Olaparib in combination with pegylated liposomal doxorubicin for platinum-resistant ovarian cancer regardless of BRCA status: a GEICO phase II trial (ROLANDO study)

Abstract

Background: There is limited evidence for the benefit of olaparib in platinum-resistant ovarian cancer (PROC) patients with BRCA wild-type tumors. This study investigated whether this combination of a DNA-damaging chemotherapy plus olaparib is effective in PROC regardless BRCA status.

Patients and methods: Patients with high-grade serous or endometrioid ovarian carcinoma and one previous PROC recurrence were enrolled regardless of BRCA status. Patients with ≤4 previous lines (up to 5 in BRCA-mut) with at least one previous platinum-sensitive relapse were included; primary PROC was allowed only in case of BRCA-mut. Patients initially received six cycles of olaparib 300 mg b.i.d. (biduum) + intravenous pegylated liposomal doxorubicin (PLD) 40 mg/m2 (PLD40) every 28 days, followed by maintenance with olaparib 300 mg b.i.d. until progression or toxicity. The PLD dose was reduced to 30 mg/m2 (PLD30) due to toxicity. The primary endpoint was progression-free survival (PFS) at 6 months (6m-PFS) by RECIST version 1.1. A proportion of 40% 6m-PFS or more was considered of clinical interest.

Results: From 2017 to 2020, 31 PROC patients were included. BRCA mutations were present in 16%. The median of previous lines was 2 (range 1-5). The overall disease control rate was 77% (partial response rate of 29% and stable disease rate of 48%). After a median follow-up of 10 months, the 6m-PFS and median PFS were 47% and 5.8 months, respectively. Grade ≥3 treatment-related adverse events occurred in 74% of patients, with neutropenia/anemia being the most frequent. With PLD30 serious AEs were less frequent than with PLD40 (21% versus 47%, respectively); moreover, PLD30 was associated with less PLD delays (32% versus 38%) and reductions (16% versus 22%).

Conclusions: The PLD-olaparib combination has shown significant activity in PROC regardless of BRCA status. PLD at 30 mg/m2 is better tolerated in the combination.

Trial registration: ClinicalTrials.gov NCT03161132.

Keywords: BRCA wild-type; PARP inhibitor; olaparib; pegylated liposomal doxorubicin; platinum-resistant recurrent ovarian cancer.

Conflict of interest statement

Disclosure JAP-F has participated in the advisory boards for AstraZeneca, GSK, Clovis, and Ability Pharma and has participated as a speaker and received travel and accommodation grants from AstraZeneca and GSK. MI has participated in advisory and consultancy boards for Roche, GSK, Tesaro (A GSK Company), and PharmaMar; participated in the speakers bureau for AstraZeneca, Roche, GSK, Tesaro (A GSK Company), Eisai, Clovis, and PharmaMar; and received travel/accommodation expenses from Novartis, AstraZeneca, MSD, Tesaro (A GSK Company), PharmaMar, Roche, GSK, Pfizer, and Eisai. AC reports consulting or advisory role for Lilly, Clovis; is on the speaker bureau for GSK, Roche Genentech, AstraZeneca, Eisai, MSD, Pfizer; and has received research funding from Pfizer; travel, accommodation, and other expenses were covered by Pfizer and Roche Genentech. EG has received advisory/consultancy honorarium from AstraZeneca-MSD, Clovis Oncology, GSK- Tesaro (A GSK Company), PharmaMar, and Roche; has received speaker bureau/expert testimony honorarium from AstraZeneca, PharmaMar, Roche, and GSK; and has received travel/accommodation/expenses from Roche, Tesaro (A GSK Company), and Baxter. AR reports receiving honoraria from and plays advisory/consultancy roles for MSD, AstraZeneca, Roche, GSK, Clovis, PharmaMar, Lilly, and Amgen; research grant/funding to his institution from Eisai, PharmaMar, and Roche; travel/accommodation/expenses from AstraZeneca, Tesaro (A GSK Company), PharmaMar, and Roche; and serves on the speakers bureau of MSD, AstraZeneca, Roche, GSK, Clovis, and PharmaMar, outside the submitted work. All other authors have declared no conflicts of interest.

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

CONSORT patient flowchart. ITT, intention to treat; PLD, pegylated liposomal doxorubicin; PP, per protocol

Figure 2

Progression free and overall survival. (A) Progression-free survival (PFS) in the intention-to-treat (ITT) analysis set. (B) PFS in the ITT analysis set that was clustered according to the pegylated liposomal doxorubicin (PLD) dose administration: 30 mg/m2 (PLD30) and 40 mg/m2 (PLD40). (C) Overall survival (OS) in the ITT analysis set. (D) PFS in the pegylated liposomal doxorubicin (PLD) + olaparib (per-protocol [PP]) analysis set. (E) OS in the PP analysis set. CI, confidence interval; HR, hazards ratio.

Figure 3

Safety analysis in the intention-to-treat (ITT) set. (A) Bar plot representation of adverse event frequencies clustered by type and pegylated liposomal doxorubicin 30 mg/m2 (PLD30) and 40 mg/m2 (PLD40). (B) Bar plot representation of treatment-related adverse event (TRAE) frequencies clustered by type and PLD30 and PLD40.