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Disclaimer This slide deck in its original and unaltered format is for educational purposes and is current as of June 2015. All materials contained herein reflect the views of the faculty, and not those of Educational Concepts Group, LLC 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 of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. 2 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 Educational Concepts Group, LLC. Additional terms and conditions may apply. 3 FACULTY Thomas J. Herzog, MD – Chair University of Cincinnati Michael J. Birrer, MD, PhD Harvard Medical School Susan M. Domchek, MD University of Pennsylvania Kristin K. Zorn, MD University of Arkansas for Medical Sciences Welcome, Introduction, and Updates in Guideline Recommendations for Advanced Ovarian Cancer and Unmet Needs Thomas J. Herzog, MD – Chair University of Cincinnati Objectives • Identify and select appropriate genetic testing/companion diagnostics to evaluate the tumor profiles of patients with ovarian cancer to aid in therapy individuation and ultimately the delivery of high quality care • Review and summarize the concept of synthetic lethality in ovarian cancer and value of PARP inhibition in patients with BRCA mutations • Compare and contrast clinical outcomes from clinical trials evaluating the safety and efficacy of PARP inhibitors in the treatment of BRCA-driven ovarian cancer and how these may be safely and effectively integrated into practice when available • Increase awareness of recent and ongoing clinical trials evaluating PARP inhibitors in patients with ovarian cancer Ovarian Cancer Landscape The Case for No Residual % Progression-Free Survival 100% 75% 0 mm HR 1-10 mm vs 0 mm: (95%CI) 2.52 (2.26;2.81) 50% > 10 mm vs 1-10 mm: 1.36 (1.24;1.50) Log-rank: P < 0.0001 1-10 mm 25% > 10 mm 0% 0 12 24 36 48 60 72 84 96 108 120 132 144 Generated from 3 prospective phase III trials (OVAR 3, 5, & 7) N = 3126 pts 100% 0 mm % Overall Survival 75% HR (95%CI) 50% 1-10 mm vs 0 mm: 1-10 mm 2.70 (2.37; 3.07) > 10 mm vs 1-10 mm: 1.34 (1.21; 1.49) 25% Log-rank: P < 0.0001 > 10 mm 0% 0 12 24 36 48 60 72 84 96 108 120 132 144 du Bois A, et al. Cancer. 2009;115(6):1234-1244. Shaping Current Standard Study PI/Author Results Pub GOG 111 N = 384 McGuire PFS = 18 vs 13 mos OS = 38 vs 24 mos NEJM, 1996 EORTC-OV10 N = 680 Piccart PFS = 16 vs 12 mos OS = 43 vs 44 mos JNCI, 2000 AGO N = 798 du Bois PFS = 17 vs 19 mos OS = 43 vs 44 mos JNCI, 2003 GOG 158 N = 792 Ozols PFS = 19 vs 21 mos OS = 49 vs 57 mos JCO, 2003 McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. du Bois A, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. When is the Recurrence? 0 months 6 months 12 months Primary Treatment Resistant Refractory End of Frontline Therapy Sensitive How to Treat: Platinum-Resistant Disease Surgery Rarely Benefits; Sxs? Combination Therapy Increased Toxicity Radiation Isolated Cases Clinical Trials Eligibility limited Balance Hope vs Efficacy ? PsychoSocial Support & Hospice Hormonal Low Toxicity Single Agent Chemo Best Therapeutic Index How to Treat: Platinum-Sensitive Disease Surgery Benefit in Selected Patients Single Agent Therapy Best Therapeutic Index? Radiation Isolated Cases Clinical Trials Eligibility Limited Balance Hope vs Efficacy ? PsychoSocial Support & Hospice Hormonal Low Toxicity Combination Therapy Phase III Evidence What About Histology? Months Winter WE, 3rd, et al. J Clin Oncol. 2007;25(24):3621-3627. FDA-Approved Drugs for Ovarian Cancer For 1st-line therapies both RR and OS have been the basis of drug approvals For 2nd- and 3rd-line therapy, RR, PFS, and OS have been the basis of approvals Carboplatin (1989) Paclitaxel (1992, 1998) PLD-Accelerated (1999)* Gemcitabine Carboplatin (2006) 1978 Cisplatin (1978) Olaparib (2014) 2015 Altretamine (1990) Topotecan (1996) Objective response (RR) “Clinical” benefit (RR, no PFS, no OS) PLD-Full (2005)^ Chemo + Bevacizumab (2014) “Clinical” benefit (no PFS, no OS*, OS^) “Clinical” benefit (RR, PFS, no OS) State-of-the-Science Updates on the Molecular Genetics of Ovarian Cancer and Implications on Management Michael J. Birrer, MD, PhD Harvard Medical School Case 1 • 53-year-old woman presents with 6 weeks of abdominal bloating and early satiety • Her CT scan shows a large pelvic mass, ascites, and peritoneal carcinomatosis • She undergoes staging laparotomy, which reveals optimally debulked stage III high-grade endometrioid ovarian cancer • She undergoes initiation of adjuvant chemotherapy with carboplatin and taxol. While under treatment she arranges to have her peripheral blood cell DNA tested for mutations in BRCA1/2 and her tumor for a “complete genomic analysis” • The results show no mutation in BRCA1/2, a mutation in PI3 Kinase, no methylation of BRCA1/2 and a gene expression signature for improved survival Which of the Following Molecular Analyses is the Most Valuable for Treating Patients With Ovarian Cancer? 