Patient Counseling and Management of Symptoms During Olaparib Therapy for Recurrent Ovarian Cancer

Abstract

: Our primary objective is to review the safety and tolerability profile of olaparib, a novel anticancer therapy, and to discuss key considerations for symptom management in patients with advanced ovarian cancer. Olaparib is the first of a new class of anticancer therapies, poly (ADP-ribose) polymerase (PARP) inhibitors that target tumors that have deficits in homologous recombination repair (such as BRCA mutations) by a process known as synthetic lethality. Through this process, neither the deficiency in homologous recombination repair nor PARP inhibition alone is cytotoxic, but the combination of these two conditions leads to cell death. In December 2014, olaparib received accelerated approval by the U.S. Food and Drug Administration (FDA) as monotherapy for patients with known or suspected deleterious germline BRCA-mutated (as detected by an FDA-approved test) advanced ovarian cancer who had been treated with at least three lines of chemotherapy. Most adverse events (AEs) reported during olaparib clinical trials conducted in patients with recurrent ovarian cancer and measurable disease were of grade 2 or less severity according to the National Cancer Institute's Common Terminology Criteria for Adverse Events. Fatigue and gastrointestinal AEs are among the most common in ovarian cancer clinical trials and can be particularly bothersome to patients. We focus on interventions to address these AEs in patients who are candidates for treatment with olaparib and allow them to remain on therapy for as long as clinically indicated.

Implications for practice: Olaparib therapy represents a new approach to treating recurrent ovarian cancer. Some associated adverse events can have a substantial effect on quality of life. It is therefore important for patients, caregivers, and health care providers to have realistic expectations and a thorough understanding of the safety and tolerability profile of olaparib to prevent or alleviate key symptoms so that therapy can continue uninterrupted if possible. This report summarizes a practical approach to supportive care for patients receiving olaparib therapy.

Keywords: BRCA mutation; Homologous recombination pathway; Olaparib; Ovarian cancer; Poly(ADP-ribose) polymerase inhibitor (PARP); Toxicities.

Figure 1.

PARP inhibitors induce synthetic lethality in BRCA-deficient cells. (A): Functioning PARP enzyme. In the presence of a functioning PARP enzyme, single-strand DNA breaks are repaired. (B): PARP enzyme inhibited. When the PARP enzyme is inhibited, single-strand DNA breaks are converted into a double-strand DNA break through collapse of the replication fork. In BRCA-deficient tumor cells, homologous recombination repair of double-strand DNA breaks is impaired and cells are directed toward the error-prone repair process of nonhomologous end joining, which leads to genetic instability and cell death. (C): Deficiency in HR and BER together leads to synthetic lethality. Cells deficient in HR or BER maintain viability, whereas cells deficient in both through BRCA deficiency and PARP inhibition undergo synthetically lethal cell death [7]. Reprinted from with permission from Elsevier. Abbreviations: BER, base excision repair; HR, homologous recombination; PARP, poly (ADP-ribose) polymerase.