LYNPARZA, Olaparib Form

Olaparib (Lynparza®) is a poly (ADP-ribose) polymerase (PARP) inhibitor.
FDA Approved Indication(s) Lynparza is indicated for:
• Maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum- based chemotherapy.
• Use in combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in 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: o a deleterious or suspected deleterious BRCA mutation, and/or o genomic instability • Maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm or sBRCAm recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy
• Adjuvant treatment of adult patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER-2)- negative high risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy. • Treatment of adult patients with deleterious or suspected deleterious gBRCAm, HER2- negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy.
• 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. • 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. • Use in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) mCRPC.

• Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza Page 1 of 12

  CLINICAL POLICY
  Olaparib Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
  It is the policy of health plans affiliated with Centene Corporation® that Lynparza is medically necessary when the following criteria are met:
  I. Initial Approval Criteria
  A. Ovarian Cancer (must meet all):

  1. Diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal cancer;
  2. Prescribed by or in consultation with an oncologist;
  3. Age ≥ 18 years;
  4. For brand Lynparza requests, member must use generic olaparib, if available, unless contraindicated or clinically significant adverse effects are experienced;
  5. Member meets one of the following (a, b, or c): a. Completed ≥ 2 platinum-based chemotherapy regimens and is in a complete or partial response; b. Both i and ii: i. Documentation of a deleterious or suspected deleterious germline or somatic BRCA mutation as confirmed on a CLIA approved diagnostic test (e.g., Foundation One CDx or BRAC Analysis CDx); ii. Completed a platinum-based chemotherapy regimen and is in a complete or partial response; c. Both i and ii: i. Disease is associated with HRD-positive status defined by one of the following (1 or 2): 1) Documentation of a deleterious or suspected deleterious BRCA mutation as confirmed on a CLIA approved diagnostic test (e.g., Foundation One CDx or BRAC Analysis CDx); 2) Documentation of genomic instability; ii. Both of the following (1 and 2): 1) Completed a bevacizumab- and platinum-based chemotherapy regimen as first-line therapy, and is in a complete or partial response (see Appendix B); 2) Lynparza is prescribed in combination with bevacizumab;
  6. Member has not previously received a PARP inhibitor (e.g., Rubraca®, Talzenna®, Zejula®);
  7. Request meets one of the following (a or b):
     a. Dose does not exceed any of the following (i or ii): i. 600 mg per day; ii. 4 tablets per day; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN
     Approval duration:
     Medicaid/HIM – 6 months Page 2 of 12

  CLINICAL POLICY
  Olaparib Commercial – 12 months or duration of request, whichever is less B. Breast Cancer (must meet all):

  1. Diagnosis of breast cancer;
  2. Prescribed by or in consultation with an oncologist;
  3. Age ≥ 18 years;
  4. For brand Lynparza requests, member must use generic olaparib, if available, unless contraindicated or clinically significant adverse effects are experienced;
  5. Disease has both of the following characteristics (a and b): a. Deleterious germline BRCA 1/2 mutations as confirmed on a CLIA approved diagnostic test (e.g., Foundation One CDx or BRAC Analysis CDx); b. High risk, metastatic or recurrent;
  6. Member has not previously received a PARP inhibitor (e.g., Rubraca, Talzenna, Zejula);
  7. Request meets one of the following (a or b): a. Dose does not exceed any of the following (i or ii): i. 600 mg per day; ii. 4 tablets per day; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN
     Approval duration:
     Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less C. Pancreatic Adenocarcinoma (must meet all):
  8. Diagnosis of pancreatic adenocarcinoma;
  9. Prescribed by or in consultation with an oncologist;
  10. Age ≥ 18 years;
  11. For brand Lynparza requests, member must use generic olaparib, if available, unless contraindicated or clinically significant adverse effects are experienced;
  12. Documentation of deleterious or suspected deleterious germline BRCA mutation as confirmed on a CLIA approved diagnostic test (e.g., Foundation One CDx or BRAC Analysis CDx);
  13. Received > 16 weeks of platinum-based chemotherapy with no disease progression;
  14. Member has not previously received a PARP inhibitor (e.g., Rubraca, Talzenna, Zejula);
  15. Request meets one of the following (a or b): a. Dose does not exceed any of the following (i or ii): i. 600 mg per day; ii. 4 tablets per day; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN
      Approval duration:
      Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less Page 3 of 12

  CLINICAL POLICY
  Olaparib D. Prostate Cancer (must meet all):

