US Pharm. 2018;9(43):HS-10-HS16.

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.

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

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.

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

GENETIC TESTING

In general, if personal or family history is suggestive of a possible harmful mutation, patients should consult a healthcare provider.^17,18 Screening tools assess various risk factors, including early (prior to age 50 years) breast cancer diagnosis; bilateral breast cancer; personal or family history of breast and ovarian cancer; family history of multiple breast cancers; male breast cancer; Ashkenazi Jewish ethnicity; and family history of BRCA1- or BRCA2-related cancers.¹⁷ Genetic testing and counseling are recommended for adult patients who have a relatively higher risk of developing a BRCA-related malignancy.^17,18

There are hundreds of laboratory facilities capable of genetic testing, which requires a DNA sample from blood or saliva.¹⁷ While specific BRCA testing is an option, multigene-panel testing (using next generation sequencing) can determine potentially harmful mutations in many other genes.^17,18

AVAILABLE PARP INHIBITORS

As mentioned previously, PARP enzymes utilize NAD⁺.¹ From a biochemical perspective, currently approved PARP inhibitors contain a nicotinamide moiety (i.e., aromatic ring, carboxamide) to mimic the substrate-protein interaction of NAD⁺ with PARP (FIGURE 2).^1,19,20

Olaparib (Lynparza)

In 2014, the FDA approved olaparib for maintenance therapy for recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer if patients had a complete or partial response to platinum-based chemotherapy (i.e., platinum-sensitive disease).^4,21 Study 19 (cited in the package insert) evaluated 265 adult patients (ages 21 to 89 years, median age 58 years, in the olaparib group) with platinum-sensitive ovarian cancer who had received >2 prior platinum-containing regimens.⁴ Patients were randomized to receive either olaparib capsules 400 mg twice daily or placebo until there was unacceptable toxicity or progressive disease.⁴ In the olaparib group, 36% of patients had gBRCAm, 13% had prior bevacizumab use, and 81% had an Eastern Cooperative Oncology Group Scale (ECOG) performance status (PS) of 0.⁴ Of all patients, 45% were in complete response (CR) and 40% had a progression-free interval (PFI) of 6 to 12 months since their prior platinum dose.⁴ The median progression-free survival (PFS) of olaparib compared with placebo was 8.4 versus 4.8 months, with a hazard ratio (HR) of 0.35; 95% confidence interval (CI), 0.24-0.49; P <.0001; the overall survival (OS) was similar between olaparib and placebo (29.8 vs. 27.8 months).⁴ Grade 3 reactions in the olaparib group included neutropenia, anemia, thrombocytopenia, nausea, vomiting, diarrhea, constipation, fatigue/asthenia, and respiratory tract infections.⁴ The investigators concluded that there was a statistically significant improvement in PFS in patients treated with olaparib.⁴

In 2017, the FDA approved olaparib for suspected/deleterious gBRCAm advanced ovarian cancer if patients received >3 prior chemotherapies.^4,21 The SOLO-2 study evaluated 295 patients (aged 28 to 83 years, median age 5 to 6 years, in the olaparib group) with gBRCAm platinum-sensitive ovarian/fallopian tube/primary peritoneal cancers who had received > 2 prior platinum-containing regimens.⁴ Patients received olaparib tablets 300 mg twice daily or placebo until unacceptable toxicity or progressive disease.⁴ In the olaparib group, 17% had prior bevacizumab use, 83% of patients had an ECOG PS of 0, and 44% had received >3 platinum-containing regimens.⁴ Of all patients, 47% were in CR and 40% had a PFI of 6 to 12 months since their prior platinum dose.⁴ The median PFS of olaparib compared with placebo was 19.1 versus 5.5 months (HR, 0.3 [95% CI, 0.22-0.41], P <.0001), but complete OS data have yet to be published from this study.⁴ Grade 3 reactions in the olaparib group included neutropenia, anemia, thrombocytopenia, nausea, vomiting, diarrhea, stomatitis, fatigue/asthenia, and headache.⁴ The investigators concluded that there was a statistically significant improvement in PFS in patients treated with olaparib.⁴

