Rucaparib in the landscape of PARP inhibition in ovarian cancer

ABSTRACT

Introduction: The landscape of poly (ADP-ribose) polymerase (PARP) inhibition in ovarian cancer is rapidly evolving and becoming increasingly complex. Ovarian cancer is leading therapeutic innovation by providing the proof of concept for DNA repair as a target. Three different PARP inhibitors have now received approvals in the US and Europe in different indications. Subtle but crucial differences can be found among the licensed indications for each PARP inhibitor in terms of histology, type of BRCA mutation (germline and/or somatic), number of prior lines of chemotherapy and whether the indication is in the treatment or maintenance settings.

Areas covered: We review the latest clinical data regarding the PARP inhibitor rucaparib in ovarian cancer, provide an update on the evolving landscape of PARP inhibition in ovarian cancer, and summarize avenues of ongoing and future research.

Expert opinion: All eligible patients should be offered a PARP inhibitor. SOLO1 trial results demonstrated an unprecedented benefit maintenance with PARP inhibitors in first line. Results from trials evaluating PARP inhibitors as maintenance in first line regardless of BRCA status and from trials evaluating combinatorial strategies are eagerly awaited.

KEYWORDS:

• Rucaparib
• PARP inhibitor
• ovarian cancer
• synthetic lethality

Article highlights

• Approximately half of patients with high-grade serous ovarian cancer (HGSOC) present a homologous recombination deficiency (HRD)-mediated DNA repair, in half of these cases HRD is attributable to germline or somatic mutations in breast cancer type 1 and type 2 (BRCA1 or BRCA2).

• In the maintenance setting, there is an increasing body of evidence to support that demonstrated sustained platinum responsiveness may be a robust surrogate marker for HRD.

• In the treatment setting, a predictive biomarker, such as a deleterious BRCA mutation, may be required to select the patients most likely to respond to PARP inhibition.

• FDA approved single-agent rucaparib for the treatment of recurrent BRCA-mutated (germline or somatic) ovarian cancer patients previously treated with at least two prior chemotherapy regimens, regardless of platinum interval.

• EMA approved rucaparib for the treatment of relapsed HGOC-associated germline or somatic BRCA mutations, but restricted the indication to platinum-sensitive relapse and to patients not eligible to chemotherapy.

• Olaparib, niraparib, and rucaparib are currently approved in the US as maintenance therapy for women with recurrent epithelial ovarian cancer in CR/PR to platinum-based chemotherapy, while only olaparib and niraparib are currently licensed in this indication in Europe.

Declaration of interest

E Colomba reports acting in a consultant or advisory role for Ipsen, Bristol-Myers Squibb, and Pfizer. A Leary reports acting in a consultant or advisory role for AstraZeneca, Clovis Oncology, Gritstone Oncology, GamaMabs Pharma, Tesaro and Pfizer. They also report their institution receiving research funding GamaMabs Pharma, Merck, Bristol-Myers-Squibb, Merus, Clovis Oncology, Genentech, and Pierre Fabre. They have also received fees for travel, accommodation and expenses from Roche, Pharmamar, Tesaro and AstraZeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.