Professor of Medicine Harvard Medical School Boston MA Update on PARP inhibitors Ursula Matulonis, M.D. Chief, Division of Gynecologic Oncology Brock-Wilson Family Chair Dana-Farber Cancer Institute
History of PARP inhibitor development
Single agent olaparib has activity in gbrcam ovarian cancer Audeh et al, Lancet 2010 NCT00494442
3 Randomized phase 2 studies were started: Doxil versus olaparib 200 mg or 400 mg BID for recurrent germline + BRCA ovarian cancer Results: no differences in RR or PFS for the 3 groups (Kaye et al, JCO 2012) Carboplatin/paclitaxel/olaparib vs Carbo/paclitaxel alone for platinum sensitive recurrent ovarian cancer Results: improved PFS for triplet; best results for BRCA+ cancers (Oza et al, JCO 2015) Maintenance olaparib versus placebo in pts with platinum sensitive recurrent ovarian cancer Results: Better PFS for olaparib in ITT (Ledermann et al, NEJM 2012)
History of PARP inhibitors 2011: Astrazeneca decides to halt development of olaparib as a maintenance therapy for ovarian cancer 2012: Study 19 NEJM paper published 2014: Lancet Oncology paper published showing improved length of remission benefit of olaparib-treated women with BRCAm+ compared to BRCAwt patients (preplanned retrospective analysis)
2012 2014
History of PARP inhibitors 2011: Astrazeneca decides to halt development of olaparib as a maintenance therapy for ovarian cancer 2012: Study 19 NEJM paper published 2014: Lancet Oncology paper published showing improved length of remission benefit of olaparib-treated women with BRCAm+ compared to BRCAwt patients (preplanned retrospective analysis) June 2014: US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) voted 11 to 2 that current evidence from clinical studies does not support an accelerated approval for use of olaparib as a maintenance treatment for women with platinum-sensitive relapsed ovarian cancer who have the germline BRCA (gbrca) mutation, and who are in complete or partial response to platinum-based chemotherapy. December 2014: Olaparib wins FDA approval for ovarian cancer based on single agent data 2017: niraparib receives FDA approval for maintenance therapy
PARP Inhibitors: Dose/Schedule and Current Regulatory Approvals 1 PARP Dosage FDA Approvals Inhibitor Olaparib (Lynparza) Rucaparib (Rubraca) Niraparib (zejula) 300 mg twice daily (tablet formation) 1) Treatment of germline BRCAm ovarian cancer in patients who have received 3 lines of treatment (December 2014) 2) Maintenance in patients with recurrent ovarian cancer 1 who are in complete or partial response to platinum-based chemotherapy, regardless of tumor BRCA status or histology (August 2017) 600 mg twice daily 1) Treatment of BRCAm (either germline or somatic) ovarian cancer in patients who have received 2 lines of treatment (December 2016) 2) Maintenance in patients with recurrent ovarian cancer 1 who are in complete or partial response to platinum-based chemotherapy, regardless of tumor BRCA status and histology (March 2017) 300 mg once per day* *patients who weigh <77 kg or have baseline platelet counts of <150k should consider using 200 mg starting dose 2,3 Maintenance in patients with recurrent ovarian cancer 1 who are in complete or partial response to platinum-based chemotherapy, regardless of tumor BRCA status and histology (March 2017) 1. Matulonis UA. 2018. 2. Moore et al. Gyn Onc. 2018.. 3. Berek et al, Ann of Onc 2018.
