Written by: Katie Carter, PharmD, BCPS, Indiana University Health
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Olaparib (Lynparza) 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

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.

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 22% 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 (Full indication list in Supplemental Information)

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 The capsules were discontinued as of 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
  • Storage: Olaparib should be stored at room temperature and protected from moisture
  • Handling: though not on the NIOSH list, Olaparib is considered hazardous due to its toxicity profile. Appropriate handling should be advised.
  • 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: www.MyAccess360.com

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. To view the most recent and complete version of the guideline, go online to NCCN.org.
  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)·  PFS results (p-value <0.0001): olaparib vs placebo: NR vs 13.8 months

·  70% lower risk of disease progression or death with olaparib than with placebo.

·  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
·  Adverse reactions (Grade 1-4) occurring in ≥10% of patients treated with olaparib/bevacizumab in PAOLA-1 and at ≥5% frequency compared with the placebo/bevacizumab arm were nausea (53%), fatigue (including asthenia) (53%), anemia (41%), lymphopenia (24%), vomiting (22%), and leukopenia (18%).

·  Most common adverse reactions (≥10%) for patients receiving olaparib/bevacizumab were 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 (SOLO-2 trial)·  PFS (p-value <0.0001): olaparib vs placebo: 19.1 months vs 5.5 months·  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

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, intestinal obstruction, and pleural effusion
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 (p-value 0.0009):

·  Olaparib vs chemotherapy: 7 months vs 4.2 months

·  Rate of grade 3 or higher AEs was lower with olaparib (36.6%) vs chemotherapy (50.5%)

·  AEs that occurred more frequently in the olaparib group: 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 (p-value 0.0035): olaparib vs. placebo: median 7.4 months vs. 3.8 months

·  ORR: 23% in olaparib arm (12% in placebo arm)

·  Most common AE at grades 3-4 for olaparib: anemia (11%)

·  All grades AE that were >30%: Fatigue (60%), Nausea (45%), Abdominal pain (34%)

·  All grade Diarrhea at 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 maiden of 7.4 months vs. 3.6 months with enzalutamide or abiraterone in men with BRCA1/2 or ATM gene-mutated mCRPC

·  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%).1

·  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
    • First or second-degree blood relatives with a known germline susceptible gene mutation or variant
      • Should be offered individualized genetic risk evaluation/counseling and genetic testing
    • Genetic evaluations can be conducted in conjunction with HCPs 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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Written by: Yonatan Resnick, PharmD, New England Cancer Specialists
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This PQI will discuss the development and rationale of the oral DNMT/CDA inhibitor for the management of intermediate-1, intermediate-2, and high-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).

Background

INQOVI® is a fixed-dose combination of the hypomethylating agent decitabine and the cytidine deaminase inhibitor cedazuridine, which prevents degradation of decitabine in the gastrointestinal tract and liver and enables its absorption via oral dosing. The therapy was approved in July 2020.6 It is indicated for the treatment of adult patients with MDS, including previously treated and untreated, de novo and secondary MDS with the following French American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and CMML and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups).  It has long been noted that the development of an oral DNMT inhibitor would alleviate much of the burden associated with the treatment of MDS/CMML for those patients on IV DNMT inhibitors.  Specifically, an oral option would decrease clinic visits, reduce travel time associated with treatment, reduce the need for IV access and the associated infection risks, and decrease exposures to the health care system.

Published data of the phase 1/2 trial as well as preliminary data of the phase 3 trial demonstrates the safety and efficacy of the administration of decitabine plus cedazuridine, administered orally.1,3

PQI Process:

  • Utilize the reporting tools available in your EMR to identify patients who are receiving IV decitabine for MDS or CMML and discuss the option of converting them to oral decitabine/cedazuridine with their physician.
    • Inclusion of therapy alteration: Do NOT substitute INQOVI® for an intravenous decitabine product within a
    • Confirm diagnosis and dosing strategy
  • Educate providers on the availability of a new formulation of decitabine to administer to patients as an alternative to traveling to the clinic for 5 consecutive days for IV infusion.
    • Note feasibility and change of clinic visits
  • Educate the providers in your practice on the rationale behind the approval of INQOVI® using the following data:
    • Phase 3 Study (ASCERTAIN study): Presented at ASH 2019 – Compared oral decitabine/cedazuridine (DEC-C) to IV decitabine.
      • 138 MDS intermediate or MDS high risk or CMML patients randomized to receive sequence A (DEC-C35/100mg daily x 5 days or IV decitabine 20mg/m2 daily x 5 days) or sequence B (IV decitabine 20mg/m2 daily x 5 days or DEC-C- (35/100mg) daily x 5 days). All patients then received DEC-C on cycles 3 and onward.
      • 5 day oral:IV AUC ratio was 99% demonstrating equivalent systemic exposure of the two formulations.
      • LINE 1 demethylation is a PD marker and the difference between IV and PO was < 1%, confirming the PK findings.
      • Overall response rate of 65% (complete response + partial response + marrow CR + hematologic improvement) is in line with what is seen with conventionally dosed IV decitabine.
      • Transfusion independence noted in 50% of patients in phase 2 trial and 32.7% of patients in phase 3 trial.
      • No differences were noted in any common side effects between the IV and PO formulations.