Earlier this year, the FDA approved olaparib for suspected/deleterious gBRCAm, HER2-negative metastatic breast cancer for patients who have received chemotherapy in neoadjuvant/adjuvant/metastatic settings.^4,22 According to the package insert, patients with ER/PR-positive breast cancer should either have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy.⁴ The OlympiAD study evaluated 302 patients (aged 22 to 76 years, median age 44 years, in the olaparib group) with gBRCAm HER2-negative metastatic breast cancer who had received an anthracycline (unless contraindicated) or taxane in the neoadjuvant/adjuvant/metastatic settings, >1 endocrine therapies in the adjuvant/metastatic settings (or have been deemed inappropriate for endocrine therapy), and have no evidence of disease progression during platinum treatment (if treated with a prior platinum-containing regimen).⁴ Patients received olaparib tablets 300 mg twice daily or chemotherapy (e.g., capecitabine, eribulin, vinorelbine) until progression or unacceptable toxicity.⁴ All patients had an ECOG PS of either 0 or 1, and 50% had triple-negative disease, while 50% had ER/PR-positive with HER2-negative disease.⁴ In the olaparib group, 7% and 21% had received prior platinum-based regimens for localized and metastatic disease, respectively.⁴ The median PFS of olaparib compared with placebo was 7 versus 4.2 months (HR, 0.58 [95% CI, 0.43-0.8]; P = .0009), but complete OS data have yet to be published from this study.⁴ Grade 3 reactions in the olaparib group included neutropenia, anemia, thrombocytopenia, diarrhea, respiratory tract infections, fatigue/asthenia, and headache.⁴ The investigators concluded that there was a statistically significant improvement in PFS in patients treated with olaparib.⁴

Rucaparib (Rubraca)

In 2016, the FDA approved rucaparib for deleterious BRCA mutation-associated (germline and/or somatic)advanced ovarian cancer if patients had received >2 prior chemotherapies.^5,23 Study 10 (cited in the package insert) and ARIEL2 evaluated a total of 106 patients (aged 33 to 84 years, median age 59 years) who had advanced BRCA-mutant ovarian cancer and progressed after >2 prior chemotherapies.^5,24 All patients received rucaparib tablets 600 mg twice daily until disease progression or unacceptable toxicity occurred.⁵ All patients had an ECOG PS of either 0 or 1 and had received >2 prior (43% had >3 prior) platinum-based regimens.⁵ There was an objective response rate of 54% (range: 44% to 64%), CR rate of 9%, partial response (PR) rate of 45%, and median duration of response of 9.2 months (95% CI, 6.6-11.6).⁵ Of note, in the ARIEL2 study, the median PFS of rucaparib in patients with BRCA mutations, compared with patients with high and low loss of heterozygosity, was 12.8 months (95% CI, 9-14.7) versus 5.7 months versus 5.2 months, respectively (HR, 0.27 [95% CI, 0.16-0.44]; P <.0001).²⁴ Grade 3 reactions included nausea, vomiting, constipation, diarrhea, abdominal pain, fatigue/asthenia, neutropenia, anemia, thrombocytopenia, dysgeusia, decreased appetite, dyspnea, increased serum creatinine, increased liver function tests (AST, ALT), and increased cholesterol.⁵ The investigators of the ARIEL2 study concluded that there was a statistically significant and relatively longer improvement in PFS for BRCA mutant (vs. wild type) patients treated with rucaparib.²⁴

Earlier this year, the FDA approved rucaparib for the maintenance treatment of recurrent epithelial ovarian/fallopian tube/primary peritoneal cancers if patients had a CR or PR to platinum-based chemotherapy.^5,25 The ARIEL3 study evaluated 564 patients (ages 39 to 84 years, median age 61 years, in the rucaparib group) with recurrent epithelial ovarian/fallopian tube/primary peritoneal cancer who had had a prior response (CR or PR) to recent platinum-based chemotherapy.⁵ Patients received either rucaparib tablets 600 mg twice daily or placebo until disease progression or unacceptable toxicity.⁵ All patients had an ECOG PS of either 0 or 1 and had received >2 prior (up to 7) platinum-based regimens.⁵ About 34% of patients were in CR after their most recent chemotherapy, and in the rucaparib group 22% had prior bevacizumab use.⁵ The median PFS of rucaparib compared with placebo was 10.8 versus 5.4 months (HR, 0.36 [95% CI, 0.30-0.45]; P <.0001), but complete OS data have yet to be published from this study.⁵ Grade 3 reactions included nausea, abdominal pain/distention, constipation, vomiting, diarrhea, stomatitis, fatigue/asthenia, rash, increased liver function tests (AST/ALT), increased serum creatinine, increased cholesterol, neutropenia, anemia, thrombocytopenia, nasopharyngitis, upper respiratory tract infections, and decreased appetite.⁵ The investigators concluded that there was a statistically significant improvement in PFS in patients treated with rucaparib, including the homologous recombination deficiency and tumor BRCA subgroups.⁵

Niraparib (Zejula)