1. Gene expression profiling 2. BRCA 1/2 mutation testing 3. Somatic mutation testing 4. BRCA 1/2 methylation Are There Clinically Relevant Predictors for the Treatment of Ovarian Cancer? TCGA Analysis of HGSOC Lots of CNV and low mutation rate Methylation, expression microRNA subsets? HGSOC, high grade serous ovarian cancer. The Cancer Genome Atlas Network. Nature. 2011;474(7353):609-615. 1 2 6 3 7 12 8 13 19 3 4 5 15 10 16 20 2 13 14 19 20 1 2 12 13 9 10 16 21 5 11 15 12 17 18 22 3 X 4 15 X 4 8 14 18 22 3 7 11 17 21 6 2 5 9 14 1 1 4 16 5 17 18 In a tumor with genomic chaos are there predictors of tumor behavior? Prognostic Gene Expression Signatures Prognostic Gene Signatures of Ovarian Cancer Meta-Analysis Overview Literature review Prognostic models Database of curated gene expression 101 candidate papers 5 review papers Standardized clinical annotation and gene ID 23 studies, 2,908 samples Inclusion Criteria Training sample size > 40 Focus on late-stage serous Multivariate model Continuous risk score Claims to predict survival Possible to reproduce model 14 prediction models implemented 100 pages documentation survHD Bioconductor package Waldron L, et al. J Natl Cancer Inst. 2014;106(5). Inclusion Criteria Sample size > 40 Primary tumors Overall survival available Events (deaths) > 15 Late stage, high-grade tumors Serous subtype 10 datasets, 1,455 samples curatedOvarianData Bioconductor package Assessment of Prognostic Signatures 14 Prognostic Signatures C-Index = Pr(g(Z1)>g(Z2) | T2>T1) T1,T2 = times to death of two patients g(Z1,g(Z2) = predicted risk scores C = 0.5 expectation for random prediction C = 1 if the exact order of all deaths is predicted Survival Kaplan-Meier estimate 10 Microarray Datasets Time Waldron L, et al. J Natl Cancer Inst. 2014;106(5). Assessment of Prognostic Signatures 14 Prognostic Signatures C-Index = Pr(g(Z1)>g(Z2) | T2>T1) T1,T2 = times to death of two patients g(Z1,g(Z2) = predicted risk scores C = 0.5 expectation for random prediction C = 1 if the exact order of all deaths is predicted Study Forest plot 10 Microarray Datasets C-Index Waldron L, et al. J Natl Cancer Inst. 2014;106(5). 14 Prognostic Signatures Assessment of Prognostic Models Cancer Genome Atlas Research Network. Nature. 2011; 474(7353):609-615. Integrated genomic analyses of ovarian carcinoma. Bonome et al. Cancer Res. 2008; 68(13):5478-5486. A gene signature predicting for survival in suboptimally debulked patients with ovarian cancer. 10 Microarray Datasets Waldron L, et al. J Natl Cancer Inst. 2014;106(5). Assessment of Prognostic Models 14 Prognostic Signatures Dressman et al. J Clin Oncol. 2007; 25(5):517-525. An integrated genomic-based approach to individualized treatment of patients with advancedstage ovarian cancer. Baggerly et al. J Clin Oncol. 2008;26(7):1186-1187. Run batch effects potentially compromise the usefulness of genomic signatures for ovarian cancer. Dressman et al. J Clin Oncol. 2012; 30(6):678. Retraction. 10 Microarray Datasets Waldron L, et al. J Natl Cancer Inst. 2014;106(5). Assessment of Prognostic Models Conclusions: • Most models make better predictions than random • Large, consortium studies performed best • Validation datasets can be biased • None of these models are ready for the clinic Waldron L, et al. J Natl Cancer Inst. 2014;106(5). Are there predictors which are clinically useful? Establishment of Debulking Signature • Based upon the biologic basis of disease spread • Analyzed 1525 microarrays of primary ovarian cancers • 22% suboptimal (> 1 cm) • Supervised analysis/signature identification • Generate pathway Riester M, et al. J Natl Cancer Inst. 2014;106(5). Riester M, et al. J Natl Cancer Inst. 2014;106(5). Expression of Three Proteins Provides 93% Accuracy for Determining Suboptimal Debulking Status Riester M, et al. J Natl Cancer Inst. 2014;106(5). Gynecologic Cancer Oral Abstract Session