Upon receiving a prescription for INQOVI®:

  • Recommended dosage of is 1 tablet (containing 35 mg decitabine and 100 mg cedazuridine) orally once daily on days 1 through 5 of each 28-day cycle for a minimum of 4 cycles until disease progression or unacceptable toxicity.
    • A complete or partial response may take longer than 4 cycles.
  • Obtain complete blood cell counts and comprehensive metabolic panel prior to initiating therapy and before each cycle.
    • Delay the next cycle if absolute neutrophil count (ANC) is less than 1,000/µL and platelets are less than 50,000/µL in the absence of active disease. Monitor complete blood cell counts until ANC is 1,000/µL or greater and platelets are 50,000/µL or greater
    • If hematologic recovery occurs (ANC at least 1,000/µL and platelets at least 50,000/µL) within 2 weeks of achieving remission, continue at the same dose.
    • If hematologic recovery does not occur (ANC at least 1,000/µL and platelets at least 50,000/µL) within 2 weeks of achieving remission
      • Delay therapy for up to 2 additional weeks AND resume at a reduced dose by administering on Days 1 through 4. Consider further dose reductions if myelosuppression persists after a dose reduction.
      • Maintain or increase dose in subsequent cycles as clinically indicated.
      • Recommended dose reductions for myelosuppression
        • First dose reduction: 1 tablet orally once daily on Days 1 through 4
        • Second dose reduction: 1 tablet orally once daily on Days 1 through 3
        • Third dose reduction: 1 tablet orally once daily on Days 1, 3 and 5
      • Serum bilirubin or AST/ALT ≥ 2x ULN
        • Delay next cycle and resume at same or reduced dose upon resolution

Patient Centered Activities:

  • Educate patient on schedule of administration: 5 consecutive days every 4 weeks
    • Consider Monday-Friday (Days 1-5) when defining proper schedule
  • Educate patient not to consume food 2 hours before and 2 hours after each dose.
  • Discuss with patient the infectious risks associated with bone marrow suppression and how to mitigate those risks
    • g. avoiding sick contacts, prompt recognition and reporting of fever, signs and symptoms of bleeding/bruising, feelings of excessive fatigue.
  • Educate the patient on when to contact the care team
    • Fever of 100.4 (38 degrees Celsius)
    • Nausea, vomiting
      • Ensure that patient has adequate anti-nausea medication at home including at least two different medications with different mechanisms of action which can be alternated if one agent does not sufficiently control nausea symptoms.
    • Unusual bleeding
    • Black/tarry stools
    • Bloody urine
    • Painful mouth sores
  • Discuss the management (dietary/lifestyle/pharmacologic management) of both constipation and diarrhea which can occur with treatment
  • Monitor lab values before each cycle, focusing on neutropenia
  • Educate patient to avoid taking over the counter medication that can excessively thin blood (acetylsalicylic acid[Aspirin], NSAIDS).

References:

  1. Savona, et al. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1   Lancet Haematol 2019; 6: e194-203
  2. Garcia-Manero, et al. Oral Cedazuridine/decitabine: a phase 2, pharmacokinetic/pharmacodynamic, randomized, crossover study in MDS and CMML. Blood April Epub ahead of print.
  3. Garcia-Manero, et al. Pharmacokinetic Exposure Equivalence and Preliminary Efficacy and Safety from a Randomized Cross-Over Phase 3 Study (ASCERTAIN) of an Oral Hypomethylating Agent ASTX727 (cedazuridine/decitabine) Compared to IV Decitabine. 61st ASH Annual Meeting, Orlando, FL. Dec 7-10, 2019. Abstract #846.
  4. Aster et al. UpToDate. Clinical manifestations and diagnosis of myelodysplastic syndrome (MDS). Apr, 2020.
  5. Decitabine drug monograph.
  6. Inqovi® (decitabine and cedazuridine) [prescribing information]. Princeton, NJ: Taiho Oncology; July 2020.
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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Written by: Alyson Leonard, PharmD, BCPS,BCOP Cone Health
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Cabazitaxel is indicated for treatment of patients with metastatic castration-resistant prostate (mCRPC) cancer previously treated with a docetaxel-containing treatment regimen in combination with prednisone.1 The purpose of this PQI is to provide guidance for initiating cabazitaxel.

Continue reading Cabazitaxel (Jevtana) for patients with metastatic castration-resistant prostate cancer

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Written by: Jon Suyko Pharm.D., BCPS UCHealth Highlands Ranch
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The purpose of this PQI is to discuss the option of using isatuximab-irfc (Sarclisa®) for multiple myeloma patients who have been refractory to two prior treatment therapies including treatment with lenalidomide and a protease inhibitor.

Continue reading Isatuximab-irfc in Patients with Relapsed Refractory Multiple Myeloma

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