  1. Diagnosis of metastatic castration-resistant prostate cancer;
  2. Prescribed by or in consultation with an oncologist or urologist;
  3. Age ≥ 18 years;
  4. Documentation of a deleterious or suspected deleterious germline or somatic HRR gene mutation (including BRCA mutation) as confirmed on a CLIA approved diagnostic test (e.g., Foundation One CDx or BRAC Analysis CDx);
  5. One of the following (a or b): a. Member has BRCA mutation, and Lynparza is prescribed in combination with abiraterone (Zytiga®) and either prednisone or prednisolone; b. Both of the following (i and ii): i. Documentation of disease progression despite bilateral orchiectomy or other androgen deprivation therapy (ADT) (see Appendix D); ii. Failure of abiraterone (Zytiga) or Xtandi® (enzalutamide), unless clinically significant adverse effects are experienced or both are contraindicated;
  6. Member does not have a PPP2R2A gene mutation;
  7. For brand Lynparza requests, member must use generic olaparib, if available, unless contraindicated or clinically significant adverse effects are experienced;
  8. Member will use a gonadotropin-releasing hormone (GnRH) analog concurrently or has had a bilateral orchiectomy;
  9. Member has not previously received a PARP inhibitor (e.g., Rubraca, Talzenna, Zejula);
  10. Request meets one of the following (a or b): a. Dose does not exceed any of the following (i or ii): i. 600 mg per day; ii. 4 tablets per day; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN
      Approval duration:
      Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less E. Other diagnoses/indications (must meet 1 or 2):
  11. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or Page 4 of 12

  CLINICAL POLICY
  Olaparib

  2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
     II. Continued Therapy A. All Indications in Section I (must meet all):
  3. Currently receiving medication via Centene benefit or documentation supports that member is currently receiving Lynparza for a covered indication and has received this medication for at least 30 days;
  4. If request is for use in an adult member with deleterious or suspected deleterious gBRCAm advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy, provider attestation of acknowledgement for withdrawal of this indication due to risk of potential detrimental effect on overall survival (OS) in patients who used Lynparza (see Appendix E);
  5. Member is responding positively to therapy;
  6. For brand Lynparza requests, member must use generic olaparib, if available, unless contraindicated or clinically significant adverse effects are experienced;
  7. For HRD-positive ovarian cancer within the first 15 months of combination therapy with bevacizumab: Documentation of continued bevacizumab therapy, unless contraindications or clinically significant adverse effects to bevacizumab have developed;
  8. For adjuvant therapy in breast cancer, total duration of therapy does not exceed 1 year;
  9. If request is for a dose increase, request meets one of the following (a or b):
     a. New dose does not exceed any of the following (i or ii): i. 600 mg per day; ii. 4 tablets per day; b. New dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN
     Approval duration: Medicaid/HIM – 12 months Commercial – 12 months or duration of request, whichever is less B. Other diagnoses/indications (must meet 1 or 2):
  10. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: Page 5 of 12

  CLINICAL POLICY
  Olaparib CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

  2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
     III. Diagnoses/Indications for which coverage is NOT authorized:
     A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid, or evidence of coverage documents. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key ADP: adenosine diphosphate
     ADT: androgen deprivation therapy AML: acute myeloid leukemia
     BRCA: breast cancer gene FDA: Food and Drug Administration gBRCAm: mutations in the germline HRR: homologous recombination repair LHRH: luteinizing hormone-releasing hormone mCRPC: metastatic castration-resistant prostate cancer MDS: myelodysplastic syndrome NCCN: National Comprehensive Cancer BRCA genes Network GnRH: gonadotropin-releasing hormone HER: human epidermal growth factor receptor 2 HR: hormone receptor HRD: homologous recombination deficiency OS: overall survival PARP: poly (ADP-ribose) polymerase sBRCAm: mutations in the somatic BRCA genes Appendix B: Therapeutic Alternatives This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent and may require prior authorization.
     Drug Name Dosing Regimen Dose Limit/ Maximum Dose Ovarian Cancer Alimta® (pemetrexed) Alkeran® (melphalan) Avastin® (bevacizumab)
     carboplatin (Paraplatin®) cisplatin (Platinol-AQ®) cyclophosphamide (Cytoxan®) docetaxel (Taxotere®) doxorubicin (Doxil®, Adriamycin®) etoposide (Vepesid®) Various Various Various Various Various Various Various Various Various Varies Varies Varies Varies Varies Varies Varies Varies Varies Page 6 of 12

