Since the discovery of PARP inhibitors (PARPi) in 2005, there has been rapid clinical development of five different agents (olaparib, rucaparib, niraparib, veliparib, talazoparib), leading to seven indications approved by the US Food and Drug Administration (FDA) across breast and ovarian cancer (Table 1). In 2014, olaparib became the first PARPi approved by the FDA for use as treatment of recurrent ovarian cancer, followed by rucaparib in 2016 and niraparib in 2019. Over this same time period, the FDA approved all three of these PARPi for a different indication – as maintenance therapy intended to prolong the disease-free interval following chemotherapy. Across different drugs and clinical settings, use of PARPi has resulted in a prolonged period without cancer recurrence – or disease-free interval – particularly among patients with BRCA1 and BRCA2 mutations, owing to their mechanism of action (Table 2).
PARPi are a class of oral targeted therapy whose effect is dependent upon a tumor’s inability to repair its DNA. The PARP1 and PARP2 proteins are instrumental in repairing DNA single-strand breaks, which prevents formation of double-strand breaks at the time of DNA replication. PARPi block this repair process and thus dramatically increase the number of double strand breaks. Cells can typically repair these resultant double strand breaks in an error-free fashion using the homologous recombination (HR) pathway, but when the pathway is defective, PARPi result in cell death. This homologous recombination deficiency (HRD) is frequently a result of a germline or somatic mutation in a gene involved in the HR pathway, notably BRCA1 and BRCA2, but can also be detected in tumors in the absence of such mutations. With germline and somatic testing, patients with genetic mutations or tumors with HRD can be identified as those who may derive significant clinical benefit from PARPi use.
With more than 20 trials of PARPi in ovarian cancer alone, there is a growing body of literature on the common side effects of these drugs and their management, as well as their unique financial challenges. Ongoing clinical questions being addressed include how best to predict patient response to PARPi therapy, combat drug resistance, and determine the optimal setting(s) for use in individual patients.
Adverse effects with PARPi use
Many of the adverse events (AEs) encountered with use of PARPi are shared across agents. Most patients experience some degree of nausea and fatigue. Serious hematologic side effects can occur with any PARPi, and myelosuppressive effects can be exacerbated when these drugs are combined with other therapies. Dose reductions are often necessary in the event of a serious side effect, and if they persist, the drug may need to be discontinued. Of note, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are serious but rare AEs occurring in up to 1% of patients and they have been associated with several different PARPi. Embryo-fetal toxicity has been documented in animal studies with exposure to PARPi. These drugs should not be used in pregnant patients, and pregnancy should be avoided for 6 months following last exposure.1-4
- Lynparza (olaparib) tablets [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals; December 2019.
- Talzenna (talazoparib) [prescribing information]. New York, NY: Pfizer Labs; September 2019.
- Zejula (niraparib) [prescribing information]. Waltham, MA: Tesaro; October 2019.
- Rubraca (rucaparib) [prescribing information]. Boulder, CO: Clovis Oncology; April 2018.
- Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382-1392. doi:10.1056/NEJMoa1105535
- Moore KN, Secord AA, Geller MA, et al. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019 May;20(5):636-648.
- Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. N Engl J Med. 2019;381(25):2416-2428.
- Kristeleit R, Shapiro GI, Burris HA, et al. A Phase I–II study of the oral PARP inhibitor rucaparib in patients with germline BRCA1/2-mutated ovarian carcinoma or other solid tumors. Clin Cancer Res. 2017 Aug;23(15):4095-4106.
- Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (London, England). 2017;390(10106):1949-1961.
- Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med. 2016;375(22):2154-2164.
- Coleman RL, Sill MW, Bell-McGuinn K, et al. A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation - An NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol. 2015;137(3):386-391.
- de Bono J, Ramanathan RK, Mina L, et al. Phase I, dose-escalation, two-part trial of the PARP inhibitor talazoparib in patients with advanced germline BRCA1/2mutations and selected sporadic cancers. Cancer Discov. 2017;7(6):620.
- Moore KN, Monk BJ. Patient counseling and management of symptoms during olaparib therapy for recurrent ovarian cancer. Oncologist. 2016;21(8):954-963.
- NCCN Clinical Practice Guidelines in Oncology. https://www.nccn.org/professionals/physician_gls/default.aspx#supportive.
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- Doshi JA, Li P, Huo H, Pettit AR, Armstrong KA. Association of patient out-of-pocket costs with prescription abandonment and delay in fills of novel oral anticancer agents. J Clin Oncol. 2017;36(5):476-482.
- Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917-921.
- Watkins JA, Irshad S, Grigoriadis A, Tutt ANJ. Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers. Breast Cancer Res. 2014;16(3):211.
- Bell D, Berchuck A, Birrer M, et al. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609-615.
- Fong PC, Yap TA, Boss DS, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA Carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol. 2010;28(15):2512-2519.
- Lin KK, Harrell MI, Oza AM, et al. BRCA reversion mutations in circulating tumor DNA predict primary and acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma. Cancer Discov. 2019;9(2):210.
- Lord CJ, Ashworth A. Mechanisms of resistance to therapies targeting BRCA-mutant cancers. Nat Med. 2013;19(11):1381-1388.
- Murai J, Feng Y, Yu GK, et al. Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition. Oncotarget. 2016;7(47):76534-76550.
- Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(9):1274-1284.