The Nuances of Managing Patients on PARP Inhibitor Therapy: Key Information for Advanced Practitioners

The treatment of ovarian cancer is steadily evolving, which can largely be attributed to the impact of poly ADP ribose polymerase (PARP) inhibitors on the management of women with epithelial ovarian cancers.1 Ovarian cancer causes more deaths than any other gynecologic cancer in the United States.2 Because localized disease is often asymptomatic or ambiguous, the majority of women are diagnosed with advanced disease, bearing a 5-year survival rate of only 30%.3 Many women initially achieve remission with optimal surgical intervention and chemotherapy; however, most will eventually relapse.4 Oncology advanced practitioners treating patients in this setting will need to know how to optimize treatment options, manage side effects, and convey important information about taking the agents safely to their patients. 

Background

BRCA1 and BRCA2 proteins are necessary for repair of double-strand breaks of DNA through the homologous recombination repair pathway. Therefore, tumors harboring a mutation in the homologous recombination repair pathway—including BRCA1/2 mutations—are incapable of repairing the damage delivered when PARP is suppressed, resulting in cell death.5 These mutations can be classified as either germline or somatic mutations.6 Germline mutations are inherited and are present in all cells at birth, while somatic mutations are acquired after birth and are present only in the tumor itself. It is estimated that approximately 50% of high-grade serous ovarian tumors have a degree of homologous recombination repair deficiency, either germline or somatic mutations, and would likely benefit from PARP inhibitors.7

Genetic testing is not only crucial for members of the clinical team to make informed treatment decisions, but also to identify family members who may also carry a BRCA mutation or other homologous repair deficiency (HRD), putting them at a higher risk of a variety of cancers. The National Comprehensive Cancer Network (NCCN) Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian recommend that all women diagnosed with ovarian cancer receive genetic counseling.8 While testing for BRCA mutations has been widely available for more than 20 years, an assay that determines HRD status—including BRCA mutations and other types of genomic instability—was recently approved by the U.S. Food and Drug Administration (FDA) for commercial use,9 making testing more widely accessible beyond academic institutions.

Continued below

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Genetic Mutations and Testing

A genetic mutation, which is a permanent alteration in DNA sequence, can be classified as either germline or somatic.

Germline, or hereditary, mutations are inherited from a parent and are present throughout a person’s life in virtually every cell in the body. They are passed to the next generation because the mutation is present in germ cells: sperm and eggs.

Somatic mutations, also known as acquired mutations, occur after conception and are present only in certain cells. Acquired mutations can be caused by environmental factors, such as ultraviolet radiation or errors in cell division. Mutations in somatic cells cannot be passed to offspring.1,2

Additionally, de novo mutations can occur for the first time in a germ cell or a fertilized egg during early embryogenesis. De novo mutations may explain genetic disorders in which an affected child has a mutation in every cell in the body but the parents do not.1,2

Tests are commercially available to assess both germline and somatic variants. Testing for germline mutations uses either a saliva sample or a blood sample. Somatic testing requires tumor cells, either through tumor biopsy or by isolating cancer cells circulating in peripheral blood, called a liquid biopsy.3 All women diagnosed with epithelial ovarian, tubal, and peritoneal cancers should receive genetic counseling and be offered genetic testing, even when there is no family history of disease.2,4

Mutations found in ovarian cancers that are most susceptible to the effects of PARP inhibitors—including tumors with BRCA1/2 pathogenic variants and other homologous recombination repair deficiencies—can arise from either germline or somatic origins. In a woman who does not carry a germline pathogenic variant, somatic tumor testing should be offered.5 Therefore, both tests are essential for assessment and identification of patients that may benefit most from treatment with PARP inhibitors.

References

  1. National Institutes of Health. Genetics Home Reference. January 2020. https://ghr.nlm.nih.gov/primer/mutationsanddisorders/genemutation
  2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 1.2020. December 2019. https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf
  3. Reed EK, Steinmark L, Seibert DC, Edelman E. Somatic Testing: Implications for Targeted Treatment. Seminars in Oncology Nursing. 2019;35(1):22-33. http://doi.org/10.1016/j.soncn.2018.12.009
  4. SGO Clinical Practice Statement: Genetic testing for ovarian cancer. October 2014. sgo.org/clinical-practice/guidelines/genetic-testing-for-ovarian-cancer
  5. Konstantinopoulos PA, Norquist B, Lacchetti C, et al. Germline and somatic tumor testing in epithelial ovarian cancer: ASCO Guideline. Journal of Clinical Oncology. 2020. Accessed online January 27, 2020. http://doi.org/10.1200/JCO.19.02960

