Results of the phase 2 EFFORT study support the efficacy of adavosertib, with and without olaparib, in patients with poly (ADP-ribose) polymerase inhibitor–resistant ovarian cancer, with manageable adverse events.
The randomized 2-arm noncomparative phase 2 EFFORT study (NCT03579316) evaluated the efficacy of the WEE1 inhibitor adavosertib with or without the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in patients with recurrent PARP inhibitor–resistant ovarian cancer. The results of the study were presented at the 2021 American Society of Clinical Oncology Annual Meeting.
Women with recurrent ovarian, fallopian tube, or primary peritoneal cancer with documented progressive disease on a PARP inhibitor, measurable disease, and adequate end-organ function were enrolled. Eligible patients were randomized to receive adavosertib 300 mg (orally on days 1-5 and 8-12 of a 21-day cycle), or adavosertib (150 mg orally twice a day on days 1-3 and 8-10) plus olaparib (200 mg orally twice a day on days 1-21 of a 21-day cycle). The primary end point was objective response rate (ORR) per RECIST version 1.1; secondary end points included safety, tolerability, duration of response, clinical benefit rate (CBR), progression-free survival (PFS), and efficacy based on BRCA status.
A total of 80 patients were enrolled and treated in the study; of these, 39 received adavosertib and 41 received adavosertib/olaparib. The median age of the study population was 60 years; the majority of patients had platinum-resistant disease (64%) and high-grade serous histology (93%). Patients received a median of 4 previous therapies; the majority received previous olaparib treatment and had achieved clinical benefit from previous PARP inhibitor therapy (86%). Nearly half of all patients had BRCA mutation–positive disease (48%).
Of the 70 patients evaluable for efficacy, 35 patients were randomized to each arm. ORRs were comparable in both the adavosertib-alone and adavosertib/olaparib combination treatment groups (23% vs 29%, respectively); duration of response was 5.5 months and 6.4 months, respectively. The CBR was 63% in the adavosertib-alone arm, and 89% in the adavosertib/olaparib combination arm. Median PFS was 5.5 months in the adavosertib-alone arm, and 6.8 months in the adavosertib/olaparib combination arm. Although responses were achieved in both treatment groups irrespective of BRCA mutation status, responses were lower in the BRCA mutation cohorts.
Grade 3/4 toxicities were higher in the combination arm compared with the adavosertib-alone arm (76% vs 51%); however, most were manageable with dose modifications. Adavosertib-related grade 3/4 toxicities included neutropenia, thrombocytopenia, and diarrhea; 72% required at least 1 dose interruption, and 51% required dose reduction. Grade 3/4 toxicities in the combination arm included thrombocytopenia, neutropenia, diarrhea, fatigue, and anemia; 88% of patients required at least 1 dose interruption, 71% required dose reduction, and 10% discontinued treatment as a result of toxicity.
These data suggest that adavosertib with or without olaparib demonstrates efficacy in patients with PARP inhibitor–resistant ovarian cancer. Adverse events were manageable with supportive care, dose interruptions, and dose reductions.
Source: Westin SN, Coleman RL, Fellman BM, et al. EFFORT: EFFicacy of adavosertib in PARP ResisTance: a randomized two-arm non-comparative phase II study of adavosertib with or without olaparib in women with PARP-resistant ovarian cancer. J Clin Oncol. 2021;39(suppl_15). Abstract 5505.
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