Role of PARP Inhibitors in BRCA-Related Malignancies

Sana Iqbal, PharmD; Mohammad A. Rattu, PharmD, BCOP, BCPS, BCGP; Neal Shah, PharmD

US Pharmacist. 2018;43(9):HS10-HS17.

Abstract and Introduction

Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors target an important enzyme involved in DNA repair. The agents olaparib, rucaparib, and niraparib are currently indicated for ovarian, fallopian tube, and primary peritoneal cancers. Olaparib is also indicated for breast cancer. PARP inhibitors have demonstrated statistically significant improvements in progression-free survival. Most adverse effects have been related to the gastrointestinal tract and the blood. Major limitations to the long-term use of PARP inhibitors include the development of bone marrow disorders and drug resistance. There are several more PARP inhibitors and combination strategies under investigation for solid and hematologic malignancies.

Introduction

In recent years, target-specific chemotherapies and biotherapies have gained prominence in the field of oncology. One pertinent drug class is poly ADP ribose polymerase (PARP) inhibitors, which target a key enzyme involved in DNA repair. When a single-strand break (SSB) occurs in DNA, it is typically remedied through base excision repair via various PARP enzymes.^[1,2] PARP-1 is recruited/activated by SSBs, and it transfers ADP ribose moieties from cellular nicotinamide-adenine-dinucleotide (NAD⁺) to acceptor proteins, a process known as PAR-ylation.^[1,3] This eventually restores genomic integrity and normal cell function.^[1] In the absence of PARP enzymes, alternate DNA repair mechanisms still exist.^[1,2] An SSB can progress to a double-strand break (DSB), which can then be repaired via a precise process called homologous recombination.^[1–3] Wild-type BRCA1 and BRCA2 are part of the complex that permits homologous recombination.^[1,2] On the other hand, if DSBs cannot be repaired via homologous recombination (e.g., due to BRCA deficiencies mutations), there will be irreversible DNA damage and subsequent cell death.^[1,2] PARP inhibitors promote the progression of SSBs to DSBs, and can induce synthetic lethality in cells with impaired homologous recombination mechanisms.^[1–3] An overactivation of PARP-1 can also deplete NAD⁺ and lead to apoptosis (Figure 1).^[1,3]

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Figure 1.

Schematic mechanism of PARP inhibitors
SSBs in DNA recruit PARP. With a PARP inhibitor, more DSBs occur. In normal cells, SSBs and DSBs can be repaired. In BRCA-mutated cells, DSBs are not repaired effectively. DSB: double-strand break; HR: homologous recombination; PARP: Poly (ADP-ribose) polymerase; SSB: single-strand break. Source: References 1, 2.

PARP inhibitors have demonstrated clinical activity in somatic and/or germline BRCA-mutated malignancies (gBRCAm). Collectively, they are indicated for breast, ovarian, fallopian tube, and primary peritoneal cancers.^[4–6] This drug class remains under investigation for its potential utility in solid and hematologic malignancies.

