Learning Objectives. Page 1

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1 Learning Objectives 1) Analyze the main signaling pathways and key mechanisms in DNA damage repair and how deficiencies in these pathways can lead to tumor proliferation and growth. 2) Examine the pharmacology of PARP inhibitors and how these agents induce tumor cell death by exploiting the concept of synthetic lethality in cells with BRCA mutations. 3) Explore the evolving data regarding the efficacy and adverse event profiles of PARP inhibitors currently approved and in clinical development for patients with ovarian, breast, prostate, and pancreatic cancers. 4) Using a case based approach, assess challenging questions regarding PARP inhibitors and discuss the ways that the oncology pharmacist can optimize therapy, anticipate adverse effects, and improve adherence. Page 1

2 Disclaimer This slide deck in its original and unaltered format is for educational purposes and is current for the date of this live symposium. All materials contained herein reflect the views of the faculty, and not those of Creative Educational Concepts, Inc. or the commercial supporter(s). Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for specific patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient s conditions and possible contraindications on dangers in use, review or any applicable manufacturer s product information, and comparison with recommendations of other authorities. Usage Rights: This slide deck is provided for educational purposes and individual slides may be used for personal, non commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published or distributed in print or electronic format without prior written permission from Creative Educational Concepts, Inc. Additional terms and conditions may apply. Evading DNA Damage Response: A Key to Tumor Growth James M. Ford, MD, FASCO Professor of Medicine/Oncology and Genetics Director, Clinical Cancer Genomics Stanford University School of Medicine Page 2

3 Outline DNA repair in tumorigenesis Major DNA repair pathways Chemical synthetic lethality Opportunities for therapeutics and biomarker discovery Targeting the Hallmarks of Cancer Hanahan D, Weinberg RA. Cell Page 3

4 Ford JM, Kastan MB. Abeloff s Clinical Oncology. 5 th ed DNA Double Strand Break Repair Pathways Ford JM, Kastan MB. Abeloff s Clinical Oncology. 5 th ed Page 4

5 DNA Excision Repair Pathways Ford JM, Kastan MB. Abeloff s Clinical Oncology. 5 th ed Targeting DNA Repair: DNA Repair Defects DNA Repair DNA Damage Page 5

6 Targeting DNA Repair: DNA Repair Inhibitor DNA Repair DNA Repair Inhibitor Targeting DNA Repair: DNA Damage Sensitizer DNA Repair Inhibitor DNA Damage DNA Repair Page 6

7 Targeting DNA Repair: Pathway Dependence DNA Repair Targeting DNA Repair: Chemical Synthetic Lethality DNA Repair DNA Repair Inhibitor Page 7

8 DNA Repair Pathways in a BRCA Mutation Carrier Normal Cells Endogenous DNA damage BRCA1/2 +/ PARP DNA Repair Cell Viability DNA Repair Defects in BRCA Associated Tumors Tumor Cells DNA damage BRCA1/2 +/ PARP DNA Repair Cell Viability Page 8

9 Chemical Synthetic Lethality Tumor Cells DNA damage BRCA1/2 / PARP PARP Inhibitor Cell Death Sensitivity to PARP Inhibition in BRCA1/2 Mutant Cells BRCA2 / BRCA2 / BRCA1 / BRCA1/2 deficient cells are markedly sensitive to PARP inhibitors 11CO=BRCA1 wild type; D3=BRCA2 wild type; Cre6/Cre15=heterozygous ES cells; Cre10/Cre24=deficient ES cells Farmer H, et al. Nature. 2005; Bryant HE, et al. Nature Page 9

10 Targeting DNA Repair: Synergy DNA Repair DNA Damage DNA Repair Inhibitor Two Primary Clinical Strategies for Targeting PARP in Cancer Sensitization to DNA Damaging Therapy Chemical Synthetic Lethality in Genetically Susceptible Tumors PARPi, Gemcitabine + Carboplatin in Triple Negative Breast Cancer PARPi in BRCA+ Breast & Ovarian CA Telli ML, Ford JM. Clin Breast Cancer Page 10

11 Moderate Penetrance: Fanconi Pathway A B C E F G L M I D2 Homologous recombination Biallelic BRCA2 mutations (FA) Breast cancer risk, 2 3 fold: ATM BARD1 BRIP1 CHEK2 MRE11A NBN (NBS1) PALB2 RAD50 RAD51C Other FA genes Ovarian cancer risk: RAD51C RAD51D (6 fold) Other FA genes Pennington et al, Gynecol Oncol 2012 Pennington KP, et al. Gynecol Oncol Potential Indications for PARP Inhibitors Breast and Ovarian Cancer Prostate Cancer Colorectal Cancer Pancreatic Cancer Leukemia/Lymphomas Lung, Bladder, others Prevention in BRCA carriers Page 11

