DUETTE: a phase II randomized, multicenter study to investigate the efficacy and tolerability of a second maintenance treatment in patients with platinum-sensitive relapsed epithelial ovarian cancer, who have previously received poly(ADP-ribose) polymerase (PARP) inhibitor maintenance treatment

Abstract

Background: With the success of poly(ADP-ribose) polymerase (PARP) inhibitor therapy in the first-line and second-line treatment settings, a new patient population is emerging with platinum-sensitive relapsed ovarian cancer, who have previously received a PARP inhibitor in the maintenance setting and for whom no second maintenance standard of care exists. DUETTE (NCT04239014) will evaluate the combination of ceralasertib (a potent, selective inhibitor of the serine/threonine kinase ataxia telangiectasia and Rad3-related protein (ATR) + olaparib, or olaparib monotherapy, compared with placebo, in this patient population of unmet need.

Primary objective: The primary objective is to assess the efficacy of ceralasertib + olaparib combination, and olaparib monotherapy, compared with placebo, as second maintenance therapy in platinum-sensitive relapsed ovarian cancer.

Study hypothesis: This study will test the hypothesis that ceralasertib + olaparib, or olaparib monotherapy, is tolerable, and effective at prolonging progression-free survival compared with placebo.

Trial design: This is a phase II, multicenter study where patients will be randomized in a 1:1:1 ratio to receive either (Arm 1) ceralasertib + olaparib, (Arm 2) olaparib monotherapy, or (Arm 3) placebo. The olaparib and placebo arms will be double-blinded, whereas the ceralasertib + olaparib arm will be open label. Patients will be stratified according to BRCA status, and response to platinum-based chemotherapy.

Major inclusion/exclusion criteria: Eligible patients will have histologically diagnosed high-grade epithelial ovarian cancer, with platinum-sensitive relapse on, or after, completion of at least 6 months of any prior PARP inhibitor maintenance therapy (a minimum of 12 months is required if the patient received PARP inhibitor maintenance following first-line chemotherapy). If the prior PARP inhibitor used was olaparib then patients must have received treatment without significant toxicity or the need for a permanent dose reduction. Disease relapse in the second-line or third-line setting is allowed. Patients who have received secondary debulking surgery are potentially eligible if they meet all other inclusion criteria.

Primary endpoints: The primary endpoint is progression-free survival determined by blinded independent central review according to RECIST 1.1, with sensitivity analysis of progression-free survival using investigator assessments according to RECIST 1.1.

Sample size: 192 patients.

Estimated dates for completing accrual and presenting results: December 2022.

Trial registration: NCT04239014.

Keywords: medical oncology; ovarian cancer.

Figure 1

DUETTE study design overview. 1⁰, primary; 2⁰, secondary; 2L, second line; 3L, third line; BID, twice daily; tBRCAm, tumor breast cancer susceptibility gene-mutant; tBRCAwt, tumor breast cancer susceptibility gene-wildtype; chemo, chemotherapy; CR, complete response; CT, chemotherapy; DCR, Disease Control Rate; DoR, duration of response; HRQoL, health-related quality of life; OC, ovarian cancer; ORR, objective response rate; OS, overall survival; PARP, polyadenosine 5’diphosphoribose (poly(ADP ribose)) polymerase; PD, progressive disease; PFS, progression-free survival; PK, pharmacokinetic(s); po, oral; PR, partial response; PSR, platinum-sensitive relapsed; q28, every 28 days; QD, once daily; R, randomization; SD, stable disease.