A Biomarker-enriched, Randomized Phase II Trial of Adavosertib (AZD1775) Plus Paclitaxel and Carboplatin for Women with Platinum-sensitive TP53-mutant Ovarian Cancer

Abstract

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/m 2 ), 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 þ C; n ¼ 59) and placebo (P þ C; n ¼ 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 ¼ 0.080], meeting the predefined significance threshold (P < 0.2). Clinical benefit was observed following A þ C for patients with different TP53 mutation subtypes, identifying possible response biomarkers. An increase in adverse events was seen with A þ C versus P þ 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.

WEE1 Inhibition in Combination With Targeted Agents and Standard Chemotherapy in Preclinical Models of Pancreatic Ductal Adenocarcinoma

“…AZD1775 has also been shown to be tolerable when combined with irinotecan in pediatric solid refractory tumors ( 31 ). In a recent phase II study, the addition of AZD1775 to carboplatin enhanced median progression free survival in patients with p53 mutant ovarian cancer ( 34 ). Consistently, biopsy and blood samples collected in these studies have reported decreased phospho-CDC2 activity and increased γH2AX activity after AZD1775 combination therapy.…”

Advances in ovarian cancer, from biology to treatment

“…Cell-cycle modulation has been pursued for OC treatment, as cell-cycle control mechanisms represent a critical component clinical outlook of the DNA-damage response, able to effectively detect DNA damage and halt cellular replication in order to initiate repair. Adavosertib (AZD1775), which inhibits the nuclear kinase WEE1, has emerged as a promising compound that is able to regulate G 2 -M transition and sensitize tumor suppressor p53-mutant cells to chemotherapy 7 . This year, the results of a double-blind phase 2 trial (NCT01357161) were reported in which 141 women with recurrent platinum-sensitive OC in which TP53 is mutated were randomized to receive oral adavosertib or placebo, in addition to chemotherapy 7 .…”

“…Adavosertib (AZD1775), which inhibits the nuclear kinase WEE1, has emerged as a promising compound that is able to regulate G 2 -M transition and sensitize tumor suppressor p53-mutant cells to chemotherapy 7 . This year, the results of a double-blind phase 2 trial (NCT01357161) were reported in which 141 women with recurrent platinum-sensitive OC in which TP53 is mutated were randomized to receive oral adavosertib or placebo, in addition to chemotherapy 7 . The addition of adavosertib improved progression-free survival (PFS) according to the enhanced RECIST 1.1 guidelines (ePFS; hazard ratio (HR), 0.63; 95% confidence interval (CI) 0.38-1.06; two-sided P = 0.080), meeting the predefined significance threshold (P < 0.2) 7 .…”

“…The addition of adavosertib improved progression-free survival (PFS) according to the enhanced RECIST 1.1 guidelines (ePFS; hazard ratio (HR), 0.63; 95% confidence interval (CI) 0.38-1.06; two-sided P = 0.080), meeting the predefined significance threshold (P < 0.2) 7 . Clinical benefit was broadly observed for patients with a variety of different subtypes of TP53 mutation, which identified potential response biomarkers 7 . The clinical potential of adavosertib gained momentum following early results of two other studies.…”

Pharmacological Inhibition of WEE1 Potentiates the Antitumoral Effect of the dl922-947 Oncolytic Virus in Malignant Mesothelioma Cell Lines

“…Among the drugs targeting the DDR pathway, AZD1775 (MK-1775, adavosertib), an inhibitor of the tyrosine kinase WEE1, has shown efficacy in sensitizing many cancer types to DNA damaging agents in both preclinical studies and phase I/II clinical trials [29][30][31][32][33][34]. WEE1 is a crucial activator of the G2/M checkpoint, which stalls the cell cycle in response to DNA damage, by phosphorylating and inhibiting cyclin-dependent kinase 1/2 (CDK1/CDK2).…”