12 Clinical PARPi Synthetic Lethality: Challenges Breast Pancreatic Prostate Ovarian Substantial fraction of BRCA1m, BRCA2m and BRCAness Approvals in ovarian cancer Breakthrough status in prostate cancer (To PARP) PFS improvement in gbrcam breast (OlympiAD) Clinical trials on going in pancreatic cancer and others Mechanism of Drug Resistance? How to delay resistance? How to treat resistant disease? How to use drug combinations with PARPi? What are the predictive biomarkers of combination therapy? Lord CJ, Ashworth A. Science. 2017; Robson M, et al. N Engl J Med Exploiting Combinations to Enhance Responses? Platinum salts GEM Top1 poisons Top2i/poisons Radiation CHK1/2i CDKi METi PARP TMZ Taxanes EGFRi VEGFR1i HDACi PI3K/mTORi HSP90i Trastuzumab Anti endocrine Accumulation of DNA damage PARP dependency for repair PARP1 trapping Induce BRCAness phenotype Adapted from Dréan A, et al. Crit Rev Oncol Hematol Page 12

13 Clinical Resistance to PARP Inhibition Through BRCA Reversion Afghahi A, et al. Clin Cancer Res Mutation frequencies in human CRC Non silent Silent The Cancer Genome Atlas Network. Nature Page 13

14 Germline Tumor Causation Crosstalk Between the DDR and Immune System: Mutational Burden and Neo epitopes Mutational Burden: A Molecular Determinant of Response Highest prevalence of somatic mutations Highest benefit from immune checkpoint inhibitors Alexandrov LB, et al. Nature Page 14

15 Ongoing Studies DDRi Target ICB Target Phase Tumor Type Olaparib PARP1/2 Tremelimumab CTLA 4 I/II BRCA mut OC Veliparib PARP1/2 Atezolizumab PD L1 II BRCA mut TNBC Olaparib PARP1/2 Durvalumab PD L1 I/II SCLC BRCA mut OC BRCA mut BC Gastric cancer Niraparib PARP1/2 Pembrolizumab PD 1 I/II TBNC OC BGB 290 PARP1/2 BGB A317 PD 1 I Solid tumors Olaparib PARP1/2 Tremelimumab + CTLA 4 I/II BRCA mut OC durvalumab + PD L1 AZD6738 ATR Durvalumab PD L1 I/II Solid tumors PARP Inhibitors: A New Frontier in Cancer Therapy Judith A. Smith, PharmD, BCOP, CPHQ, FCCP, FISOPP Associate Professor and Director of Women s Health Integrative Medicine Research Program Department of Obstetrics, Gynecology, and Reproductive Sciences Division of Gynecologic Oncology UT Health Sciences Center at Houston Medical School Page 15

16 Synthetic Lethality Concept was first described in 1922 by Bridges and colleagues Dobzhansky and colleagues labeled the concept synthetic lethality in 1946 What is synthetic lethality? When two non lethal mutations occurring individually have no effect BUT when combined/occurring at the same time will lead to cell death Cancer research application identify single mutation present in cancer cells but not in normal cells, then inhibit the partner gene/enzyme/compensatory mechanism Bridges CB. Amer Nat. 1922; Dobzhansky T. Genetics BRCA1/2 Genes Tumor suppressor genes Function is to repair double stranded DNA breaks via homologous repair Germline (inherited, detected in all cells) or somatic (tumor) mutation in BRCA1/2 allele Compensated by wild type allele; double stranded break repair function is maintained Loss of heterozygosity (LOH) Occurs if there is loss of the wild type allele = ineffective homologous repair pathway Ashworth A. J Clin Oncol. 2008; Inglehart JD, Silver DP. N Engl J Med Page 16

17 Mechanism of PARP in Cell Growth Poly(adenosine diphosphate ribose) polymerase (PARP) proteins play essential part in the repair of single strand DNA breaks, through the base excision repair (BER) pathway (PARP1) Inhibition of PARP1 Accumulation of single strand unrepaired breaks leads to Stalling and collapse of DNA replication fork Double strand DNA breaks that need homologous repair lead to genomic instability and then to CELL DEATH Patel AG, et al. Proc Natl Acad Sci USA Olaparib December 19, 2014 FDA granted accelerated approval to olaparib for treatment of advanced ovarian cancer associated with defective germline BRCA genes, as detected by an FDA approved test, for patients who have received three or more prior chemotherapy treatments Approval based on study by Kaufman and colleagues Kaufman B, et al. J Clin Oncol. 2015; Jones P, et al. J Med Chem Page 17

18 Olaparib Phase II study enrolled 298 patients with germline BRCA1/2 mutations, including ovarian, breast, pancreatic, and prostate cancers Well tolerated Common ADRs: fatigue, N/V >Grade 3: anemia (17%) Tumor Response (CR/PR/SD), n (%) Progression/ unevaluable (%) Ovarian (n=193) 138 (71.5) 55 (28.5) Breast (n=62) 37 (59.7) 25 (40.3) Pancreatic (n=23) 13 (56.5) 10 (43.5) Prostate (n=8) 6 (75) 2 (25) PFS Ovarian (median, 7.0 months) Breast (median, 3.7 months) Pancreas (median, 4.6 months) Prostate (median, 7.2 months) Prostate Pancreas Ovarian Breast Time From First Dose (months) Kaufman B, et al. J Clin Oncol Olaparib in the Maintenance Setting August 2017 FDA granted approval to olaparib for the maintenance treatment of advanced ovarian cancer who are in complete or partial response to platinum based chemotherapy regardless of BRCA mutation status In addition, olaparib tablets were introduced and approved for use with both FDAapproved indications at the same dose Olaparib 150 mg tablets ARE NOT interchangeable with olaparib 50 mg capsules Approval based on data from the SOLO2 and Study 19 trials SOLO2 (N=295) Randomized phase III study of recurrent platinumsensitive serous ovarian cancer Germline BRCA1/2 300 mg twice daily (tablets) Study 19 (N=265) Randomized phase II study of platinum sensitive, relapsed serous ovarian cancer BRCA mut and BRCA wild type 400 mg twice daily (capsules) Pujade Lauraine E, et al. Lancet Oncol. 2017; Gourley C, et al. ASCO Abstract Page 18

