Adavosertib, a WEE1 kinase inhibitor, plus carboplatin and paclitaxel improved progression-free survival (PFS) in women with TP53-mutated, platinum-sensitive ovarian cancer compared with chemotherapy alone, according to results from a phase 2 study.
Preclinical studies of adavosertib indicated that the drug increased sensitization of TP53-mutated cells to chemotherapy.
The study randomly assigned 121 women to the experimental arm with adavosertib plus chemotherapy, or the control arm of chemotherapy alone. The primary endpoint was PFS by enhanced RECIST v1.1 criteria (ePFS).
With a 59.5% data maturity, the median ePFS for adavosertib was 7.9 months compared with 7.3 months for chemotherapy alone (hazard ratio [HR], 0.63; 95% CI, 0.38-1.06; P =.080). This met the prespecified criterion for superiority of P <.2. When assessed with standard RECIST — instead of enhanced RECIST criteria — median PFS was 1.9 months longer with adavosertib.
“We acknowledge that the difference in median ePFS with A+C versus P+C was small, but the HR (0.63) and separation of the PFS Kaplan–Meier curves demonstrate potential efficacy of this combination,” the researchers wrote.
The overall response rate with adavosertib was 75% vs 69% with chemotherapy alone. Rate of complete response for adavosertib was 11.9% compared with 8.9% with chemotherapy alone. According to the researchers, clinical benefit was seen for patients assigned to adavosertib with different TP53 mutation subtypes, “identifying possible response biomarkers.”
Use of adavosertib was associated with an increase in certain adverse events including diarrhea, vomiting, anemia, and all grade 3 or worse adverse events.
The researchers noted that both study arms compared worse than historical controls. They posited that one explanation could be because patients had known or suspected loss-of-function TP53 mutation.
Oza AM, Estevez-Diz M, Grischke EM, et al. A biomarker-enriched, randomized phase II trial of adavosertib (AZD1775) plus paclitaxel and carboplatin for women with platinum-sensitive TP53-mutant ovarian cancer [published online July 1, 2020]. Clin Can Res. doi: 10.1158/1078-0432.CCR-20-0219