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.

Epidemiology and Etiology

Breast Cancer

Breast cancer is the second leading cause of cancer-related death among women in the United States.^[7] The likelihood of developing breast cancer increases with age (the majority are diagnosed after age 50 years), with the highest mortality rate observed between ages 65 and 74 years.^[7,8] The lifetime risk for women to develop breast cancer is about 1 in 8 (12.5%).^[7] There is a 5-year survival rate of 90% among all races with breast cancer, with a much greater survival rate (99%) observed with localized disease.^[7] There is a high incidence of breast cancer in non-Hispanic white and non-Hispanic black women, and the mortality rate is greatest in non-Hispanic black women.^[7] The American Cancer Society (ACS) estimates that about 268,670 new cases and 41,400 deaths from breast cancer will occur this year in the U.S.^[7] Breast cancer mortality has declined over the last two decades, predominantly because of reductions in smoking and advances in early cancer detection and treatment.^[7]

According to the CDC, there are numerous, identifiable risk factors for developing breast cancer.^[8] These include female gender; advanced age; genetic mutations (BRCA1 or BRCA2); early menarche (before age 12 years); late pregnancy (after age 30 years); nulliparity; late menopause (after age 55 years); physical inactivity; postmenopausal overweight/obesity; increased mammographic breast density; hormone replacement therapy (e.g., estrogen, progestin); oral contraceptives; personal/family (first-degree relative) history of breast cancer; proliferative breast disease (e.g., atypical hyperplasia, lobular carcinoma in situ); prior treatment with radiation therapy to the chest wall before age 30; and alcohol use.^[8] In the U.S., around 7% to 10% of cases, including triple-negative (i.e., ER/PR/HER2-negative) breast cancer, are thought to occur due to gBRCAm.^[9–11]

Ovarian Cancer

Ovarian cancer is the fifth leading cause of cancer-related deaths among women in the U.S.^[7] The likelihood of developing ovarian cancer increases with age (the majority are diagnosed between ages 55 and 64 years), with the highest mortality rate observed between ages 65 and 74 years.^[7,12] The lifetime risk of developing ovarian cancer is about 1 in 77 (1.3%).^[13] There is a 5-year survival rate of 47% among all races with ovarian cancer, with a much greater survival rate (93%) observed with localized disease.^[7,13] There is a relatively higher incidence and mortality rate of ovarian cancer in non-Hispanic white women.^[13] The ACS estimates that about 22,240 new cases and 14,070 deaths from ovarian cancer will occur this year in the U.S.^[7,13] Ovarian cancer cases and mortality have also declined over the last decade.^[13]

According to the CDC, multiple risk factors exist for developing ovarian cancer.^[12] These include advanced age; family (first-degree relative) history of ovarian cancer; genetic mutations (e.g., BRCA1, BRCA2, Lynch syndrome); personal history of breast/uterine/colorectal cancer; Eastern European or Ashkenazi Jewish background; endometriosis; nulliparity, and long-term (more than 10 years) estrogen use without concomitant progesterone.^[12] In the U.S., around 10% to 15% of ovarian cancer cases are thought to occur due to gBRCAm.^[9,14]

Conversely, certain factors have been associated with a decreased risk of developing ovarian cancer.^[15] These include combined oral contraceptive use for greater than 5 years; childbirth; breastfeeding for greater than 1 year; and certain surgical procedures (e.g., tubal ligation, oophorectomy, hysterectomy).^[15]

Fallopian tube and primary peritoneal cancers are often subgrouped with ovarian cancer, but they are rare.^[16] These have also been associated with BRCA mutations.^[16]

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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.