All 3 studies showed remarkably similar results, and all showed an improvement in how long the cancer stays in remission for after chemotherapy compared to placebo NOVA NEJM 2016 SOLO 2 Lancet Onc 2017 ARIEL3 Lancet 2017 3 PARP inhibitor maintenance studies NOVA (niraparib = Zejula) SOLO2 (olaparib = Lynparza) ARIEL3 (rucaparib = rubraca) All 3 were phase 3 studies, randomized and placebo controlled; treatment was started AFTER completion of platinum-based chemotherapy
PARP Enzyme Required to Repair Single Strand DNA Breaks PARP Single strand breaks Normal Cell Repair by base excision repair PARP = poly (ADP ribose) polymerase
Homologous Recombination Repairs Double Strand DNA Breaks Double strand breaks Normal Cell Repair by Homologous Recombination
PARP inhibitors need 2 abnormal genetic events to work PARP inhibitor PARP Increase in double strand breaks Single strand breaks Double strand breaks gbrcam Cancer Cell Cell Death Non functioning BRCA protein and abnormal DNA repair
Differences in Metabolism and Drug Drug Interactions Exist Among PARP Inhibitors Each drug is metabolized differently Other drugs being taken may influence PARPi levels Drug-drug interactions can occur based on CYP inhibition or induction Effect on renal transporter proteins MATE1 and MATE2-K can increase serum creatinine (exception is niraparib) PARP Inhibitor CYP Enzymes Used for Metabolism Drug Drug Interactions Effect on Cell Transporters Niraparib 1 Carboxylesterases (non-cyp) Can induce CYP1A2 (weak) No interaction with the major hepatic or renal uptake transporters Inhibits BCRP (weak) Substrate of P- glycoprotein and BCRP Olaparib 1 CYP3A4 Reduce dosage if strong or moderate CYP3A inhibitors are co-administered Inhibits CYP3A4 and induces CYP2B6 Inhibits MDR1, BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1, MATE2-K Substrate of P- glycoprotein Rucaparib 1 1. FDA Prescribing Information.. CYP2D6 (predominant) CYP1A2 and CYP3A4 (lesser extent) Reversibly inhibits CYP1A2, CYP2C19, CYP2C9, CYP3A and induces CYP1A2 Inhibits MATE1 and MATE2-K, OCT1 Substrate of P- glycoprotein
PARP inhibitor side effects Gastrointestinal toxicities include: Nausea Vomiting Decreased appetite Diarrhea Constipation Abdominal pain Upset stomach Taste changes Bone marrow suppression: Drop in RBC, WBC, platelets, and small risk ~1-2% risk of AML and/or MDS *higher risk of grade 3 and 4 thrombocytopenia with niraparib (300 mg dose) but this is mitigated by starting at the 200 mg dose for weight <77kg or platelet count <150 Fatigue Hypertension, tachycardia, palpitations (niraparib) Liver function test elevations, cholesterol rise (rucaparib) Serum creatinine elevation (olaparib, rucaparib) Pneumonitis, increased risks of infections/infestations (olaparib) FDA PI for niraparib, olaparib and rucaparib SGO 2018 Berek et al, Ann Onc 2018
Addressing PARP Inhibitor-Associated Adverse Events Side effects are generally mild-moderate 1 Common side effects include anemia, fatigue, nausea, and vomiting Frequently occur during early stage of treatment and then get better over 4-6 weeks Often transient and do not require PARPi discontinuation Fatigue requires assessment for other underlying causes 2 Screen for fatigue should occur Moderate or worse fatigue may require pharmacologic/nonpharmacologic intervention Dose modification/interruption may be necessary Matulonis U, et al. 2015 ASCO Annual Meeting. Abstract 5550. Moore KN, Monk BJ. Oncologist. 2016;21(8):954-963.
Challenge: Price of PARP Inhibitors Insurance coverage, household income, pharma support, etc Value-Based Benchmark Prices per Month of Ovarian Cancer Treatment, by Population Drug Name WAC per Month Net Price per Month* Recurrent BRCA-Mutated Population Olaparib $13,679 $12,310 Rucaparib $13,940 $12,546 Maintenance Therapy for Platinum-Sensitive Disease Olaparib $13,679 $12,310 Niraparib $14,965 $13,468 Rucaparib $13,940 $12,546 *Assumed 10% discounted price. WAC indicates wholesale acquisition cost. Hopeful outcome: Access a PARP inhibitor that is affordable Adapted from ICER Final Report 2017 accessed from www.icer-review.org
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