29

September

Olaparib (Lynparza®) Clinical Management

Written by: Katie Carter, PharmD, BCPS, Indiana University Health
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Olaparib is a poly ADP-ribose polymerase (PARP) enzyme inhibitor and is FDA approved as a targeted therapy for BRCA-mutated breast cancer, ovarian, and pancreatic cancer as well as prostate cancer.  This PQI will highlight its place in therapy in these disease states, safety profiles, and clinical pearls regarding dose adjustment.

Background: 

Breast Cancer

Breast Cancer – About 5-10% of breast cancers can be associated with gene mutations inherited from a parent, most commonly mutations in the BRCA1 and BRCA2 genes.12

Lifetime Risk of Developing Breast Cancer
MutationWomenMen
BRCA1Up to 72%6.8%
BRCA269%Less frequent cause

Ovarian Cancer

Currently, ovarian cancer is primarily treated with surgery and systemic chemotherapy. About 25% of ovarian cancer cases are related to a BRCA mutation (15% germline and 7% somatic).14,15

Pancreatic Cancer

Up to 7% of patients with pancreatic cancer have a gBRCA mutation. 16,17

Prostate Cancer

Olaparib approved in May 2020 for patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer in combination with gonadotropin-releasing hormone analog or prior bilateral orchiectomy (full indication list in supplemental information).7

PQI Process: 

  • Verify the dosage form is correct
    • Olaparib was previously available as both a tablet and a capsule, and the two dosage forms had different bioavailability and therefore were not interchangeable on a milligram-per-milligram basis.
      • Capsules were discontinued August 2018 and only the tablets are currently available
    • Olaparib is available as 100 mg and 150 mg tablets
  • Verify the dose is correct
    • Typical starting dose for all FDA-approved indications: 300 mg orally twice daily
      • See Supplemental Information Section for current FDA-approved indications
    • The dose of olaparib must be adjusted to 200 mg twice daily for renal dysfunction when creatinine clearance is < 50 mL/minute. Olaparib has not been studied in patients with creatinine clearance < 30 mL/minute
  • Dose adjustments for adverse reactions
    • Consider holding treatment or dose reductions if patients experience adverse reactions
Dose reductionRecommended DoseHow to Supply
1st dose reduction250 mg BIDOne 150 mg tablet + one 100 mg tablet BID
2nd dose reduction200 mg BIDTwo 100 mg tablets BID
  • Drug interactions
    • Avoid concomitant use with moderate and/or strong CYP3A4 inhibitors
      • If a strong CYP3A4 inhibitor must be used concomitantly, the olaparib dose should be reduced to 100 mg twice daily
      • If a moderate CYP3A4 inhibitor must be used concomitantly, the olaparib dose should be reduced to 150 mg twice daily
    • Avoid concomitant strong CYP3A inducers; if a moderate CYP3A inducer must be used, there is the potential for reduced efficacy of olaparib
  • Laboratory monitoring
    • Complete blood counts should be performed at baseline and monthly thereafter
    • Renal function should be verified at baseline and periodically thereafter

Patient Centered Activities:

  • Provide Oral Chemotherapy Education Sheet
  • Counsel patient on side effect profile (see supplemental information)
  • Instruct patient to avoid grapefruit, grapefruit juice, Seville oranges, and/or Seville orange juice

Copay Assistance:

  • Commercially insurance patients who qualify can enroll in a $0 copay card assistance program through AstraZeneca’s Access 360 program

References:

  1. Birrer, M. Ask an expert: how do PARP inhibitors work? Cancer Updates, Research & Education. Published March 27, 2018.
  2. Domchek SM, Aghajanian C, Shapira-Frommer R, et al. Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecol Oncol. 2016;140(2):199-203.
  3. How common are BRCA mutations? INSIGHT from Dana-Farber Cancer Institute. Updated March 1, 2018. Available at: https://blog.dana-farber.org/insight/2018/03/brca-mutations-common.
  4. How do PARP inhibitors work in cancer? INSIGHT from Dana-Farber Cancer Institute. July 2016. Available at: https://blod.dana-farber.org/insight/2016/07/how-do-parp-inhibitors-work-in-cancer.
  5. Key statistics for ovarian cancer. American Cancer Society. Last updated January 8, 2019. Accessed April 8, 2019. Available at: https://www.cancer.org/cancer/ovarian-cancer/ about/key-statistics.html.
  6. Lexicomp Online, Hudson, Ohio: Lexi-Comp, Inc.; updated 2/22/19; accessed 2/25/19.
  7. LYNPARZA® (olaparib) [Prescribing Information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020.
  8. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med2018; 379:2495-2505.
  9. NCCN Clinical Practice Guidelines in Oncology. Ovarian Cancer including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 2.2018. Available at: https://www.nccn.org/professionals/physician_gls/default.aspx#ovarian.
  10. Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2mutation (SOLO2/ENGOT-Ov21): a double-blind, randomized, placebo-controlled, phase 3 trial. Lancet Oncology; 2017:18(9):1274-1284.
  11. Robson M, Im A, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCAmutation (OlympiAD trial). N Engl J Med. 2017; 377:523-533.
  12. S. Breast Cancer Statistics. Breastcancer.org. Last updated Feb 13,2019. Accessed Mar 19, 2019. Available at: www.breastcancer.org/symptoms/understand_bc/statistics.
  13. Konstantinopoulos et al. Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer. J Clin Oncol
  14. Pal T et al. Cancer. 2005;104(12):2807-2816.
  15. Pennington KP et al. Clin Cancer Res. 2014;20(3):764-775.
  16. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pancreatic Adenocarcinoma. V.1.2020. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed March 20, 2020.
  17. SEER Cancer Stat Fact Sheets: Pancreatic Cancer. National Cancer Institute website. https://seer.cancer.gov/statfacts/html/pancreas.html.  Accessed March 20, 2020.

Supplemental Information:

Current FDA-approved indications: (Starting dose is 300 mg twice daily for all indications)

IndicationEfficacySafety
Ovarian cancer
First-line maintenance treatment for deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer for patients who are in a complete or partial response to first-line platinum-based chemotherapy (SOLO-1 trial)
  • mPFS results: olaparib 56 months vs placebo 13.8 months
    (p-value <0.0001)
  • 5-Year PFS: olaparib 48% vs placebo 21%
  • Most common AEs with olaparib: nausea, vomiting, fatigue, anemia, diarrhea
  • Serious AEs occurred in 21% of olaparib patients vs 12% of placebo patients, most commonly anemia
In combination with bevacizumab for maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer for patients who are in a complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either:

  • Deleterious or suspected deleterious BRCA mutation and/or
  • Genomic instability

PAOLA-1 trial

  • Reduced the risk of disease progression or death by 67% (equal to HR of 0.33) and improved progression-free survival to a median of 37.2 months vs 17.7 months with bevacizumab alone
  • Higher Risk: mPFS olaparib 36.0 vs. 16.0 bevacizumab
  • Lower Risk: mPFS olaparib Not Reached vs. 22.1 bevacizumab
  • Adverse reactions (Grade 1-4) occurring in ≥10% of patients treated with olaparib/bevacizumab in PAOLA-1 compared with the placebo/bevacizumab arm were nausea (53%), fatigue (including asthenia) (53%), anemia (41%), lymphopenia (24%), vomiting (22%), and leukopenia (18%), diarrhea (18%), neutropenia (18%), urinary tract infection (15%), and headache (14%)
Maintenance treatment for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer for patients who are in a complete or partial response to platinum-based chemotherapy – 2 randomized trails completed10

SOLO-2 trial

Study 19

SOLO-2:

  • PFS: olaparib 19.1 months vs placebo 5.5 months, p-value <0.0001
  • OS: olaparib 51.7 months vs placebo 38.8 months, p-value 0.0537