One Patient’s Story

Susan is a 58-year-old Caucasian female who was diagnosed with stage IIIC high-grade serous ovarian cancer at age 55. She underwent optimal cytoreductive surgery followed by 6 cycles of adjuvant paclitaxel and carboplatin. Her preoperative and postoperative cancer antigen (CA) 125 levels were 2,536 U/mL and 958 U/mL, respectively. After 6 cycles of chemotherapy, her CA-125 level was 7 U/mL and her postchemotherapy imaging showed no evidence of cancer.

Susan met with a genetic counselor and underwent multigene panel testing for hereditary cancer predisposition. She tested negative for a pathogenic variant in BRCA1/2 and associated genes. Her family history is significant for a maternal grandmother with breast cancer in her 70s and a paternal cousin with postmenopausal breast cancer in her late 50s. Her ancestry is Irish and Italian. She denies a known family history of ovarian, pancreatic, endometrial, colon, or other cancers. In addition to surveillance follow-up every 3 months with a physical, pelvic exam, and CA-125, Susan receives yearly imaging of her chest, abdomen, and pelvis.

Susan remained asymptomatic until 3 years postchemotherapy, when she reported increased right lower quadrant discomfort. Her CA-125 increased from single digits to 127 U/mL. Imaging showed a 3 cm peritoneal mass in the right lower quadrant adjacent to the cecum. She underwent surgery with complete tumor resection; pathology was consistent with recurrent ovarian cancer. At the time of surgery, her oncology team decided to send her tumor for molecular profiling to determine if she had a somatic mutation. Her genomic profile reported an HRD-positive tumor with loss of heterozygosity > 16%.

Because her last chemotherapy was 3 years ago, Susan is considered platinum-sensitive and an ideal patient for re-treatment with platinum-based therapy. After discussing treatment options, the team agreed to proceed with carboplatin every 21 days, gemcitabine days 1 and 8, and bevacizumab every 21 days for a total of 6 cycles. Susan received growth factors to prevent neutropenia and treatment delays. After completing cycle 2, Susan developed hypertension, a known side effect of bevacizumab.10 Her diastolic blood pressure was 100 mm Hg. She was prescribed a calcium channel blocker, and her blood pressure returned to normal levels. Susan also received 2 units of packed red blood cells after cycle 5 for grade 3 anemia.

Upon completion of 6 cycles of chemotherapy for recurrent disease, Susan’s CA-125 normalized to 5 U/mL and imaging of her chest, abdomen, and pelvis showed no evidence of disease.

The clinical team explained to Susan and her husband that the likelihood of another recurrence was high; therefore, a proactive option with maintenance therapy was in her best interest. The team agreed to start Susan on a PARP inhibitor based on her HRD-positive status, as this option may give her the best chance to prevent or delay a recurrence. The PARP inhibitors rucaparib (Rubraca), olaparib (Lynparza), and niraparib (Zejula) each have an indication for maintenance therapy in the recurrent ovarian cancer setting. But which PARP inhibitor is the best option for Susan?

Choosing an Agent

Three PARP inhibitors are FDA-approved for the maintenance treatment of patients with recurrent ovarian cancer regardless of BRCA1/2-associated pathogenic variant or somatic mutation (Table 1).11–13 In clinical trials, the use of a PARP inhibitor for platinum-sensitive, recurrent maintenance therapy significantly increased progression-free survival in patients with either a germline or somatic mutation (Table 2). This benefit was greatest in patients with a germline or somatic BRCA1/2-associated mutation, followed by those with HRD-positive tumors. Patients with the absence of a pathogenic variant in BRCA1/2-associated genes or HRD-negative tumors reported less benefit from a PARP inhibitor in clinical trials.14,15

In patients receiving rucaparib in the ARIEL3 study, the median investigator-assessed progression-free survival (PFS) in tumor subgroups with a germline BRCA1/2 mutation or HRD-positive carcinoma was 16.6 and 13.6 months, respectively, compared with 5.4 months in the placebo group. Results confirmed by blind independent central radiology review were similar, with a median PFS of 26.8 months for the BRCA1/2 mutation subgroup vs. 5.4 months for placebo; and median PFS of 22.9 months for HRD-positive patients vs. 5.5 months for placebo.14