In 2017, the FDA approved niraparib for the maintenance treatment of recurrent epithelial ovarian/fallopian tube/primary peritoneal cancers if patients had a CR or PR to platinum-based chemotherapy.^6,26 The NOVA study evaluated 553 patients (aged 57 to 64 years, in the niraparib group) with platinum-sensitive recurrent epithelial ovarian/fallopian tube/primary peritoneal cancers who had had a prior response (CR or PR) to recent platinum-based chemotherapy.⁶ Patients received either niraparib capsules 300 mg daily or placebo within 8 weeks of recent chemotherapy.⁶ All patients had received >2 prior (40% had >3 prior) platinum-containing regimens.⁶ In the niraparib group, 76% of patients had an ECOG PS of 0, and 26% had prior bevacizumab use.⁶ In the gBRCAm cohort, the median PFS of niraparib compared with placebo was 21 versus 5.5 months (HR, 0.26 [95% CI, 0.17-0.41]; P <.0001).⁶ In the non-gBRCAm cohort, the median PFS of niraparib compared with placebo was 9.3 versus 3.9 months (HR, 0.45 [95% CI, 0.34-0.61]; P <.0001).⁶ Complete OS data have yet to be published from this study.⁶ Grade 3 reactions included neutropenia, anemia, thrombocytopenia, nausea, constipation, vomiting, abdominal pain/distention, mucositis/stomatitis, diarrhea, xerostomia, fatigue/asthenia, decreased appetite, urinary tract infection, increased liver function tests (AST/ALT), myalgia, back pain, arthralgia, headache, insomnia, anxiety, dyspnea, rash, and hypertension.⁶ The investigators concluded that there was a statistically significant improvement in PFS in patients treated with niraparib (versus placebo), in both gBRCAm and non-gBRCAm cohorts.⁶ Table 1 lists characteristics of approved PARP inhibitors.

Investigational PARP Inhibitors and Combinations

There are various PARP inhibitors under investigation, either as monotherapy or in combination with other chemotherapeutic drugs.²⁷ Olaparib has been combined with other drugs for the following cancers: bladder (with durvalumab); colorectal (with irinotecan); endometrial (with cyclophosphamide); gastric (with paclitaxel); head and neck (with cisplatin); prostate (with degarelix or abiraterone/prednisone); and small cell lung (with temozolomide, AZ6738 [ATR inhibitor], or CRLX101 [modified camptothecin]).²⁷ Rucaparib has been combined with other drugs for the following cancers: breast (with cisplatin); cervical/endometrial (with bevacizumab); nonsquamous non–small cell lung (with pembrolizumab); and prostate (with docetaxel/carboplatin or nivolumab).²⁷ Niraparib has been combined with other drugs for the following cancers: breast (with pembrolizumab); pancreatic (with nivolumab or ipilimumab); prostate (with radium-223, enzalutamide, JNJ-63723283 [PD-1 inhibitor], apalutamide, or abiraterone/prednisone); and urothelial (with cabozantinib).²⁷

Additional PARP inhibitors include talazoparib (BMN-673), veliparib (ABT-888), pamiparib (BGB-290), iniparib (BSI-201, SAR240550), INO-1001, ABT-767, CEP-9722, E7016 / GPI-21016, and 2X-121.²⁷

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

ROLE OF THE PHARMACIST

There are various factors for pharmacists to consider with the currently approved PARP inhibitors. Niraparib does not require dosage modifications with respect to CYP3A4 (i.e., olaparib is a CYP3A4 substrate, while rucaparib weakly inhibits CYP3A4).^4-6 This is significant because most patients who receive chemotherapy are often taking medications that interact with various metabolizing enzymes. Niraparib is also the only PARP inhibitor administered once daily.⁶ Olaparib is available in capsule and tablet formulations, with the tablets having a higher bioavailability; therefore, the two dosage forms cannot be interchanged.⁴ All three drugs can be taken with food, which may relieve some of the nausea that patients can experience while taking these medications.^4-6 Niraparib and rucaparib are moderately emetogenic, and may require using antinausea medications.^5,6 While no dosage adjustment is required for mild hepatic (Child-Pugh classification A) disease or renal impairment (CrCl >30 mL/min) for niraparib or rucaparib, the AUC and C_max of olaparib are greatly increased in the presence of hepatic or renal impairment, warranting close monitoring and potential dosage changes (especially with regard to renal function for olaparib).^4-6 All three PARP inhibitors are administered orally, which allows patients to take medications at the setting of their choice, rather than at an infusion or oncology center.^4-6 Common adverse effects of approved PARP inhibitors are listed in Table 2.

CONCLUSION

PARP enzyme inhibition is a rational, specific approach in the ever-growing field of oncology. There are ongoing studies with drug combinations as well as investigations of potential utility in other malignancies. Current data support the use of PARP inhibitors to prolong PFS, but the drug class has yet to demonstrate statistically significant improvements in OS. Pharmacists should remain involved with other members of the healthcare team, in order to educate patients regarding PARP inhibitors’ adverse effects and their management.

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