Study 19:

  • PFS: olaparib 8.4 months vs placebo 4.8 months, p-value <0.0001

OS: olaparib 29.8 months vs placebo 27.8 months (p-value 0.73)PFS (p-value <0.0001): olaparib vs placebo: 19.1 months vs 5.5 months

SOLO-2:

  • Most common grade 1-2 AEs in both groups: nausea, fatigue, vomiting, abdominal pain, and diarrhea
  • Most common grade 3 or higher AE with olaparib: anemia

Study 19:

  • Most common AEs of all grads in olaparib arm included nausea (71%), fatigue (63%), vomiting (35%), diarrhea (28%), anemia (23%), constipation (22%), respiratory tract infection (22%), decreased appetite (21%), and headache (21%)
Deleterious or suspected deleterious gBRCAm advanced ovarian cancer after > 3 prior lines of chemotherapySingle arm trial PFS results:

  • ORR: 34%
  • Median DoR: 7.9 months
  • Serious AEs reported in 30% of patients, most frequently anemia, abdominal pain
Breast Cancer
Deleterious or suspected deleterious gBRCAm, HER2-negative metastatic breast cancer after treatment with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting (OlympiAD trial)
  • PFS:   olaparib 7 months vs chemotherapy 4.2 months (p-value 0.0009)
  • Rate of grade 3 or higher AEs was lower with olaparib (36.6%) vs chemotherapy (50.5%)
  • AEs that occurred more frequently with olaparib: anemia, nausea, vomiting, fatigue, headache, and cough
Pancreatic Cancer
Maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen (POLO trial)
  • PFS results: olaparib vs. placebo: median 7.4 months vs. 3.8 months (p-value 0.0035)
  • ORR: 23% in olaparib arm (12% in placebo arm)
  • OS: olaparib 19.3 months vs placebo 17.1 months (p-vale NS)
  • Most common AE at grades 3-4 for olaparib: anemia (11%)
  • All grades AE >30% for olaparib: Fatigue (60%), nausea (45%), abdominal pain (34%)
  • All grade diarrhea occurred at a rate of 29%
Prostate Cancer
Treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone (PROfound trial)
  • Reduced risk of disease progression or death by 66% (HR 0.34, p-value <0.0001)
  • Radiographic PFS median of 7.4 months vs. 3.6 months with enzalutamide or abiraterone in men with BRCA1/2 or ATM gene-mutated mCRPC
  • OS: olaparib 19.1 months vs placebo 14.7 months (p-value 0.0175)
  • Most common AE (Grade 1-4) occurring in ≥10% in the olaparib arm (N=256) were anemia (46%), nausea (41%), fatigue including asthenia (41%), decreased appetite (30%), diarrhea (21%), vomiting (18%), thrombocytopenia (12%), cough (11%) and dyspnea (10%)
  • Venous thromboembolic events, including pulmonary embolism occurred in 7% of patients with mCRPC who received olaparib plus androgen deprivation therapy (ADT) compared to 3.1% of patients receiving enzalutamide or abiraterone plus ADT

PFS – progression free survival; AEs – adverse events; ORR – objective response rates; DoR – duration of response

Based on current February 2020 ASCO Guidelines13:

  • Women diagnosed with epithelial ovarian cancer
    • Offer germline genetic testing for BRCA1/2 and other ovarian cancer susceptibility genes at time of diagnoses
    • Preform somatic tumor testing for BRCA1/2 and other likely pathogenic variants in women who are negative for a germline mutation
    • First/second-degree blood relatives with a known germline susceptible gene mutation/variant should be offered individualized genetic risk evaluation/counseling and genetic testing
    • Genetic evaluations can be conducted in conjunction with health care professionals including genetic counselors
Important notice: National Community Oncology Dispensing Association, Inc. (NCODA), has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional. This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented. NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.
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