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Table 1. Characteristics of Currently Approved PARP Inhibitors
	Niraparib	Olaparib	Rucaparib
Emetic Potential	Moderate	Low	Moderate
Administration	Administer whole capsule, with or without food, preferably at bedtime to diminish nausea/vomiting potential May need antiemetics for moderate nausea/vomiting	Administer whole capsule/tablet, with or without food Do not substitute capsules for tablets, owing to dosing/bioavailability differences More nausea/vomiting occurred when in a fasting state (tablets)	Administer with or without food May need antiemetics for moderate nausea/vomiting
Dietary considerations	NA	Avoid grapefruit and Seville oranges, including their juices	NA
Absorption	No data	Rapid; delayed with a high-fat meal (extent of absorption not significantly altered)	C_max increased 20%, AUC increased 38%, and T_max delayed 2.5 hours following high-fat meal (as compared to the fasting state)
Oral bioavailability	~73%	Tablet has higher bioavailability	36% (range: 30% to 45%)
Time to peak	Within 3 h	Capsule: 1 to 3 h; tablet: 1.5 h	1.9 h
Distribution (V_d)	1,074 L	Capsule: 167 ± 196 L Tablet: 158 ± 136 L	113 to 262 L
Protein binding	83%	~82%	70%
Metabolism	Substrate of BCRP/ABCG2, P-glycoprotein/ABCB1 Inhibits BCRP/ABCG2 Metabolized via carboxylesterases to inactive metabolite, which subsequently undergoes glucuronidation	Substrate of CYP3A4 (major), P-glycoprotein/ABCB1 Metabolized primarily via CYP3A4; majority via oxidation with some metabolites undergoing subsequent glucuronide or sulfate conjugation	Substrate of BCRP/ABCG2, CYP1A2 (minor), CYP2D6 (minor), CYP3A4 (minor), P-glycoprotein/ABCB1 Inhibits CYP1A2 (moderate), CYP2C19 (weak), CYP3A4 (weak) Metabolized primarily via CYP2D6; minor pathways include CYP1A2 and CYP3A4
CYP3A4 inhibitor adjustment	NA	If moderate CYP3A4 inhibitor: reduce olaparib to 200 mg bid (capsules) or 150 mg bid (tablets) If strong CYP3A4 inhibitor: reduce olaparib to 150 mg bid (capsules) or 100 mg bid (tablets)	NA
CYP3A4 inducer adjustment	NA	Avoid concomitant use with moderate or strong CYP3A4 inducers Olaparib efficacy may be reduced if CYP3A4 inducers cannot be avoided	NA
Renal adjustment	NA	CrCl 51–80 mL/min: monitor closely for toxicity CrCl 31–50 mL/min: reduce olaparib to 300 mg bid (capsules) or 200 mg bid (tablets) CrCl <30 mL/min: no data	NA
Hepatic adjustment	NA	NA	NA
Half-life elimination	36 h	Capsule: 11.9 ± 4.8 h Tablet: 14.9 ± 8.2 h	17 to 19 hours
Excretion	Urine (~48%); 11% unchanged Feces (~39%); 19% unchanged	Urine (44%, mostly metabolites) Feces (42%, mostly metabolites)	No data

CrCl: creatinine clearance; min: minute; NA: not applicable; PARP: poly (ADP-ribose) polymerase;
V_d : volume of distribution.
Source: References 4–6.

Table 2. Reported Common Adverse Effects of Currently Approved PARP Inhibitors
	Niraparib	Olaparib	Rucaparib
Gastrointestinal
Nausea/vomiting	X	X	X
Diarrhea	X	X	X
Constipation	X	X	X
Dysgeusia	X	X	X
Abdominal pain/distention	X		X
Mucositis/stomatitis	X	X	X
Dyspepsia	X	X
Dry mouth/xerostomia	X
Decreased appetite	X	X	X
Blood
Leukopenia/neutropenia	X	X	X
Anemia	X	X	X
Thrombocytopenia	X	X	X
MDS or AML^a	X	X	X
Musculoskeletal
Myalgia	X	X
Back Pain	X
Arthralgia	X	X
Fatigue/asthenia	X	X	X
Respiratory
Nasopharyngitis	X		X
Upper respiratory tract infection		X	X
Influenza		X
Dyspnea	X		X
Cough	X
Pneumonitis		X
Central Nervous System
Headache	X	X
Dizziness	X
Insomnia	X
Anxiety	X
Cardiac
Palpitations	X
Hypertension	X
Increased cholesterol			X
Hepatic
AST/ALT elevation	X		X
Renal
Increased serum creatinine		X	X
Other
Urinary Tract infection	X
Rash	X		X
Embryo-fetal toxicity	X	X	X

^aDiscontinue PARP inhibitor if patient develops MDS or AML.
ALT: alanine aminotransferase; AML: acute myeloid leukemia; AST: aspartate aminotransferase; MDS: myelodysplastic syndrome; PARP: poly (ADP-ribose) polymerase.
Source: References 4–6.