Abstract #5505 9:24 AM - 9:36 AM Retrospective analysis of candidate predictive tumor biomarkers (BMs) for efficacy in the GOG-0218 trial evaluating frontline carboplatin– paclitaxel (CP) ± bevacizumab (BEV) for epithelial ovarian cancer (EOC). However, these are experimental and require validation! Genomic Instability/HRD Does it provide prognostic or predictive biomarkers? PARP Inhibition and Tumor-Selective Synthetic Lethality DNA damage (SSBs) PARP PARP inhibition DNA replication (accumulation of DNA DSBs) Normal cell with functional HR pathway HR-deficient tumor cell (eg, BRCA 1/2-/-) HR-mediated DNA repair No HR-mediated DNA repair Cell survival Cell death Tumor-selective cytotoxicity Farmer H, et al. Nature. 2005;434(7035):917-921. Bryant HE, et al. Nature. 2005;434:913-917. McCabe N, et al. Cancer Res. 2006;66:8109-8115. DSB, double-strand break; HR, homologous recombination; SSB, single-strand break. Best % Change From Baseline in Target Lesions 100 Olaparib 400 mg bid cohort Best % Change From Baseline 80 BRCA1 BRCA2 60 * 40 Increasing tumor shrinkage 20 0 * * -20 -40 * -60 -80 -100 *Platinum-sensitive patients. Figure includes 3 unconfirmed responses. Audeh MW, et al. Lancet. 2010;376(9737):245-251. * Background: GOG-0218 and GOG0262 GOG-218 GOG-262 Chemotherapy Arms Carbo/Taxol +/- Bev, Bev maint Carbo/Taxol q 3wk vs Dose-dense, + Bev < 40 22 (2.8%) 19 (2.7%) 40 - 49 108 (13.9%) 86 (12.4%) 50 - 59 242 (31.1%) 210 (30.3%) 60 - 69 262 (33.7%) 233 (33.7%) 70 - 79 136 (17.5%) 120 (17.3%) > 80 8 (1.0%) 24 (3.5%) White 688 (88.4%) 592 (85.5%) Black 28 (3.6%) 38 (5.5%) Hispanic 32 (4.1%) 27 (3.9%) Stage IV 184 (23.7%) 217 (31.4%) Optimal 333 (42.8%) 0 (not allowed) Neoadjuvant 0 (not allowed) 88 (12.7%) High-Grade Serous Histology 632 (81.2%) 556 (80.3%) Age Race Stage/Debulking Norquist BS, et al. SGO Annual Mtg. 2014. Abstract 10. There is More to DNA-Repair Than BRCA1/2 Meindl A, et al. Nat Genet. 2010;42(5):410-414. Loveday C, et al. Nat Genet. 2011;43(9):879-882. Rafnar T, et al. Nat Genet. 2011;43(11):1104-1107. Casadei S, et al. Cancer Res. 2011;71(6):2222-2229. Walsh T, et al. Proc Natl Acad Sci U S A. 2011;108(44):18032-18037. Summary of Mutation-Carriers: GOG-0218 and GOG-0262 • 258/1346 (19.2%) with loss of function mutations BRCA1 8.7% BRCA2 5.1% Cancerassociated (non-BRCA) 5.3% Wild-Type 81% N = 1346 Norquist BS, et al. SGO Annual Mtg. 2014. Abstract 10. 28% of mutation-carriers had mutations in nonBRCA1/2 genes Summary of Cancer-Associated Mutations: GOG-0218 and GOG-0262 ATR, 0.8% XRCC2, 0.4% FAM175A, 0.4% SLX4, 0.4% MRE11A, 0.4% BARD1, 0.8% LYNCH, 1.9% RAD51C, 2.3% CHEK2, 2.6% TP53, 0.8% RAD51D, 2.6% NBN, 2.6% ATM, 3.0% PALB2, 3.4% BRIP1, 7.5% N = 20 BRCA2, 26.0% N = 69 Norquist BS, et al. SGO Annual Mtg. 2014. Abstract 10. BRCA1, 44.2% N = 117 N = 265 mutations in 258 women Summary of Cancer-Associated Mutations: GOG-0218 and GOG-0262 ATR, 0.8% XRCC2, 0.4% BARD1, 0.8% LYNCH, 1.9% RAD51C, 2.3% CHEK2, 2.6% FAM175A, 0.4% SLX4, 0.4% MRE11A, 0.4% TP53, 0.8% RAD51D, 2.6% NBN, 2.6% ATM, 3.0% PALB2, 3.4% BRIP1, 7.5% N = 20 BRCA1, 44.2% N = 117 BRCA2, 26.0% N = 69 N = 265 mutations in 258 women Norquist BS, et al. SGO Annual Mtg. 2014. Abstract 10. Summary of Cancer-Associated Mutations: GOG-0218 and GOG-0262 ATR, 0.8% XRCC2, 0.4% BARD1, 0.8% LYNCH, 1.9% FAM175A, 0.4% SLX4, 0.4% RAD51C, 2.3% MRE11A, 0.4% TP53, 0.8% CHEK2, 2.6% RAD51D, 2.6% NBN, 2.6% ATM, 3.0% PALB2, 3.4% BRIP1, 7.5% N = 20 BRCA1, 44.2% N = 117 BRCA2, 26.0% N = 69 N = 265 mutations in 258 women Norquist BS, et al. SGO Annual Mtg. 2014. Abstract 10. Genomic Instability/HRD This prognostic signature may be predictive Diagnostic Development Cutoff Defined for BRCA-Like Signature, Being Tested and Refined TCGA and AOCS Overall Survival Data Used to Develop LOH Cutoff to Identify High-Grade Ovarian Cancer Patient Tumors With BRCA-Like Signature 0.30 Log-rank P Value (high vs low LOH groups) 0.25 0.20 0.15 0.10 Optimal LOH cutoff 0.05 Overall Survival (% probability) 100 High genomic LOH (n = 97) Low genomic LOH (n = 212) 80 Log-rank: P = 0.0047 Hazard ratio = 0.62 60 Independent predictor from BRCAmut status 40 20 Median overall survival: 56.4 vs 38.2 months 0 0 0 Genomic LOH Cutoff 25 50 75 100 125 Overall Survival (months) Prospective testing of prespecified cutoff in ARIEL2 and ARIEL3 The Cancer Genome Atlas (TCGA) Research Network. Nature. 