19 Study 19 Olaparib Maintenance PFS Progression free survival (PFS) 8.4 months with olaparib vs 4.8 months with placebo HR=0.35 (95% CI: ) P<0.001 Adverse drug reactions higher in olaparib group Nausea (68% vs 35%) Fatigue (49% vs 38%) Vomiting (32% vs 14%) Anemia (17% vs 5%) Ledermann J, et al. N Engl J Med Study 19 Overall Survival Olaparib 400 mg BID Placebo OS advantage suggested, although criterion for statistical significance was not met because of the alpha spending approach used Maintenance therapy with olaparib provides a clinically significant, longterm treatment benefit to ovarian cancer patients, irrespective of BRCAm status Gourley C, et al. ASCO Abstract Page 19

20 SOLO2/ENGOT Ov21 Olaparib Maintenance Therapy Multicenter, randomized, double blind, placebo controlled phase III trial 295 platinum sensitive, relapsed ovarian cancer patients with BRCA1/2 mutation who had received 2 lines of previous chemotherapy Olaparib 300 mg tablets BID (n=136) Placebo (n=99) Results PFS=19.1 months compared to 5.5 months with placebo; HR=0.30 (95% CI: ) P< Adverse effects Grade 3 Anemia (19%), fatigue/asthenia (4%), neutropenia (5%) Olaparib tablet maintenance treatment provided a significant improvement in PFS with no impact on quality of life Pujade Lauraine E, et al. Lancet Oncol Rucaparib December 19, 2016 FDA granted approval to rucaparib as monotherapy treatment of patients with deleterious BRCA mutated (germline and/or somatic detected by FDAapproved companion diagnostic) ovarian cancer who have been treated with >2 chemotherapies Approval based on Study 10 and ARIEL2 trials Assessment of Rucaparib In Ovarian CancErTriaL (ARIEL) ARIEL2 (phase II): aimed to identify patients more likely to respond to PARP inhibitor using tumor genetic analysis ARIEL3 (phase III): is a randomized, double blind, placebocontrolled study of rucaparib vs placebo Jones P, et al. J Med Chem. 2015; Page 20

21 204 patients treated with rucaparib Stratified by: BRCA mutation (BCRA mut ) BRCA wild type/loss of heterozygosity high (BRCA wt /LOH high ) BRCA wild type/loss of heterozygosity low (BRCA wt /LOH low ) Study Endpoints Progression free survival Overall response rate Response Evaluation Criteria in Solid Tumors (RECIST) RECIST and/or Cancer Antigen 125 (CA 125) Duration of response Safety Pharmacokinetics ARIEL2 Study Rucaparib Treatment: Rucaparib 600 mg BID Swisher EM, et al. Lancet Oncol ARIEL2 Study Rucaparib Patient Distribution Based on Tumor Molecular Testing (N=204) BRCA mut 20% BRCA wt /LOH high 40% HRD Subgroup Median PFS, mo (90% CI) Overall Response Rate, % (n) RECIST RECIST + CA 125 BRCAmut 12.8 (9 14.7) 80% (32) 85% (34) BRCA like (BRCA wt /LOH high ) 5.7 ( ) 29% (24) 44% (36) Biomarker Negative (BRCA wt /LOH low ) 5.2 ( ) 10% (7) 20% (14) BRCA wt /LOH low 34% Unclassified 6% Swisher EM, et al. Lancet Oncol Page 21

22 ARIEL2 Study PFS by Tumor Molecular Testing BRCA mutant BRCA wild type/loh high BRCA wild type/loh low Swisher EM, et al. Lancet Oncol ARIEL3 Study Rucaparib Multicenter, randomized, double blind, placebo controlled trial 564 platinum sensitive, high grade serous relapsed ovarian cancer patients who have had >2 prior platinum based chemotherapy regimens with complete or partial response Randomized 2:1 nested cohorts based on: BRCA1/2 mutation, homologous recombination deficiency (HRD), or no mutations and platinum free interval Rucaparib 600 mg BID (n=375) Placebo (n=189) Primary outcome was investigator assessed PFS Independent radiological review was also completed Coleman RL, et al. Lancet Page 22