The results of the ENGOT-OV16/NOVA trial had similarly impressive results. Patients receiving niraparib had a significantly longer PFS than did those in the placebo group, including 21.0 vs 5.5 months in the germline BRCA mutation cohort; and 12.9 months vs 3.8 months in the non-germline BRCA cohort for patients who had tumors with homologous recombination deficiency.15

Table 1. Indications of FDA-Approved PARP Inhibitors in Ovarian Cancer*
Pharmacologic Agent Indication(s)
Olaparib12
  • Maintenance treatment of patients with germline or somatic BRCA-mutated advanced ovarian cancer after responding to first-line platinum-based chemotherapy
  • Maintenance treatment for recurrent advanced ovarian cancer after responding to chemotherapy
  • Treatment of germline BRCA-mutated advanced ovarian cancer in patients with 3 or more prior lines of chemotherapy
Rucaparib11
  • Maintenance treatment of recurrent ovarian cancer after responding to platinum-based chemotherapy
  • Treatment of patients with germline and/or somatic BRCA-mutated ovarian cancer who have been treated with 2 or more chemotherapies
Niraparib13
  • Maintenance treatment of recurrent ovarian cancer after responding to platinum-based chemotherapy
  • Treatment of advanced ovarian cancer in patients who have been treated with 3 or more prior chemotherapy regimens AND whose cancer is associated with HRD-positive status (either BRCA mutation or genomic instability AND platinum-sensitive disease)

While the SOLO2/ENGOT-Ov21 trial did not include an analysis of HRD-positive tumors, it did report that patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer—and a pathogenic variant in BRCA1/2—who received olaparib or placebo achieved a median progression-free survival of 19.1 vs 5.5 months, respectively.16 These study results demonstrated that patients with ovarian cancer and a germline pathogenic variant or a somatic mutation benefit from the addition of a PARP inhibitor.

Table 2. Pivotal Studies of PARP Inhibitors in Patients With Recurrent Ovarian Cancer After Response to Platinum
Study Study 1925 SOLO-216 bBRCAm NOVA26 gBRCAm NOVA26 Non-gBRCAm ARIEL-314 BRCAm ARIEL-314 ITT
Agent Olaparib Olaparib Niraparib Niraparib Rucaparib Rucaparib
Difference in PFS (mo) 8.4 vs 4.8 19.1 vs 5.5 21.0 vs 5.5 9.3 vs 3.9 16.6 vs 5.4 10.8 vs 5.4
PFS HR (investigator assessed) 0.35 (95% CI, 0.25–0.49; p < .001) 0.30 (95% CI, 0.22–0.41; p < .0001) 0.27 (95% CI, 0.18–0.40) 0.53 (95% CI, 0.41–0.68) 0.23 (95% CI, 0.16–0.34; p < .0001) 0.36 (95% CI, 0.30–0.45; p < .0001)
PFS HR (BICR) 0.39 (95% CI, 0.27–0.55; p < .001) 0.25 (95% CI, 0.18–0.35; p < .0001) 0.27 (95% CI, 0.17–0.41; p < .0001) 0.45 (95% CI, 0.34–0.61; p < .0001) 0.20 (95% CI, 0.13–0.32; p < .0001) 0.35 (95% CI, 0.28–0.45; p < .0001)

Considering Side-Effect Profiles

The side-effect profile for each PARP inhibitor varies slightly.11–13 As a class effect, the most common adverse events are consistently fatigue and nausea. Hematologic toxicities, especially anemia, are also common; however, grade 3/4 anemia was reported in 25% of cases or less (Table 3). Personalizing and individualizing each patient case history is important when choosing a PARP inhibitor. Because Susan has a history of high blood pressure, her advanced practitioner explained that niraparib was ruled out as a treatment choice due to a 19% all-grade incidence of hypertension. Rucaparib reported a slightly lower incidence of grade 3/4 anemia, and because of Susan’s history of blood transfusion–dependent anemia, the clinical team decided to begin rucaparib 600 mg by mouth twice daily for maintenance of recurrent ovarian cancer.