2011;474:609-615; Wang ZC, et al; Australian Ovarian Cancer Study (AOCS). Clin Cancer Res. 2012;18:5806-5815. ARIEL2 Goal: Assess Rucaparib Sensitivity in Prospectively Defined Molecular Subgroups Primary Endpoint Key Eligibility • High-grade serous or endometrioid ovarian cancer • ≥ 1 prior platinum chemotherapy • Platinum-sensitive, relapsed, measurable disease • Adequate tumor tissue (screening biopsy and archival) • No prior PARPi 600 mg bid rucaparib continuously until progression by RECIST • PFS (RECIST) in: – BRCAmut – BRCA-like (excludes BRCAmut) – Biomarker negative N = 180 Cap on known germline BRCAmut Secondary Endpoints • ORR (RECIST & CA-125) • Safety • Pharmacokinetics CA-125, cancer antigen 125 test; ORR, overall response rate; PFS, progression-free survival; RECIST, Response Evaluation Criteria In Solid Tumors. Swisher EM. 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. 2014. Abstract 215. The Majority of BRCAwt Patient Tumors Exhibit BRCA-Like Signature Tumor BRCA/BRCA-like status as determined by HRD Test (N = 121) • 17 germline BRCAmut • 12 somatic BRCAmut • 1 indeterminate • High genomic LOH LOH, loss of heterozygosity. Swisher EM. 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. 2014. Abstract 215. Greatest Rucaparib Activity Observed in BRCAmut Patients … – 61% ORR (RECIST) – 70% ORR (RECIST & CA-125) – 83% of patients continuing on treatment (+) • Responses observed in germline and somatic BRCAmut tumors Best Target Lesion Response 120 Germline Somatic Indeterminate 100 80 Change From Baseline (%) • Robust clinical activity observed in BRCAmut patients (n = 23) 60 40 20 0 -20 -40 + + + + + + -60 + + + + + + + + + + + + -80 -100 + +=ongoing Swisher EM. 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. 2014. Abstract 215. … and Differential Rucaparib Activity Seen in Patients With/Without BRCA-Like Signature • Clinical activity observed in BRCAwt patients with BRCA-like signature (n = 25) • Few responses observed in BRCAwt patients without BRCA-like signature (n = 13) Change From Baseline (%) – 32% ORR (RECIST) – 40% ORR (RECIST & CA-125) – 52% of patients continuing on treatment (+) Best Target Lesion Response 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 BRCA-like + + + + + + + + + + + + 120 Biomarker 100 80 negative – 8% ORR (RECIST) 60 40 – 8% ORR (RECIST & CA-125) 20 + 0 – 38% of patients continuing + + + +=ongoing on treatment (+) 20 -40 -60 -80 -100 + Swisher EM. 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. 2014. Abstract 215. + Genomic Assays • Multiple different companies • Multiple genomic platforms – Sequencing – Expression profiling – IHC • Accurate assessments but clinical correlations not validated • Could be used to identify appropriate clinical trial Conclusions • High-grade serous ovarian cancer is a disease of genomic chaos • BRCA/Fanconi pathway/HRD testing is reasonable for all patients with ovarian cancer • Mutational analysis of tumors can be considered but will not alter initial management and can be used only for clinical trial identification • Gene expression profiling remains experimental PARP Inhibitor Sensitivity in Ovarian Cancer: Rationale and Proof of Concept Susan M. Domchek, MD University of Pennsylvania Case • 62-year-old woman presents for second opinion about treatment options for recurrent ovarian cancer • Review of her path report shows stage IIIC high-grade serous ovarian cancer at the time of diagnosis • She has received 2 courses of chemotherapy – First with carboplatin/paclitaxel with an 18-month disease-free interval – Second with carboplatin/paclitaxel with a 5-month disease-free interval • She underwent genetic testing and is found to have a germline mutation in BRCA1 Is she eligible for a PARP inhibitor based on FDA approved indication? 1. No, because her ovarian cancer is cisplatin resistant 2. Yes, because she has a germline mutation in BRCA1 3. No, because she has received only 2 prior courses of chemotherapy 4. No, because the drug is approved for maintenance therapy only Objectives • Review the mechanism of action of PARP inhibitors • Proof of concept studies • Challenges for development Clinical Trials of PARP Inhibitors Proof of principle of synthetic lethality in BRCA1/2 mutation carriers (NEJM 2009) Unselected triple negative breast cancer (TNBC) with iniparib/chemo (NEJM 2011) Phase III study in TNBC did not meet primary endpoint December 2014: Approval of olaparib for ovarian cancer by FDA and EMA (although for different indications) Fong PC, et al. N Engl J Med. 2009;361(2):123-134; O'Shaughnessy J, et al. N Engl J Med. 2011;364(3):205-214. Targeting BRCAness for Tumor Selective Killing BRCA1 or BRCA2 Carrier BRCA1 or BRCA2 Normal tissues Carrier Tumor tissue DNA DAMAGE HR NHEJ SSA BER NER etc x DNA DAMAGE HR NHEJ SSA BER NER etc x x Tumor specific lethality Tutt A, et al. Cold Spring Harb Symp Quant Biol. 2005;70:139-148; McCabe N, et al. Cancer Res. 2006;66:8109-8115. Mechanisms of PARPi Shah GM, et al. Front Oncol. 