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.

Drug Resistance

Acquired resistance to PARP inhibitors is increasing, and proposed mechanisms include 1) BRCA gene mutations could reverse and restore homologous recombination functions; 2) Nonhomologous end-joining functions may decrease, causing DSBs to be more accurately repaired through homologous recombination; 3) PARP levels or activity may decrease, leading to decreased target sites for PARP inhibitors; 4) P-glycoprotein efflux pumps may upregulate and remove PARP inhibitors from cells; 5) RAD51 activity may increase, which is a biomarker for homologous recombination function.^[3]

On the other hand, when ATR kinase is inhibited, BRCA1-independent homologous recombination and fork protection decrease, leading to a cell's resensitizing to PARP inhibitors. Therefore, ATR inhibitors represent a potentially new drug class to overcome PARP-inhibitor resistance in BRCA-deficient malignancies.^[28]

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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.

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Role of PARP Inhibitors in BRCA-Related Malignancies

Drug Resistance

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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