23 ARIEL3 Study Rucaparib for Maintenance Rucaparib had significant improvement in PFS BRCA Mutant: 16.6 months (vs 5.4 months placebo) LOH: 13.6 months (vs 5.4 months placebo) Intent to treat (included those with no mutation): 10.8 months (vs 5.4 months placebo) Investigator analysis more conservative than independent review Independent review more favorable PFS Adverse effects >Grade 3: Anemia (19%), transient elevations in AST/ALT (10%) Rucaparib tablet maintenance treatment provided significant improvement in PFS in patients with platinum sensitive ovarian cancer Progression free Survival (%) No at risk (censored) Rucaparib Placebo Investigator Intent to treat PFS Months 375 (0) 189 (0) 228 (36) 63 (12) HR 0.36 (95% CI ); P< (61) 13 (16) Rucaparib Placebo (93) 26 (123) 5 (136) 7 (18) 2 (20) 1 (21) 0 (141) 0 (22) Coleman RL, et al. Lancet Niraparib March 27, 2017 Approved by the FDA for maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum based chemotherapy regardless of BRCA mutation status Approval based on the ENGOT OV16/NOVA phase III study Jones P, et al. J Med Chem. 2015; Page 23

24 ENGOT OV16/NOVA Study Niraparib Phase III study Randomized 2:1 maintenance niraparib 300 mg PO once daily or placebo Categorized presence or absence of a germline BRCA mutation or HRD status 553 patients enrolled 203 with BRCA germline mutation 350 without BRCA mutation Primary endpoint: PFS Niraparib longer PFS compared to placebo gbrca cohort: 21 months vs 5.5 months Non BRCA mutation with HRD status: 12.9 months vs 3.8 months Most common >Grade 3 adverse effects: Thrombocytopenia (33.8%), anemia (25.3%), neutropenia (19.6%) Mirza MR, et al. N Engl J Med ENGOT OV16/NOVA Study PFS in gbrca Mirza MR, et al. N Engl J Med Page 24

25 ENGOT OV16/NOVA Study Niraparib PFS in non gbrca with or without HRD Status No Germline BRCA Mutation with HRD Positivity No Germline BRCA Mutation Mirza MR, et al. N Engl J Med FDA Approved PARP Inhibitors Olaparib Rucaparib FDA Indication(s) Fourth line treatment in patients with advanced ovarian cancer with germline BRCA1/2 mutations (as detected by an FDAapproved companion diagnostic test) Maintenance treatment in patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum based chemotherapy Third line treatment in patients with advanced ovarian cancer with germline or somatic BRCA1/2 mutations (based on an FDA approved companion diagnostic test) FDA Approval Date December 19, 2014 August 17, 2017 December 19, 2016 Niraparib Maintenance treatment in patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum based chemotherapy March 27, 2017 FDA Press Release. Page 25

26 Summary of PARP Inhibitor ADRs Olaparib Rucaparib Niraparib Adverse Events (Grades 1 4) Fatigue/asthenia (66%), nausea (64%), anemia (34%), diarrhea (31%) nasopharyngitis (26%), URI (26%), myalgia (22%) Fatigue/asthenia (77%), nausea (77%), anemia (44%), dysgeusia (39%), abdominal pain (32%), thrombocytopenia (21%) Nausea (74%), thrombocytopenia (61%), fatigue/asthenia (57%), anemia (50%), neutropenia (30%), hypertension (20%), palpitations (10%) Adverse Events (Grades 3 4) Anemia (18%), fatigue/asthenia (8%), vomiting (4%) Anemia (25%), asthenia/fatigue (11%), thrombocytopenia (5%), nausea (5%), abdominal pain (3%) Thrombocytopenia (29%), anemia (25%), neutropenia (20%), hypertension (9%), fatigue/asthenia (8%) Lab Abnormalities (Grades 1 4) Decreased hemoglobin (90%), decreased lymphocytes (56%), increased creatinine (30%), decreased platelets (30%), decreased ANC (25%) Increased creatinine (92%), increased ALT (74%) and AST (73%), decreased hemoglobin (67%), decreased lymphocytes (45%), decreased platelets (39%), decreased ANC (35%) Decreased hemoglobin (85%), decreased platelets (72%), decreased WBC (66%), decreased ANC (53%), increased AST (36%) and ALT (28%) Monitoring Parameters Complete blood count (baseline and monthly) Complete blood count (baseline and monthly) Complete blood count (weekly first month, then monthly) Blood pressure and pulse (monthly for first year) ALT=alanine transaminase; AST=aspartate aminotransferase; ANC=absolute neutrophil count; URI=upper respiratory infection; WBC=white blood cell FDA Prescribing Information. Comparing PARP Inhibitor PK Profiles Olaparib Tablet a,b Rucaparib a Niraparib a Time to peak plasma concentration (t max ) Volume of distribution (V d ) 1 to 3 hours; food delays t max by 2.5 hours 1.9 hours; high fat meal delays t max by 2.5 hours 3 hours 158 ± 136 L 113 to 262 L 1220 ± 1114 L Protein binding 82% 70% 83% Metabolism Elimination CYP3A4 Clearance: 7.4 ±3.9 L/hr 44% renal elimination, 42% fecal elimination CYP2D6 (primarily), CYP1A2, and CYP3A4 Clearance: 15.3 L/hr to 79.2 L/hr Carboxylesterases Clearance: 16.2 L/hr, 47.5% renal elimination, 38.8% fecal elimination Half life 14.9 ±8.2 hours 17 to 19 hours 36 hours a No dose adjustments are recommended in hepatic impairment b When CrCl is 31 to 50 ml/min, reduce the dose of olaparib to 200 mg BID. No dose adjustments are recommended in patients with mild renal impairment (CrCl ml/min) FDA Prescribing Information. Page 26