  CLINICAL POLICY
  Olaparib Drug Name Dosing Regimen Various Various Various Various Various Various Various Various gemcitabine (Gemzar®) ifosfamide (Ifex®) irinotecan (Camptosar®) oxaliplatin (Eloxatin®) topotecan (Hycamtin®) Hexalen® (altretamine) Pancreatic Adenocarcinoma FOLFIRINOX (leucovorin, fluorouracil, irinotecan, oxaliplatin) gemcitabine + cisplatin Prostate Cancer abiraterone (Zytiga®) + prednisone Xtandi® (enzalutamide) Dose Limit/ Maximum Dose Varies Varies Varies Varies Varies Varies Varies Varies Abiraterone 1,000 mg PO QD + prednisone 5 mg PO BID Xtandi 160 mg PO QD Abiraterone 1,000 mg/day + prednisone 10 mg/day; 2,000 mg/day if taking a strong CYP3A4 inducer 160 mg/day Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Appendix C: Contraindications/Boxed Warnings None reported Appendix D: General Information • Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) have been confirmed in patients treated with Lynparza. The majority of the cases (17 of 22) were fatal. If MDS/AML is confirmed, discontinue Lynparza. • The FDA approved Lynparza with a genetic test called BRACAnalysis CDx, a companion diagnostic that will detect the presence of gBRCAm in blood samples from patients with ovarian and breast cancer. Additional information is available at http://www.fda.gov/companiondiagnostics. • Lynparza is not indicated for patients with mCRPC with a PPP2R2A mutation due to an unfavorable risk-benefit profile for this mutation. • CRPC is prostate cancer that progresses clinically, radiographically, or biochemically despite castrate levels of serum testosterone (< 50 ng/dL). Per NCCN guidelines for the treatment of prostate cancer, ADT should be continued in the setting of CRPC while additional therapies are applied. • Examples of ADT include: o Bilateral orchiectomy (surgical castration) o Luteinizing hormone-releasing hormone (LHRH) given with or without an anti- androgen:  LHRH (or GnRH) agonists: Zoladex® (goserelin), Vantas® (histrelin), leuprolide (Lupron Depot®, Eligard®), and Trelstar® (triptorelin) Page 7 of 12

  CLINICAL POLICY
  Olaparib  Anti-androgens: bicalutamide (Casodex®), flutamide, nilutamide (Nilandron®), Xtandi (enzalutamide), Erleada® (apalutamide) o LHRH antagonist: Firmagon® (degarelix), Orgovyx® (relugolix) • There is insufficient data regarding the use of consecutive PARP inhibitors. Most PARP inhibitor pivotal trials excluded prior PARP inhibitor use, the NCCN does not make any explicit recommendations (other than for ovarian cancer, where they state data is limited), and there are no randomized controlled trials evaluating such use.
  • Per NCCN compendium and NCCN Ovarian Cancer Version 04.2023 Guidelines:
  o Single agent therapy for recurrent unresectable (local or regional) or stage IV (m1) human epidermal growth factor receptor 2 (HER2)-positive, BRCA 1/2 -germline mutated disease that is:  Hormone receptor-negative  Hormone receptor-positive Appendix E: Withdrawal of 4th-line gBRCAm Advanced Ovarian Cancer Indication • AstraZeneca Pharmaceuticals LP, manufacturer of Lynparza, voluntarily withdrew Lynparza’s FDA-approved indication for treatment of adult patients with deleterious or suspected deleterious gBRCAm advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy after a post-market subgroup analysis indicated potential detrimental effect on OS in patients who used Lynparza. • This withdrawal is based on a recent subgroup analysis that indicated a potential detrimental effect on OS for Lynparza compared to the chemotherapy control arm in the subgroup of patients who had received three or more prior lines of chemotherapy corresponding to the current scope of the treatment indication for Lynparza in the randomized Phase 3 study, SOLO3 (NCT02282020). o SOLO3 was requested by the FDA to confirm the clinical benefit of Lynparza in the above indication.
  o SOLO3 is a Phase 3, open-label, randomized, controlled, multi-center study to assess the efficacy and safety of a single agent Lynparza vs. standard of care, based on physician’s choice of single agent chemotherapy.
  o The final OS analysis occurred in 2021 and there was an imbalance in favor of the control arm for the subgroup of patients treated with 3 or more prior lines of chemotherapy (HR: 1.33).
  o The final OS results were not statistically significant for the subgroup of patients treated with 2 or more prior lines of chemotherapy [1.07 (0.76, 1.49)] or for the subgroup of patients treated with 3 or more prior lines of chemotherapy [1.33 (0.84, 2.18)]. • Physicians should not initiate new treatment with Lynparza in the treatment indication of adult patients with deleterious or suspected deleterious gBRCAm advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Physicians who are currently treating patients with Lynparza for this indication should share this information with their patients so that they can both make an informed decision about their ongoing care. Page 8 of 12

  CLINICAL POLICY
  Olaparib V. Dosage and Administration
  Indication Dosing Regimen Breast, ovarian, pancreatic, prostate cancers 300 mg PO BID Maximum Dose 600 mg/day VI. Product Availability
  Tablets: 100 mg, 150 mg VII.