In a phase 2 study, adavosertib plus gemcitabine showed signs of activity in platinum-resistant or platinum-refractory advanced high-grade serous ovarian cancer, including rare histological subtypes of ovarian cancer.
A phase 2 study (NCT02151292) published in The Lancet revealed that adding the Wee1 inhibitor adavosertib to gemcitabine in platinum-resistant or platinum-refractory advanced high-grade serous ovarian cancer significantly extended progression-free survival (PFS) and overall survival (OS) versus matched placebo.
In addition, adavosertib plus gemcitabine also showed signs of activity in rare histological subtypes of ovarian cancer, including serous and endometrioid, low-grade endometrioid, carcinosarcoma, and clear cell.
“The results from our study provide valuable insight and further assessment in larger clinical trials is recommended,” wrote the study authors, who were led by Stephanie Lheureux, MD.
In this double-blind, randomized, placebo-controlled trial, women with measurable recurrent platinum-resistant or platinum-refractory high-grade serous ovarian cancer were recruited from 11 academic centers in the United States and Canada. Participants were randomized 2:1 to receive intravenous gemcitabine at a dose of 1000 mg/m2 on days 1, 8, and 15 with either adavosertib at a dose of 175 mg or placebo once daily on days 1, 2, 8, 9, 15, and 16 in 28-day cycles until disease progression or unacceptable toxicity. In addition, a nonrandomized exploratory cohort was comprised of women with ovarian cancer of non–high-grade serous histology.
The primary end point of the study was PFS. Importantly, the safety and efficacy analysis consisted of all patients who received at least 1 dose of treatment and all patients and care providers were masked to treatment assignment.
Between Sept 22, 2014, and May 30, 2018, 124 women were enrolled, 99 of whom had high-grade serous ovarian cancer, with 65 (66%) assigned to adavosertib plus gemcitabine and 34 (34%) to placebo plus gemcitabine. Moreover, a total of 25 women were enrolled in the exploratory cohort. However, 5 patients were found to be ineligible after randomization, including 4 in the experimental group and 1 in the control group.
Ultimately, PFS was found to be longer with adavosertib plus gemcitabine at a median of 4.6 months (95% CI, 3.6-6.4) compared with 3.0 months (95% CI, 1.8-3.8) with placebo plus gemcitabine (HR, 0.55; 95% CI, 0.35-0.90; P =.015).
Median OS at the time of data cutoff for the final analysis was also longer with adavosertib plus gemcitabine at 11.4 months (95% CI, 8.2-16.5) versus 7.2 months (95% CI, 5.2-13.2) in the placebo-plus-gemcitabine group (HR, 0.56; 95% CI, 0.35-0.91; P =.017). Per RECIST 1.1, 14 of 61 participants (23%) in the adavosertib-plus-gemcitabine group had a confirmed partial response (PR) compared with 2 of 33 (6%) in the placebo-plus-gemcitabine group (P =.038); there were no complete responses.
The median duration of response (DOR) in the 14 patients with a PR in the adavosertib-plus-gemcitabine arm was 3.7 months. Among the 2 patients with a PR receiving placebo plus gemcitabine, the DOR was 5.8 months in 1 patient and 12.9 months in the other.
Regarding safety, the most frequent grade 3 or higher adverse events were hematological and included neutropenia (38 of 61 participants [62%] with adavosertib vs 10 of 33 [30%] with placebo) and thrombocytopenia (19 [31%] vs 2 [6%], respectively). There were no treatment-related deaths; however, 1 patient in each group in the high-grade serous ovarian cancer cohort died while on study medication (sepsis in the experimental group and disease progression in the control group).
“Most adverse events were hematological and managed medically without substantial complication,” the authors noted.
Among those in the high-grade serous ovarian cancer cohort, in the adavosertib-plus-gemcitabine group, day 1 adavosertib administration was delayed in 13 of 61 patients (21%) after cycle 1 and 52 (85%) had at least 1 dose modification. Further, day 1 gemcitabine administration was delayed in 11 patients (18%) in the adavosertib group and in 7 of 33 (21%) in the placebo group; the dose was modified in 56 (92%) and 23 (70%) patients, respectively. All patients in the non–high-grade serous ovarian cancer exploratory cohort had adavosertib and gemcitabine dose modifications.
Dose reduction or delays were most often due to neutropenia and thrombocytopenia in both treatment groups of the randomized cohort and in the non–high-grade serous cohort.
Importantly, the combination schedule evaluated in the current study was based on the recommended regimen from a previous phase 1 study and followed appropriate dose modification guidelines; however, the relatively high proportion of patients who required dose reduction may indicate that the regimen should be optimized for further assessment. Though this approach is reasonable for future phase 3 trials, a lower gemcitabine dose could be considered according to the investigators. Alternatively, it was also suggested that another approach could be to assess the combination earlier in the treatment course and in a less heavily pretreated population in which hematological toxicity may be less problematic.
Lheureux S, Cristea MC, Bruce JP, et al. Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomized, placebo-controlled, phase 2 trial. Lancet. 2021;397:281-92. doi: 10.1016/S0140-6736(20)32554-X