27 The Future of PARP Inhibition Clinical Trials in Breast, Prostate and Pancreatic Cancers Future of PARP Inhibitors Breast Cancer Trial Phase Treatment Arms Inclusion Primary Outcomes OlympiA NCT OlympiAD NCT ICEBERG NCT BRAVO NCT EMBRACA NCT RUBY NCT BROCADE NCT III III Olaparib Placebo Olaparib Physician s choice chemo gbrca+ gbrca+ II Olaparib BRCA+ ORR III III Niraparib Physician s choice chemo Talazoparib Physician s choice chemo gbrca+ gbrca+ II Rucaparib sbrca+ or BRCAness CBR II Paclitaxel/carboplatin Paclitaxel/carboplatin/veliparib Veliparib/temozolomide gbrca+ DFS PFS PFS PFS PFS Page 27

28 OlympiAD Olaparib in gbrca mutated Breast Cancer Phase III, Randomized, Open label Trial N=302 gbrca, HER 2 negative, metastatic breast cancer patients who have received 2 previous chemotherapy regimens RANDOMIZED MD Choice Chemotherapy* n=99 *Capecitabine, eribulin, or vinorelbine Olaparib 300 mg BID n=205 Robson M, et al. N Engl J Med OlympiAD PFS with Olaparib Monotherapy Median PFS: 7 months vs 4.2 months with standard therapy HR=0.58 (95% CI, ) P<0.001 Robson M, et al. N Engl J Med Page 28

29 Future of PARP Inhibitors Pancreatic Cancer Trial Phase Treatment Arms Inclusion Primary Outcomes POLO NCT III Olaparib Placebo gbrca1/2 mutation NCT II Olaparib Non gbrca1/2 mutation ORR NCT II Olaparib Non gbrca1/2 mutation or HR deficiency ORR NCT II Rucaparib BRCA1/2 or PALB2 mutation PFS NCT NCT II II Veliparib/FOLFIRI FOLFIRI Veliparib Veliparib/gemcitabine/ cisplatin Gemcitabine/cisplatin Metastatic pancreatic cancer BRCA1/2 or PALB2 mutation NCT I/II Veliparib/mFOLFOX BRCA1/2 mutation Dose limiting toxicities PFS OS ORR Future of PARP Inhibitors Prostate Cancer Trial Phase Treatment Arms Inclusion PROfound NCT TRITON3 NCT III III Olaparib Enzalutamide Abiraterone Rucaparib Enzalutamide Abiraterone Docetaxel NCT II Olaparib TRITON2 NCT GALAHAD NCT II II Rucaparib Niraparib NCT II Veliparib/abiraterone Abiraterone NCT II Talazoparib mcrpc, progression on androgen receptor targeted therapy HRR deficiency in tumor tissue mcrpc, progression on androgen receptor targeted therapy BRCA1/2 or ATM mutation Malignant solid tumor (including prostate) gbrca1/2 mcrpc, progression on 1 androgen receptor targeted therapy and 1 taxane BRCA1/2, ATM or other HR deficiency mcrpc, progression on >1 taxane and >1 androgen receptor targeted therapy Tumor w/ DNA repair anomalies mcrpc, progression on androgen deprivation therapy mcrpc with DDR deficiency, progression on 1 2 prior chemotherapies Primary Outcomes rpfs rpfs Tumor response rate ORR PSA response ORR PSA response ORR Page 29

30 Summary PARP inhibition capitalizes on the concept of synthetic lethality All three FDA approved PARP inhibitors have demonstrated activity in the absence of BRCA1/2 mutation Efficacy in platinum sensitive, recurrent ovarian cancer Monotherapy Maintenance Close patient monitoring of adverse effects Hematological toxicity Complete blood count with differential Hold dose until back to baseline Resume at lower dose as tolerated Nausea/vomiting Oral antiemetics readily available Take with food Optimal Patient Outcomes with PARP Inhibitors Case based Treatment Strategies for the Oncology Pharmacist Jason Bergsbaken, PharmD, BCOP Pharmacy Coordinator, Regional Oncology Services UW Health Madison, WI Page 30

31 BRCA1/2 Mutations Genetic Testing Rationale Identifying inherited mutations in genes such as BRCA1, BRCA2, allows for interventions that can significantly reduce the development of cancer and improve survival May also identify other cancers to screen for Protect family members Treatment directed towards mutations PARP inhibitors NCCN Breast/Ovarian Genetic Assessment Guidelines Version ; practice/guidelines/genetic testing for ovarian cancer/; guidelines/cancer care initiatives/genetics toolkit/assessing your patient%e2%80%99s hereditary. BRCA1/2 Mutations Who To Test? Ovarian All patients per ASCO/NCCN/SGO guidelines Epithelial Ovarian Cancer (EOC) Fallopian Tube (FT) Primarily Peritoneal Cancer (PCC) Should be covered for appropriate patients by most insurances NCCN Breast/Ovarian Genetic Assessment Guidelines Version ; practice/guidelines/genetic testing for ovarian cancer/; guidelines/cancer care initiatives/genetics toolkit/assessing your patient%e2%80%99s hereditary. Page 31

