A Biomarker-enriched, Randomized Phase II Trial of Adavosertib (AZD1775) Plus Paclitaxel and Carboplatin for Women with Platinum-sensitive TP53-mutant Ovarian Cancer. Clin Cancer Res 2020 Sep 15;26(18):4767-4776
Date
07/03/2020Pubmed ID
32611648DOI
10.1158/1078-0432.CCR-20-0219Scopus ID
2-s2.0-85092098455 (requires institutional sign-in at Scopus site) 65 CitationsAbstract
PURPOSE: Preclinical studies show that adavosertib, a WEE1 kinase inhibitor, sensitizes TP53-mutant cells to chemotherapy. We hypothesized that adavosertib, plus chemotherapy, would enhance efficacy versus placebo in TP53-mutated ovarian cancer.
PATIENTS AND METHODS: Following safety run-in, this double-blind phase II trial (NCT01357161) randomized women with TP53-mutated, platinum-sensitive ovarian cancer to oral adavosertib (225 mg twice daily for 2.5 days/21-day cycle) or placebo, plus carboplatin (AUC5) and paclitaxel (175 mg/m2), until disease progression or for six cycles. The primary endpoints were progression-free survival (PFS) by enhanced RECIST v1.1 [ePFS (volumetric)] and safety. Secondary/exploratory objectives included PFS by RECIST v1.1 (single dimension), objective response rate, overall survival, and analysis of tumor gene profile versus sensitivity to adavosertib.
RESULTS: A total of 121 patients were randomized to adavosertib (A+C; n = 59) and placebo (P+C; n = 62) plus chemotherapy. Adding adavosertib to chemotherapy improved ePFS [median, 7.9 (95% confidence interval (CI), 6.9-9.9) vs. 7.3 months (5.6-8.2); HR 0.63 (95% CI, 0.38-1.06); two-sided P = 0.080], meeting the predefined significance threshold (P < 0.2). Clinical benefit was observed following A+C for patients with different TP53 mutation subtypes, identifying possible response biomarkers. An increase in adverse events was seen with A+C versus P+C: greatest for diarrhea (adavosertib 75%; placebo 37%), vomiting (63%; 27%), anemia (53%; 32%), and all grade ≥3 adverse events (78%; 65%).
CONCLUSIONS: Establishing an optimal strategy for managing tolerability and identifying specific patient populations most likely to benefit from treatment may increase clinical benefit. Future studies should consider additional adavosertib doses within the chemotherapy treatment cycle and the potential for maintenance therapy.
Author List
Oza AM, Estevez-Diz M, Grischke EM, Hall M, Marmé F, Provencher D, Uyar D, Weberpals JI, Wenham RM, Laing N, Tracy M, Freshwater T, Lee MA, Liu J, Qiu J, Rose S, Rubin EH, Moore KAuthor
Denise S. Uyar MD Professor in the Obstetrics and Gynecology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols
Biomarkers, Tumor
Carboplatin
Double-Blind Method
Female
Humans
Middle Aged
Mutation
Ovarian Neoplasms
Paclitaxel
Pyrazoles
Pyrimidinones
Response Evaluation Criteria in Solid Tumors
Tumor Suppressor Protein p53