2013;3. Scott CL, et al. J Clin Oncol. 2015;33(12):1397-1406. Farmer H, et al. Nature. 2005;434(7035):917-921; Bryant HE, et al. Nature. 2005;434(7035):913-917. PARP Inhibitors in BRCA1/2 Mutation Carriers • Olaparib • Phase I trial – Established favorable toxicity profile – Proof of principle with responses seen only in BRCA1 and BRCA2 mutation carriers – PARP inhibition – Breast, ovarian, prostate • Using why a person developed cancer against it Fong PC, et al. N Engl J Med. 2009;361(2):123-134. Confirmed BRCA1 or BRCA2 mutation Advanced refractory breast cancer Failure of ≥ 1 prior chemotherapy Cohort 1 (enrolled first) Cohort 2 Olaparib 400 mg po bid 28-day cycles; 27 patients Olaparib 100 mg po bid 28-day cycles; 27 patients Tutt A, et al. Lancet. 2010;376(9737):235-244. Best % Change From Baseline by Genotype Best % Change From Baseline 100 Olaparib 400 mg bid cohort BRCA status 1 2 80 60 40 Increasing tumor shrinkage 20 0 -20 -40 -60 -80 -100 Tutt A, et al. Lancet. 2010;376(9737):235-244. Best % Change From Baseline by Prior Chemotherapy Olaparib 400 mg bid cohort Best % Change From Baseline 100 80 60 40 20 0 –20 –40 –60 –80 –100 Previous anthracycline, taxane, and capecitabine Increasing tumor shrinkage Tutt A. ASCO Annual Meeting. 2009. Abstract CRA501. Confirmed BRCA1 or BRCA2 mutation Recurrent ovarian cancer Cohort 1 (enrolled first) Cohort 2 Olaparib 400 mg po bid 28-day cycles; 33 patients Olaparib 100 mg po bid 28-day cycles; 24 patients Audeh MW, et al. Lancet. 2010;376(9737):245-251. Best % Change From Baseline by Genotype Audeh MW, et al. Lancet. 2010;376(9737):245-251. Other PARP Inhibitors • • • • • • • • Olaparib (AZD-2281, KU-0059436) Veliparib (ABT-888) Rucaparib (AG014699/PF01367338/CO288) Niraparib (MK-4827) Talazoparib (BMN-673) CEP-9722 E7016 Iniparib (BSI-201) BRCA1/2 Associated Ovarian Cancer: Doxorubicin vs Olaparib • Multicenter open label phase II trial • Recurrence within 12 months of platinum therapy • Germline BRCA1 or BRCA2 mutation Olaparib 200 mg bid N = 32 Olaparib 400 mg bid N = 32 Pegylated liposomal doxorubicin (PLD) 50 mg/m2 q 28 days N = 33 Kaye SB, et al. J Clin Oncol. 2012;30(4):372-379. Progression-Free Survival • • • • Response rates 25% 200 mg olaparib 31% 400 mg olaparib 18% PLD PLD, pegylated liposomal doxorubicin. Kaye SB, et al. J Clin Oncol. 2012;30(4):372-379. BRCA1/2 Cancer: Chemosensitivity • General chemosensitivity • Improved prognosis in ovarian cancer with standard chemotherapy – Bolton et al. JAMA. 2012 • Improved response rates in ovarian cancer to PLD – Adam et al. Gyn Onc. 2011 • Improved response rates to chemotherapy in breast cancer – Kriege et al. JCO. 2009 – Arun et al. JCO. 2011 Bolton KL, et al. JAMA. 2012;307(4):382-390; Adams SF, et al. Gynecol Oncol. 2011;123(3):486-491; Kriege M, et al. J Clin Oncol. 2009;27(23):3764-3771; Arun B, et al. J Clin Oncol. 2011;29(28):3739-3746. Best % Change From Baseline by Prior Chemotherapy Olaparib 400 mg bid cohort * * * * * * Best % Change From Baseline 100Phase Ib olaparib study in advanced ovarian cancer Previous anthracycline, taxane and capecitabine 80 Cisplatin sensitive: Clinical benefit 69% 60Cisplatin resistant: Increasing tumor shrinkage Clinical benefit 45% Clinical benefit 23% 40Cisplatin refractory: 20 0 –20 –40 –60 –80 –100 *Prior platinum Tx Tutt A. ASCO Annual Meeting. 2009. Abstract CRA501; Fong PC, et al. J Clin Oncol. 2010;28(15):2512-2519. More Than BRCA1/2? • The concept of “BRCA-ness” • Basal phenotype of breast cancer – Triple negative as an imperfect surrogate • Ovarian cancer • Particularly high-grade serous • Many of these may have dysregulation of BRCA1 or BRCA2 • The Cancer Genome Atlas – defect in the HR pathway in half of 489 tumors The Cancer Genome Atlas Network. Nature. 2011;474(7353):609-615. Best % Change From Baseline Gelmon KA, et al. Lancet Oncol. 