ASCO: Zentalis showcases ovarian cancer data that will take WEE1 to phase 3

A year after getting Pfizer’s backing, Zentalis Pharmaceuticals says new data for a WEE1 candidate justifies putting the asset into a phase 3 study for ovarian cancer next year.

The phase 1b trial enrolled 115 patients with platinum-resistant ovarian cancer, of which 94 were evaluable by the April 10 cutoff. The findings—published in an abstract ahead of this year’s American Society of Clinical Oncology annual meeting—showed that the synthetic lethal WEE1 inhibitor azenosertib plus the chemotherapy paclitaxel produced an overall response rate (ORR) of 50%.

When given in a regimen with other chemotherapies like gemcitabine or carboplatin, the WEE1 candidate demonstrated an ORR of 38.5% and 35.7%, respectively. A regimen with pegylated liposomal doxorubicin posted the lowest ORR at 19.4%.

As for median progression-free survival (mPFS), azenosertib plus carboplatin came out on top at 10.4 months, followed by azenosertib plus gemcitabine at 8.3 months. The regimens that included paclitaxel and pegylated liposomal doxorubicin only saw mPFS of 7.4 months and 6.3 months, respectively.

Zentalis was also able to test for expression of the Cyclin E1 protein in 82 of the patients and the biotech noted that Cyclin E1+ status was associated with a superior ORR and a longer mPFS. This finding “showcase[es] the potential synergy of WEE1 inhibition with chemotherapy in this patient population,” the biotech concluded.

The most common treatment-related adverse events of grade 3 or above across all cohorts were thrombocytopenia (27.5%), neutropenia (25.5%), anemia (15.7%) and fatigue (9.8%).

The data are enough for Zentalis to begin preparations for a phase 3 study comparing azenosertib dosed intermittently in combination with either carboplatin or paclitaxel in patients with Cyclin E1+status and with platinum-sensitive ovarian cancer. The biotech expects to launch the late-stage trial in the first quarter of 2024.

“Azenosertib is emerging as a very promising clinical candidate, with demonstrated anti-tumor activity in difficult-to-treat tumor types when used in combination with standard chemotherapy regimens,” Zentalis CEO Kimberly Blackwell, M.D., said in the release. “The addition of azenosertib increased ORRs and mPFS over those observed historically with chemotherapy alone, or compared to adavosertib in combination with chemotherapy.”

Despite Pfizer throwing its weight behind Zentalis with a $25 million investment in April 2022, the biotech was able to retain full economic ownership of azenosertib, then known as ZN-c3. At the time, Zentalis said it planned to use the Big Pharma’s cash to support clinical trials of azenosertib and ZN-d5, an oral inhibitor of BCL-2 in development in blood cancers including acute myeloid leukemia and non-Hodgkin lymphoma.

WEE1 enzymes play a role in the DNA damage response, or DDR, pathway. The idea behind WEE1 inhibitors is that they could boost the efficacy of DNA-damaging therapies by forcing tumors to replicate damaged DNA before it is fixed.