Table 3. Toxicities Reported in Key Clinical Trials of PARP Inhibitors Olaparib, Rucaparib, and Niraparib
    Olaparib16 Rucaparib14 Niraparib15
Toxicity, % Grade SOLO1 SOLO2 ARIEL-3 NOVA

Anemia

All Grades

Grades 3/4

39

22

45

19

37

19

50

25

Thrombocytopenia

All Grades

Grades 3/4

11

1

14

1

28

5

61

34

Neutropenia

All Grades

Grades 3/4

23

9

19

5

18

7

30

20

Fatigue

All Grades

Grades 3/4

63

4

66

4

69

7

59

8

Insomnia

All Grades

Grades 3/4

0.4

NR

NR

NR

NR

NR

24

<1

Headaches

All Grades

Grades 3/4

23

<1

26

1

18

<1

26

Nausea

All grades

Grades 3/4

77

1

76

3

75

4

74

3

Constipation

All grades

Grades 3/4

28

0

21

0

37

2

40

1

Vomiting

All grades

Grades 3/4

40

<1

38

3

37

4

34

2

Decreased appetite

All grades

Grades 3/4

20

0

22

0

23

1

25

<1

Abdominal pain

All grades

Grades 3/4

25

2

25

3

30

2

23

1

Diarrhea

All grades

Grades 3/4

34

3

33

1

32

1

19

<1

Dyspepsia

All grades

Grades 3/4

17

0

11

0

NR

NR

50

0

Increased creatinine

All grades

Grades 3/4

NR

NR

11

0

15

<1

NR

NR

Elevated ALT

All grades

Grades 3/4

0

0

<1

<1

34*

11*

NR

NR

Elevated AST

All grades

Grades 3/4

0

0

<1

<1

34*

11*

NR

NR

Hypertension

All grades

Grades 3/4

NR

NR

NR

NR

NR

NR

19

8

Dyspnea

All grades

Grades 3/4

15

0

12

1

NR

NR

19

1

Susan’s HRD-positive tumor is clearly an indication for the use of a PARP inhibitor. However, all patients with recurrent disease who are in a partial or complete response to platinum-based therapy—germline, somatic, homologous recombination deficient or proficient, and wild type—may benefit from rucaparib as maintenance therapy.11 A post hoc subgroup analysis of the ARIEL3 study confirmed that rucaparib’s ability to significantly improve progression-free survival compared with placebo extended beyond those with germline BRCA mutations, to include those with somatic BRCA mutation and somatic BRCA mutation + wild-type BRCA/high loss of heterozygosity, as well as those with wild-type BRCA tumors.17

Initiating Treatment

Patient education prior to initiating therapy can reduce unanticipated side effects and decrease anxiety about treatment. Advanced practitioners can discuss the most common side effects and toxicities, including the typical amount of time to onset and duration (see Table 4), provide guidance on reporting symptoms, and encourage implementation of self-care measures.

Table 4. Median Time to First Onset of the Most Frequently Reported Treatment-Emergent Adverse Events in Patients With Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Who Received ≥ 1 Dose of Rucaparib 600 mg in Study 10, ARIEL2, or ARIEL3

TEAE

Median Time to Onset (95% CI), days

Nausea

Any grade

Grade ≥ 3

5 (4–5)

35 (13–71)

Dysgeusia

Any grade

Grade ≥ 3

7 (5–9)

197 (NA)

ALT/AST increased

Any grade

Grade ≥ 3

15 (14–15)

15 (15–16)

Vomiting

Any grade

Grade ≥ 3

15 (13–23)

42 (14–85)

Asthenia/fatigue

Any grade

Grade ≥ 3

15 (13–15)

53 (37–68)

Decreased appetite

Any grade

Grade ≥ 3

22 (16–29)

85 (25–127)

Diarrhea

Any grade

Grade ≥ 3

29 (17–35)

31 (11–103)

Constipation

Any grade

Grade ≥ 3

29 (22–43)

120 (81–232)

Abdominal pain

Any grade

Grade ≥ 3

45 (33–56)

112 (46–189)

Thrombocytopenia/platelet count decreased

Any grade

Grade ≥ 3

52 (43–57)

47 (29–63)

Anemia/hemoglobin decreased

Any grade

Grade ≥ 3

56 (53–57)

83 (74–85)

Note. TEAE = treatment-emergent adverse event; CI = confidence interval; NA = not applicable; ALT = alanine aminotransferase; AST = aspartate aminotransferase. Information from Reference 19.