2011;12(9):852-861. Ledermann J, et al. N Engl J Med. 2012;366(15):1382-1392. Progression-Free Survival Ledermann J, et al. N Engl J Med. 2012;366(15):1382-1392. Ledermann J, et al. Lancet Oncol. 2014;15(8):852-861. Kaufman B, et al. J Clin Oncol. 2015;33(3):244-250. Ovarian (n = 193) Breast (n = 62) Other (n = 12) All (n = 298) 148 (76.7) 44 (22.8) 1 (0.5) 37 (59.7) 25 (40.3) 0 5 (21.7) 17 (73.9) 1 (4.3) 1 (12.5) 7 (87.5) 0 7 (58.3) 5 (41.7) 0 198 (66.4) 98 (32.9) 2 (0.7) Median (SD) prior regimens for advanced disease 4.3 (2.2) 4.6 (2.0) 2.0 (1.6) 2.0 (1.0) 2.2 (1.3) 4.0 (2.2) Tumor response rate 60 (31.1) 8 (12.9) 5 (21.7) 4 (50) 1 (8.3) 78 (26.2) Complete response 6 (3.1) 0 1 (4.3) 0 0 7 (2.3) Partial response 54 (28) 8 (12.9) 4 (17) 4 (50) 1 (8.3) 71 (23.8) Stable (> 8 wks) Stable disease Unconfirmed PR 78 (40) 64 (33) 12 (6) 29 (47) 22 (36) 7 (11) 8 (35) 5 (22) 3 (13) 2 (25) 2 (25) 0 7 (58) 6 (50) 1 (8.3) 124 (42) 99 (33) 25 (9) BRCA status, n (%) BRCA1 mutation BRCA2 mutation Both Kaufman B, et al. J Clin Oncol. 2015;33(3):244-250. Pancreas Prostate (n = 23) (n = 8) Who Will Respond? • BRCA1/2 germline mutation status is at this time the best predictor of response to PARP inhibitors • Not all BRCA1/2 mutation carriers respond to PARP inhibitors • Determining primary and secondary resistance • Will the germline or the tumor genetic testing be most important? • Specific genes or evidence of homologous recombination? • Studies are ongoing PARP Inhibitors in BRCA-Driven Cancers: Current Status and Future Promise Kristin K. Zorn, MD University of Arkansas for Medical Sciences Case • 62-year-old woman presents for second opinion about treatment options for recurrent ovarian cancer • Review of her path report shows stage IIIC high grade endometrioid ovarian cancer at the time of diagnosis What additional information is needed to decide if genetic counseling and testing is appropriate? 1. Family cancer history 2. Ancestry, especially Ashkenazi Jewish descent 3. None – already appropriate with current info 4. None – already inappropriate since not serous histology Objectives • Summarize the current approvals for olaparib in ovarian cancer • Review the options for germline and somatic testing of tumors • Review the ongoing clinical trials of PARP inhibitors in ovarian cancer Study 19 • Phase II trial of olaparib vs placebo maintenance in recurrent, platinum-sensitive HGSOC • Objective complete or partial response to last platinumbased regimen required at study entry • • • • Platinum sensitive relapsed HGSOC ≥ 2 platinum regimens PR or CR on most recent platinum regimen N = 265 Olaparib 400 mg bid continuous n = 136 1:1 PD R Primary endpoint PFS Placebo n = 129 Randomized within 8 weeks of last regimen dose Ledermann J, et al. N Engl J Med. 2012;366(15):1382-1392. HGSOC, high grade serous ovarian cancer; PR, partial response; CR, complete response; PD, progressive disease. Study 19: PFS by BRCA Mutation Status ODAC Sponsor Briefing Book. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/oncologicdrugsadvisoryco mmittee/ucm402209.pdf. European Approval of Olaparib • Approval granted to olaparib Dec 2014 based on Study 19 PFS data • First approval for maintenance treatment in women with recurrent, platinum-sensitive ovarian, fallopian tube, or peritoneal cancer – Requires germline and/or somatic BRCA mutations – Requires complete or partial response to platinum-based chemo – Genetic testing should be done in an appropriate laboratory • Dose 400 mg by mouth twice daily (8 x 50 mg capsules) with reductions to 200 mg or 100 mg twice daily if needed • Treatment to be continued until progression of disease Study 42 • Phase II trial of olaparib in patients with germline BRCA mutation and recurrent ovarian, breast, pancreatic, prostate, or other cancer • 193 heavily pretreated OC patients with platinum resistance – 31% ORR (3% CR, 28% PR) – Median time to response 56 days OC, ovarian cancer; ORR, objective response rate, CR, complete response; PR, partial response. Kaufman B, et al. J Clin Oncol. 