An update on the safety of olaparib for treating ovarian cancer

ABSTRACT

Introduction

PARP inhibitors have dramatically improved outcomes for ovarian cancer patients, transforming oncologists’ armamentarium and fueling hope for more cures and longer survival.

Areas covered

The recent PARP inhibitor randomized trials of FDA approved PARP inhibitors for ovarian cancer, olaparib, rucaparib and niraparib, and implications for clinical care are discussed with a focus on toxicity and risks. PARP adds NAD polymers to DNA-binding proteins, improving survival of cells after DNA damage, and acting as a scaffold for important DNA Damage Response (DDR) enzymes. If this system is inhibited, PARP activation cannot support DNA repair when there is synthetic lethality from BRCA mutations or homologous repair dysfunction (HRD), and the accumulation of DNA damage can kill cancer and lead to the catastrophic complications of MDS/AML. Although the risk of AML can be a < 1% risk, the incidence of MDS/AML presently approaches 10% in patients with BRCA mutations, multiple prior lines of platinum therapy, and protracted exposure to PARP inhibitors.

Expert opinion

PARP inhibitors are a well-tolerated and exciting new class of agents that improve survival despite the risk of AML. Understanding of the biology has led to optimal use and potential new strategies for overcoming PARP resistance.

KEYWORDS:

• Olaparib
• PARP inhibitor
• ovarian cancer
• BRCA 1/2
• homologous recombination deficiency
• acute myeloid leukemia

Declaration of interests

R Penson reports scientific advisory boards for AbbVie, AstraZeneca, Eisai, Genentech, Merck & Co., Roche Pharma, Sutro Biopharma, GSK Inc., and Vascular Biogenics Ltd; and research funding from Array BioPharma Inc., AstraZeneca, Eisai Inc., Genentech, Inc., Regeneron, Sanofi-Aventis US LLC, and Vascular Biogenics Ltd. 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

A peer reviewer on this manuscript reports speakers bureau and advisory role for AstraZeneca and GlaxoSmithKline/Tesaro. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Scientific accuracy review

AstraZeneca provided a scientific accuracy review at the request of the journal editor.

Additional information

Funding

This paper was not funded.