A baseline complete blood count (CBC), platelet, differential, and comprehensive metabolic panel should be obtained prior to starting rucaparib. CA-125 is usually monitored every 3 months or per physician discretion. For the first month, Susan was instructed to have her CBC drawn weekly to assess her white and red counts. Thrombocytopenia is more common with niraparib, but platelets should still be monitored with rucaparib. Creatinine levels and liver function should also be checked periodically.

Susan’s Story Continues

Susan’s advanced practitioner directed her to take two rucaparib tablets (300 mg each) twice a day, ideally 12 hours apart. For nausea and vomiting, she was counseled that some patients find it helpful to take an anti-nausea medication prior to each dose of rucaparib. Other suggestions include having a light meal or snack prior to each dose, and a light snack such as crackers or soda water if underlying queasiness persists. Most patients adjust to the nausea and fatigue after a couple weeks. Susan was reminded to inform her advanced practitioner if she was unable to do her normal activities of daily living or required more rest during the day. Differential diagnosis for increased fatigue should be considered, such as anemia and hypothyroidism.

After discussing interventions for oral adherence, Susan decided she would set an alarm on her mobile phone to alert her every 12 hours when her medication was due. Susan successfully verbalized the teach-back method of common side effects and who to call if she did not feel well. Her prescription was sent electronically to the specialty pharmacy preferred by her medical insurance.

Navigating Medication Access

Innovations in the treatment of ovarian cancer, and cancer therapy in general, are transforming patient outcomes in oncology. However, these new options can come at a substantial cost. Accessing needed drugs can be a challenge depending on insurance coverage and the use of utilization management strategies by the insurance provider, including step therapy, prior authorization, restrictive drug formularies, and specialty-specific tiers.20 As the use of targeted cancer drugs and combination therapy continue to grow, so will concerns about access for patients.

Most payers require prior authorization for PARP inhibitors, a time-consuming and burdensome process that requires healthcare providers to seek approval before the medication will be covered. However, there are strategies that can help ease the burden on the healthcare provider. Taking advantage of an electronic or automated process that the payer may offer for receiving requests and returning determinations can decrease the amount of time the provider may spend on hold. Proactively providing all necessary information that may be requested can also hasten the approval process.21

After a prior authorization has been approved, the prescription can be filled. Specialty pharmacies often have staff dedicated to patient assistance and are adept in identifying co-pay assistance programs supported by the manufacturer of the medication or available grants. Susan’s advanced practitioner explained that she would receive a call from the specialty pharmacy dispensing the medication by mail to her home, with an option to schedule complimentary follow-up calls with the specialty pharmacy for symptom review and reinforcement of patient education.

Update on Susan’s Journey

Susan’s weekly CBC was stable. She had mild fatigue and nausea that she described as “annoying,” but it was not severe enough to interfere with her work and family life. She returned to the clinic a month later for a follow-up exam. A comprehensive metabolic panel revealed an elevated alanine aminotransferase (ALT) level and an aspartate aminotransferase (AST) level 2 times the normal range. Susan was asymptomatic. Her white blood count was 1900/mm3 and her absolute neutrophil count (ANC) was 800/mm3. She was afebrile and had no signs and symptoms of infection. Her advanced practitioner instructed her to hold rucaparib for a week and educated her about infection precautions. Susan’s labs were rechecked in 1 week.

Susan’s repeat CBC was stable but still low, with a white blood count of 2500/mm3 and an ANC of 1400/mm3. Rucaparib was held 1 more week, with the intention to reduce the dose from 600 mg twice daily to 500 mg twice daily. The CBC was rechecked, and levels had improved to WBC 3500/mm3 and ANC 1900/mm3. Susan restarted rucaparib at the new, lower dose and continued weekly CBC checks for another 4 weeks. Her hematologic and metabolic panel, including her liver enzymes, stayed within normal limits. She continued to take two 250-mg rucaparib tablets orally twice daily with monthly monitoring of labs and physical exams every 12 weeks.

Conclusions

The use of PARP inhibitors continues to expand. Recent studies have investigated the use of PARP inhibitors as first-line treatment, maintenance therapy after first-line treatment, or both. PARP inhibitors substantially increased progression-free survival in these trials, especially for patients with BRCA-mutated tumors and HRD-positive disease.22–24 PARP inhibitors have shifted the landscape for the treatment of ovarian cancer and will continue to offer opportunities for women with this devastating disease. Advanced practitioners, key members of the treatment team, are in a prime position to help patients navigate their cancer journey to achieve the best possible outcomes.