2015;33(3):244-250. FDA Approval of Olaparib • Accelerated approval of olaparib in Dec 2014 based on Study 42 objective response rate and duration of response • Indication granted for treatment of recurrent OC patients with deleterious or suspected deleterious germline BRCA mutations – ≥ 3 lines of prior chemotherapy – Companion diagnostic also approved • Maintenance therapy not granted accelerated approval • Dose 400 mg by mouth twice daily (8 x 50 mg capsules) with reductions to 200 mg or 100 mg twice daily if needed FDA Approval of Olaparib • 2% of patients developed myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) • 17/22 cases of MDS/AML were fatal • Duration of olaparib therapy in those who developed secondary MDS/AML varied from < 6 months to > 2 years • Recommended to monitor for heme toxicity monthly • Pneumonitis, sometimes fatal, in < 1% • Recommended to avoid concomitant use of CYP3A inhibitors and inducers • Teratogenic – category D Package insert. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf. Objectives • Summarize the current approvals for olaparib in ovarian cancer • Review the options for germline and somatic testing of tumors • Review the ongoing clinical trials of PARP inhibitors in ovarian cancer NCCN Guidelines for Germline Testing • Personal history of epithelial ovarian, fallopian tube, or primary peritoneal cancer suffices to recommend genetic counseling and testing • Not dependent on family history • Not dependent on ethnicity (ie, Ashkenazi descent) • Not dependent on tumor pathology (ie, serous histology) Version 1.2011, www.nccn.org. Beyond BRCA1/2: Ovarian Cancer Predisposition Genes Syndrome/Gene Clinical Mutation Positivity Rate Lifetime OC Risk Other Features BRCA11 11% 35-46% OC at earlier age (50) BRCA21 6% 13-23% OC at same age as general population (60) Lynch Syndrome2,3 < 1% 3-14% OC at earlier age (43-50); endometrial and colon cancer risks are higher RAD51C4,7 1.3% (RR 6-8) 10-15% RAD51D5,7 0.6% (RR 6-9) 10-15% BRIP16 1.4% (RR 8) 10-15% 1. Walsh T, et al. Proc Natl Acad Sci U S A. 2011;108(44):18032-18037. 2. Koornstra JJ, et al. Lancet Oncol. 2009;10(4):400-408. 3. Barrow E, et al. Clin Genet. 2009;75(2):141-149. 4. Meindl A, et al. Nat Genet. 2010;42(5):410-414. 5. Loveday C, et al. Nat Genet. 2011;43(9):879-882. 6. Rafnar T, et al. Nat Genet. 2011;43(11):1104-1107. 7. Pelttari LM, et al. J Med Genet. 2012;49(7):429-432. History of BRCA1/2 Mutation Testing • Previously patented • Baseline testing involves full sequencing and analysis for 5 large BRCA1 rearrangements • Additional testing possible for other large rearrangements in BRCA1 and BRCA2 (BART) • Ashkenazi Jewish panel • Specific mutation Genetic Testing Debate • Single gene testing – Traditional Sanger sequencing approach – Low throughput – High cost if assessing multiple genes – Misses structural rearrangements VUS, variants of uncertain significance www.cancer.gov/cancertopics/pdq/genetics/overview. • Multigene panel – Recent development due to advent of massively parallel sequencing – Lower cost to assess multiple genes – Better assessment of rearrangements – Large number of VUS Current HBOC Genetic Testing • Multiple commercial providers of genetic testing with cost approximately halved • Evolving use of BRCA1/2 testing vs panel tests with expanded number of genes • Only BRCA1/2 mutation carriers eligible for olaparib outside of clinical trial • Evolving landscape of insurance coverage – To date, coverage for unaffected patients has been poor – Some insurers are using only 1 testing provider – Many insurers only allow 1 shot at genetic testing HBOC, hereditary breast and ovarian cancer. 50% of Serous OC Cases Have Germline or Somatic HR Defects BRCA1/2 mutations, 21% No HR defect Germline 15% Somatic 6% BRCA1 promoter methylation 11% EMSY amplification, 8% RAD51C hypermethylation, 3% Mutation of PTEN mutation, 7% Fanconi Anemia Mutation of ATM genes, 5% or ATR, 2% The Cancer Genome Atlas Network. Nature. 2011;474(7353):609-615. Tumor Testing for Somatic Mutations • Options include institutional research protocols and commercial testing • Result interpretation needs to factor in potential for germline mutation • Somatic mutation carriers not eligible for olaparib therapy in US outside of clinical trial Objectives • Summarize the current approvals for olaparib in ovarian cancer • Review the options for germline and somatic testing of tumors • Review the ongoing clinical trials of PARP inhibitors in ovarian cancer PARPi Under Development PARPi Treatment Population Phase Olaparib Monotherapy Combo w/Chemo Combo w/Biologic Combo w/RT BRCA1/2 mut BRCA-like tumors Maintenance I/II/III Veliparib Monotherapy Combo w/Chemo Combo w/Biologic Combo w/RT BRCA1/2 mut BRCA-like tumors I/II Rucaparib Monotherapy Combo w/Carbo BRCA1/2 mut Recurrent OC Maintenance (ongoing) I/II/III Niraparib Monotherapy Combo w/temozolomide BRCA1/2 mut Maintenance (ongoing) I/III Talazoparib Monotherapy All solid tumors I CEP-9722 Monotherapy Combo w/chemo All solid tumors I Lee JM, et al. Ann Oncol. 