32 BRCA1/2 Mutations Who To Test? Breast Individual from a family with a known deleterious BRCA1/2 gene mutation Personal history of breast cancer and any of the following: Diagnosed 45 years Diagnosed 50 years with: An additional breast cancer primary 1 close relative* with breast, pancreatic, or prostate cancer TNBC 60 years Diagnosed any age with: Ashkenazi Jewish ancestry 2 close relative* with breast, pancreatic, or prostate cancer 1 close relative* with breast cancer diagnosed 50 years 1 close relative* with ovarian carcinoma 1 close male relative* with breast cancer *Close relatives include first, second and third degree relatives on same side of family NCCN Breast/Ovarian Genetic Assessment Guidelines Version BRCA1/2 Mutations Who To Test? Other Cancers Pancreatic or prostate cancer and one of the following: 1 close relative*: Breast 50 years or ovarian cancer (any age) 2 close relatives*: Breast, pancreatic, or prostate cancer (any age) Ashkenazi Jewish with history of pancreatic cancer Personal history of metastatic prostate cancer, male breast cancer, or ovarian carcinoma Family history of BRCA1/2 mutation Somatic BRCA1/2 mutation identified in tumor *Close relatives include first, second and third degree relatives on same side of family NCCN Breast/Ovarian Genetic Assessment Guidelines Version Page 32

33 Procurement FDA Approval Olaparib Patients with BRCA mutated advanced ovarian cancer (deleterious or suspected deleterious germline) who have received at least 3 or more prior lines of chemotherapy (December 2014) Maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum based chemotherapy (August 2017) Multiplex PCR companion diagnostic approved to detect germline mutation Rucaparib Patients with BRCA mutated (either germline or somatic) advanced ovarian cancer who have received at least 2 or more prior lines of chemotherapy (December 2016) Next generation sequencing based companion diagnostic approved to test for deleterious mutations Niraparib Maintenance treatment in recurrent ovarian, fallopian or primary peritoneal who have had a complete or partial response to platinum based therapy (March 2017) FDA Prescribing Information; Procurement Dosing and Administration Olaparib Rucaparib Niraparib Recommended Starting Dose 300 mg (two 150 mg tablets) by mouth twice daily 600 mg (two 300 mg tablets) by mouth twice daily 300 mg* (three 100 mg capsules) by mouth once daily *Start treatment no later than 8 weeks after most recent platinum containing regimen Administration With or without food With or without food With or without food Available Formulations 150 mg tablets 100 mg tablets 300 mg tablets 200 mg tablets 100 mg capsules Recommended Dose Reductions for Adverse Reactions 1 st 250 mg PO BID 2 nd 200 mg PO BID 1 st 500 mg PO BID 2 nd 400 mg PO BID 3 rd 300 mg PO BID 1 st 200 mg PO daily 2 nd 100 mg PO daily FDA Prescribing Information. Page 33

34 Procurement Olaparib Formulation Change Olaparib tablet formulation introduced in August 2017 Olaparib tablets and capsules are not interchangeable Differences in the dosing and bioavailability of each formulation Olaparib capsules are being phased out of the US market and will be available only through limited speciality pharmacy networks Available formulation(s) Recommended starting dose Olaparib Capsule (Phasing out of market) 50 mg capsule 8capsules (400 mg) by mouth twice daily Olaparib Tablet (Available August 2017) 150 mg tablet 100 mg tablet 2 tablets (300 mg) by mouth twice daily FDA Prescribing Information; Mateo J, et al. Target Oncol. 2016; Procurement Olaparib Formulation Change New Patient (Following August 2017) All patients new to olaparib treatment should receive the tablet formulation Existing Patient (Currently on capsule formulation) Patients who wish to remain on capsule formulation will need to have their medication dispensed from limited speciality pharmacy networks No specific manufacturer recommendations regarding appropriate starting tablet dosage in patients receiving a reduced capsule dosage FDA Prescribing Information; Mateo J, et al. Target Oncol. 2016; Page 34

35 Counseling Points Handling of PARP Inhibitors Per NIOSH, all 3 FDA approved PARP inhibitors are NOT considered hazardous However, patient education (verbal AND electronic/written) is recommended by ASCO/ONS as part of education process before administration of treatment Procedures for handling medications in the home, including: Storage Safe handling Management of unused medication Procedures for handling body secretions and waste in the home Neuss NM, et al. Oncol Nurs Forum. 2017; 161/default.html. Counseling Points Handling of PARP Inhibitors Storage All FDA approved PARP inhibitors should be stored at room temperature (68 77 F) If possible, store in original container (required for olaparib) Safe Handling Swallow whole, do not crush/chew/divide tablets or capsules If a medication box is used, a separate one should be used for PARP inhibitor Wash hands with soap and water prior to and after administration Keep out of the reach of children and pets When traveling, keep medication on your person in sealed plastic bag Lester J. Clin J Oncol Nurs. 2012; FDA Prescribing Information. Page 35

