trial, which was the basis of U.S. Food and Drug Administration approval for bevacizumab in this disease. This trial evaluated chemotherapy plus bevacizumab in patients with platinum-resistant ovarian cancer who developed resistance even after 6 months and excluded patients with refractory  disease; the trial showed a 27% overall response rate to non-platinum chemotherapy plus bevacizumab.

“Although we certainly need to see what happens in more patients, a 41% response rate in this population is quite encouraging,” Dr. Corcoran said.

Moving forward, Dr. Corcoran said that a biomarker analysis will be key to predicting if there is a subset of patients who will respond to this treatment and added that because some p53 wild-type cancers are deficient in p53 function, this is a potentially effective strategy in these patients.

Watch the session: Visit the ASCO Virtual Meeting website.