2014;25(1):32-40. Liu JF, et al. Gynecol Oncol. 2014;133(2):362-369. PARPi, PARP inhibitor; BRCA1/2mut, BRCA1/2 mutations; OC ovarian cancer. Challenges in PARPi Development • Other PARPi compared to olaparib? • Monotherapy or combination treatment with chemotherapy, targeted therapy, and/or radiation? • Appropriate dose and schedule? Escalate PARPi or chemo dose if in combination? • Frontline, maintenance, and/or recurrent setting? • Appropriate population? Only HGS? Only platinumsensitive? Only mutation carriers? Zorn KK. Oncology. 2012;26(2):128-136. Liu JF, et al. Gynecol Oncol. 2014;133(2):362-369. GOG 3004/SOLO-1 • Randomized phase III trial of olaparib vs placebo as maintenance after frontline chemo in BRCA-mutated, high-grade serous or endometrioid ovarian cancer, fallopian tube cancer, or peritoneal cancer • 300 mg tablets twice daily GOG 3005 • First frontline trial in ovarian cancer in cooperative group setting • Randomized phase III trial of carboplatin/paclitaxel +/concurrent and maintenance veliparib in women with HGSOC, FTC, or PPC • Neoadjuvant treatment allowed Olaparib + Cediranib • Phase I of olaparib + cediranib in recurrent OC or metastatic TNBC – RP2D olaparib 200 mg twice daily + cediranib 30 mg daily – ORR in OC 44% • Randomized phase II with olaparib +/- cediranib in platinum-sensitive, BRCA-mutated or high-grade serous/endometrioid OC – ORR 56% for olaparib vs 84% for combination – Median PFS 9 months for olaparib vs 17.7 months for combination Liu JF, et al. Eur J Cancer. 2013;49(14):2972-2978. Liu JF, et al. Lancet Oncol. 2014;15(11):1207-1214. OC, ovarian cancer, TNBC, triple negative breast cancer. ARIEL2: Rucaparib for Relapsed, Platinum-Sensitive, High-Grade Ovarian Cancer Primary EP: Key Eligibility: • High-grade ovarian cancer • ≥ 1 prior platinum • Platinum-sensitive, relapsed disease • Adequate tumor tissue (archival and fresh biopsy) • No prior PARPi Courtesy Kathleen Moore, MD N = 180 600 mg bid rucaparib continuously until disease progression by RECIST ORR by RECIST and GCIG CA-125 criteria in HRD subgroups Secondary EPs: DOR PFS Safety Steady state PK ARIEL3: Rucaparib Maintenance in Patients Who Respond to PlatinumBased Treatment for Relapsed Disease N = 540 pts Rucaparib PFS Key Eligibility: • High-grade ovarian cancer • Received ≥ 2 prior platinum-based regimens • Platinum-sensitive disease • Response to last platinum • Available archival tumor tissue Courtesy Kathleen Moore, MD Primary EP: Secondary EPs: 2:1 Stratify: • HRD classification • Response to platinum regimen • Progression-free interval after penultimate platinum R A N D O M I Z A T I O N Placebo PFS by IRR PRO OS Safety Key Exploratory EP: PFS2 Selected Ongoing PARPi Trials • Ovarian cancer – Quadra: niraparib in recurrent disease – AVANOVA: Niraparib +/bev in platinum-sensitive • Other sites – Olympiad: olaparib vs chemo in HER2-negative, BRCAmutated metastatic BC – EMBRACA: talazoparib in locally advanced or metastatic BRCA-mutated BC – Bravo: niraparib in HER2negative, BRCA-mutated BC – Veliparib combination therapy vs chemo in metastatic, BRCA-mutated BC BC, breast cancer, bev, bevacizumab. Summary • Olaparib is the first PARP inhibitor to be approved for clinical use – EU: maintenance setting, germline and/or somatic BRCA mutation – US: ≥ 3 prior therapies, germline mutation • Genetic testing landscape is rapidly evolving Summary • Many gaps in our knowledge of how to best implement PARPi therapy exist • Ongoing clinical trials are testing additional PARPi, frontline setting, and drug combinations to help fill those gaps Thoughts From the Chair: Practical Guidance for an Evolving Clinical Practice Thomas J. Herzog, MD – Chair University of Cincinnati Future of PARP Inhibition When? Who? BRCAg BRCAs HDR Other Frontline Maintenance Second-line Third-line Which? Different PARPs Efficacy Toxicity Where? Single agent Chemo combo Biologic combo Evolving PARP MOA’s: How? Rouleau M, et al. Nat Rev Cancer. 2010;10(4):293-301. Conclusions • Novel agents now available to treat ovarian cancer patients – Olaparib approved 12/19/14 • Competitive landscape with multiple PARP inhibitors • Unclear as to true differences between PARPs • Genetic testing becoming more prevalent • Basic science & clinical trials will answer many questions