36 Counseling Points Handling of PARP Inhibitors Management of unused medication Prescription drug take back days US DEA sponsors every 6 months around the US Recommend against flushing down the sink or toilet May consider returning to treatment center Procedures for handling body secretions and waste in the home Non hazardous drug, but reasonable to follow general guidelines: Wash hands with soap and water after using the restroom Wash any skin that has been exposed to PARP inhibitor with soap and water Lester J. Clin J Oncol Nurs. 2012; Adverse Effects & Management of PARP Inhibitors Myelodysplastic syndrome (MDS) or Acute Myeloid Leukemia (AML) Low incidence among all agents (<1.5%) Duration of treatment varied; between <1 month to >2 years All patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy All agents with CBC monitoring recommendations (minimum monthly; weekly for first 4 weeks with niraparib) Bone Marrow Suppression Interrupt PARP inhibitor and monitor blood counts weekly until Grade 1 or less If hematological profile recovers, consider restarting drug at a reduced dose If hematological profile has not recovered to Grade 1 or less after 4 weeks, refer to hematologist (bone marrow analysis, cytogenics) FDA Prescribing Information; Zhou JX, et al. Drug Des Devel Ther Page 36

37 Adverse Effects & Management of PARP Inhibitors Fatigue Monitor for anemia Patient counseling Self monitor fatigue levels Encourage physical activity and periods of rest Maintain good nutrition and hydration Maintain good sleep hygiene May consider dose interruption or dose reduction if severe fatigue Nausea and/or vomiting Considered moderate to high emetic risk by NCCN Prophylactic antiemetics 30 minutes prior to dosing Lifestyle modifications promote small meals Behavioral modifications avoid anticipatory nausea FDA Prescribing Information; NCCN Cancer Related Fatigue Guidelines, Version ; NCCN Antiemesis Guidelines, Version Adverse Effects & Management of PARP Inhibitors Other common adverse effects (no specific monitoring recommended) Increase in serum creatinine Dyspnea Arthralgias/myalgias Decreased appetite Diarrhea and/or constipation Dysgeusia Abdominal pain FDA Prescribing Information. Page 37

38 Adverse Effects & Management Olaparib Pneumonitis Rare occurred in <1% of patients in clinical trials Interrupt treatment and promptly assess for any new or worsening respiratory symptoms such as dyspnea, cough, weight loss or fever If confirmed; discontinue treatment FDA Prescribing Information. Adverse Effects & Management Rucaparib Increased ALT/AST Close to 75% of all Grades, including up to 13% Grades 3 4 Led to treatment discontinuation in 0.3% of patients (1/377) No routine additional monitoring recommended Increased cholesterol levels 40% of all Grades; 2% of Grades 3 4 No routine additional monitoring recommended FDA Prescribing Information. Page 38

39 Adverse Effects & Management Niraparib Bone Marrow Suppression Rates of Grade 3: thrombocytopenia (29%), anemia (25%), and neutropenia (20%) Monitor CBC Month 1 = weekly Months 2 12 = monthly After Month 12 = periodically Discontinue treatment for CBC that does not resolve within 28 days following interruption Cardiovascular Hypertension (Grade 3 4 in 9% of patients) Monitor blood pressure and heart rate monthly for first year, then periodically thereafter Medically manage hypertension with antihypertensive medications and niraparib dose adjustment, if necessary Palpitations also occurred in 10% of patients Mucositis/dry mouth Urinary tract infections Insomnia FDA Prescribing Information. Other Important Counseling Information Pregnancy and Lactation Females who are able to become pregnant should use birth control during treatment and for six months after last dose for any PARP inhibitor Do not breast feed during treatment and one month (niraparib/olaparib) or two weeks (rucaparib) after last dose Drug Interactions Olaparib Avoid concomitant use of strong or moderate CYP3A inhibitors If necessary to co administer, dose reduction is recommended Avoid grapefruit, grapefruit juice, and Seville oranges during treatment FDA Prescribing Information. Page 39

40 Pharmacist led Oral Chemotherapy Programs Medication Errors High Costs Challenging Distribution Networks Why do we need an Oral Chemotherapy Program? Medication Adherence Complicated Regimens Adverse Effects Weingart SN, et al. Cancer. 2010; Wong SF, et al. Am J Health Syst Pharm Oral Chemotherapy Best Practices Safe Environment Staffing and General Policy Monitoring After Chemotherapy, including Adherence and Toxicity Oral Chemotherapy Best Practices Treatment Planning, Patient Consent, and Education Ordering, Preparing, Dispensing, and Administering Chemotherapy Neuss NM, et al. Oncol Nurs Forum Page 40

41 Oral Chemotherapy Best Practices Safe Environment Staffing and General Policy Comprehensive staff education/competency program (initial & ongoing) Policy for standardized documentation and communication of dose modification and treatment discontinuation Treatment Planning, Patient Consent, and Education Informed consent process for oral chemotherapy Verbal and written/electronic education prior to treatment initiation Neuss NM, et al. Oncol Nurs Forum Oral Chemotherapy Best Practices Ordering, Preparing, Dispensing, and Administering Chemotherapy Standardized and approved treatment plans for oral chemotherapy Process for oral chemotherapy order verification Monitoring After Chemotherapy, including Adherence and Toxicity Policy for initial adherence assessment Policy for ongoing adherence and toxicity assessment at each clinical encounter Neuss NM, et al. Oncol Nurs Forum. 2017; Weingart SN, et al. J Natl Compr Canc Netw Page 41