    References

  1. Cook SA, Tinker AV. PARP inhibitors and the evolving landscape of ovarian cancer management: A review. BioDrugs. 2019;33:255-273. http://doi.org/10.1007/s40259-019-00347-4
  2. Ovarian Cancer Statistics. May 2019. https://www.cdc.gov/cancer/ovarian/statistics/
  3. Survival Rates for Ovarian Cancer. February 2019. https://www.cancer.org/cancer/ovarian-cancer/detection-diagnosis-staging/survival-rates.html
  4. Ushijima K. Treatment for recurrent ovarian cancer—At first relapse. Journal of Oncology. 2010;2010:1-7. http://doi.org/10.1155/2010/497429
  5. Ledermann JA, Drew Y, Kristeleit RS. Homologous recombination deficiency and ovarian cancer. European Journal of Cancer. 60(June 2016):49-58. http://doi.org/10.1016/j.ejca.2016.03.005
  6. Griffiths A, Miller J, Suzuki D. An Introduction to Genetic Analysis. 7th ed. New York: W. H. Freeman; 2000. https://www.ncbi.nlm.nih.gov/books/NBK21894/.
  7. The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609-615. http://doi.org/10.1038/nature10166
  8. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 1.2020. December 2019. https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf
  9. Premarket Approval: myChoice HRD CDx. October 2019. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P190014
  10. Avastin (bevacizumab) prescribing information. June 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125085s331lbl.pdf
  11. Rubraca (rucaparib) prescribing information. April 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf
  12. Lynparza (olaparib) prescribing information. July 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208558s009lbl.pdf
  13. Zejula (niraparib) prescribing information. October 2019. https://www.zejula.com/application/files/5515/7185/8036/Zejula_PI_PPI_QUADRA_Final.pdf
  14. Coleman RL, Oza A, Lorusso D. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): A randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. 2017;390(10106):1949-1961. http://doi.org/10.1016/S0140-6736(17)32440-6
  15. 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. http://doi.org/10.1056/NEJMoa1611310
  16. Pujade-Lauraine E, Ledermann JA, Selle F, et al. SOLO2/ENGOT-Ov21: A phase 3, randomised, double-blind, placebo-controlled trial of olaparib tablets as maintenance therapy in platinum-sensitive, relapsed ovarian cancer. The Lancet Oncology. 2017;18(9):1274-1284.
  17. Coleman RL, Oza AM, Lorussso D, et al. Post hoc exploratory analysis of rucaparib in patients with platinum-sensitive recurrent ovarian carcinoma from the randomized, placebo-controlled phase 3 study ARIEL3: Effect of a deleterious germline or no germline BRCA mutation on efficacy and safety. Poster presented at SGO 50th Annual Meeting on Women’s Cancer, March 16-19, 2019, Honolulu, Hawaii.
  18. Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel–carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): A multicentre, open-label, randomised, phase 3 trial. The Lancet Oncology. 2017;18(6):779-791. http://doi.org/10.1016/S1470-2045(17)30279-6
  19. Kristeleit RS, Oza AM, Oaknin A, et al. Integrated safety analysis of the poly(ADP-ribose) polymerase inhibitor rucaparib in patients with ovarian cancer in the treatment and maintenance settings. Poster presented at ESMO Congress, September 27-October 1, 2019, Barcelona, Spain.
  20. Lee M. ASCO Opposes Payer Utilization Management Approaches that Curb Access to High-Quality, High-Value Cancer Care. April 2017. https://www.asco.org/about-asco/press-center/news-releases/asco-opposes-payer-utilization-management-approaches-curb
  21. Loria K. The impact of prior authorizations. Medical Economics. 2019;96(5). https://www.medicaleconomics.com/business/impact-prior-authorizations
  22. González-Martin A, Pothuri B, Vergote I. Niraparib in patients with newly diagnosed advanced ovarian cancer. New England Journal of Medicine. 2019;(381):2391-2402. http://doi.org/10.1056/NEJMoa1910962
  23. Ray-Coquard I, Pautier P, Pignata S. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. New England Journal of Medicine. 2019; 381:2416-2428. http://doi.org/10.1056/NEJMoa1911361
  24. Coleman RL, Fleming GF, Brady MF. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. New England Journal of Medicine. 2019;381:2403-2415. http://doi.org/10.1056/NEJMoa1909707
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  26. FDA NDA review ref 407 4987, application no. 208447

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