42 Example of a Pharmacist led Oral Chemotherapy Program Provider to initiate oral chemotherapy Financial screening & authorization Oral chemotherapy ordered in Standardized Treatment Plan Pharmacist phone follow up within 7 days to assess adherence and toxicity Informed consent obtained Pharmacist led education & initial adherence assessment Pharmacist reviews and verifies order Additional ongoing adherence & toxicity follow up at clinical encounters Weingart SN, et al. Cancer. 2010; Wong SF, et al. Am J Health Syst Pharm Adherence Why Does it Matter? Non adherence leads to poor outcomes Demonstrated survival impact in CML and breast cancer patient populations Increased costs Increased adverse effects Evidence in multiple studies that non adherence to oral chemotherapy is widely prevalent McCowan C, et al. Br J Cancer. 2008; Ganesan P, et al. Am J Hematol. 2011; Brett J, et al. Eur J Cancer Care Page 42

43 Adherence Patient Factors Education level Over adherence Financial toxicity Health Belief Model Individual self evaluation of condition Individual evaluation of risks and benefit to therapy Stimulus or cue to action (internal or external) to prompt individual to take medication Patridge AH, et al. J Natl Cancer Inst. 2002; McCowan C, et al. Br J Cancer. 2008; Ganesan P, et al. Am J Hematol. 2011; Brett J, et al. Eur J Cancer Care Adherence Who is Likely to be Non adherent? Regimen complexity and toxicity Older age Poorer physical condition Poorer cognitive function/memory Less family and social support Decreased motivation Adverse events Financial challenges Increased number of medications and comorbid conditions Impact on non oncology mediation adherence Patridge AH, et al. J Natl Cancer Inst. 2002; Yang J, et al. J Oncol Pract Page 43

44 Adherence Assessment and Intervention Adherence Assessment Tools Moriesky Medication Adherence Scales (MMAS 4 or MMAS 8) Medication Possession Ratio (MPR) Medication Event Monitoring System (MEMS) Currently, no gold standard validated assessment tool in oncology patient population Intervention Strategies Empower the patient support patient activation Incorporate the medication regimen into daily regimen Adherence aids medication boxes, alarms, diaries Patient communication (telephone calls, scheduled appointments) Technology mobile applications Adverse effect management Greer JA, et al. Oncologist. 2016; Kavookjian J, et al. Res Social Adm Pharm. 2015; Salgado TM, et al. Support Care Cancer Summary Patients with germline and/or somatic BRCA mutations may benefit from a PARP inhibitor with the goal of increased survival There are currently 3 FDA approved PARP inhibitors for recurrent ovarian cancer with differing indications and dosing schedules All patients on PARP inhibitors should receive education on procedures for handling medications in the home All PARP inhibitors display hematologic adverse effects as well as nausea and fatigue; appropriate management strategies are necessary to improve tolerability Pharmacist led oral chemotherapy programs, including adherence monitoring, are essential to maximize efficacy and safety for PARP inhibitor therapy Page 44

45 Abbreviations 5 FU: Fluorouracil ALT: alanine aminotransferase AML: acute myeloid leukemia ANC: absolute neutrophil count ASCO: American Society of Clinical Oncology ALT: alanine transaminase AST: aspartate aminotransferase BER: base excision repair BRCAm: BRCA mutated CA: cancer CA 125: cancer antigen 125 CAN: copy number aberrations CBC: complete blood count CML: chronic myeloid leukemia CRC: colorectal cancer CrCl: creatinine clearance DDR: DNA damage response DEA: Drug Enforcement Administration DFS: disease free survival DSB: double strand break EOC: epithelial ovarian cancer FA: fanconi anemia FDA: Food and Drug Administration FH: family history Abbreviations FT: fallopian tube gbrca: germline BRCA mutation GERD: gastroesophageal reflux disease HRD: homologous recombination deficiency IHC: immunohistochemistry LOH: loss of heterozygosity MDS: myelodysplastic syndrome MMR: mismatch repair MSI: microsatellite instability Mut: mutant NCCN: National Comprehensive Cancer Network NER: nucleotide excision repair NHEJ: nonhomologous end joining NIOSH: National Institute for Occupational Safety and Health OC: ovarian cancer ONS: Oncology Nursing Society ORR: objective response rate OS: overall survival PARP: poly(adenosine diphosphate ribose) polymerase PARPi: PARP inhibitor PCC: primary peritoneal cancer Page 45

46 Abbreviations PFS: progression free survival RECIST: Response Evaluation Criteria in Solid Tumors RT PCR: reverse transcription polymerase chain reaction sbrca: somatic BRCA mutation SCLC: small cell lung cancer SGO: Society of Gynecologic Oncology SH: social history SSA: single strand annealing SSBR: single strand break repair TNBC: triple negative breast cancer URI: upper respiratory infection WBC: white blood cell WF: white female WNL: within normal limits WT: wild type XRT: radiotherapy Notes Page 46