Ovarian Cancer: It s Personal

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1 Ovarian Cancer: It s Personal

2 Review ovarian cancer: Incidence, origin, and management Discuss genetic testing: Who, why and what? Review current treatments for ovarian cancer Enhance understanding of Individualized/Personalized Medicine for ovarian cancer

3 Ovarian cancer: Incidence, origin, and management

2017 Ovarian Cancer 22,440 11 th Estimated new cases 1 Most common cancer in females 2 http://www.

4 2017 Ovarian Cancer 22, th Estimated new cases 1 Most common cancer in females 2 Accessed April 30, 2017

5 1. In 2013, ~196,000 women living with ovarian cancer in the US 3 2. Incidence rates ovarian cancer slowly falling over 20 years AccessedApril 30, Gynecologic Cancers: Ovarian Cancer. Accessed August 1, SEER Stat Fact Sheets: Ovarian Cancer. Accessed August 1, 2016.

6 1. Accessed November 18, 2016 and April 30, 2017

7 Random Errors Stem Cell Divisions Types of Errors Tumor Type

https://www.uptodate.com/contents/image?

8 Accessed November 24,

9 Percent of Deaths Percent of New Cases by Age Group: Ovarian Cancer 30.0% 25.0% 20.0% 18.6% 24.2% 21.3% 15.0% 10.0% 5.0% 0.0% 8.0% 6.9% 5.9% 3.8% 1.3% < >84 Age Median Age 63 at Diagnosis = SEER Stat Fact Sheets: Ovarian Cancer. Accessed August 1, 2016.

cancers are malignant epithelial tumors Prat and FIGO

10 Its not all the same Clear Cell Low-grade serous Other Endometrioid Mucinous High-grade serous 90% of ovarian cancers are malignant epithelial tumors Prat and FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet. 2014;124(1):1-5.

Ovarian Surface Epithelium High-Grade Serous Carcinoma Fallopian Tube Uterus Ovarian Surface Epithelium Low-Grade Serous Carcinoma Ovary Cervix Vagina Fallopian Tube Epithelium Fallopian Tube

11 Ovarian Surface Epithelium High-Grade Serous Carcinoma Fallopian Tube Uterus Ovarian Surface Epithelium Low-Grade Serous Carcinoma Ovary Cervix Vagina Fallopian Tube Epithelium Fallopian Tube Epithelium Clear Cell Carcinoma Endometrium Endometrium Retrograde Menstruation? Endometriosis Endometrioid Carcinoma Mucinous Carcinoma Unknown Committee on the State of the Science in Ovarian Cancer Research; Board on Health Care Services; Institute of Medicine; National Academies of Sciences, Engineering, and Medicine Washington (DC): National Academies Press (US); 2016 Apr.

12 Stage III Epithelial Ovarian Cancer: Prognosis by Cell Type Progression-Free Survival Overall Survival

13 Cancer Type Low Grade Serous High Grade Serous Molecular alterations KRAS mutations TP53 mutations NRAS mutations BRAF mutations HER2 amplification BRCA1/2 mutations Chromosomal instability Cobb, L. et al. Gynecol Oncol Res Pract. 2015; 2: 1.

14 Genetic testing: Who, why and what?

15 Non-HRD HRD Approximately 20-25% of ovarian cancer patient have a deleterious germline or somatic mutation in the BRCA1 or BRCA2 gene BRCA 1 and 2 mutations 16-18% germline 6-7% somatic TCGA, Molecular profiling of serous ovarian cancer 2011 Pennington et al. Clin Cancer Res. 2014;20(3):

16 Other indicates the genes BRIP1, PALB2, RAD51C, RAD51D, and BARD1; MMR indicates mismatch repair genes PM52, MSH6 and MLH1 Norquist, et al. JAMA Oncol Apr; 2(4);

17 Who Should Have Genetic Testing? Leading oncology societies and guidelines recommend testing all women with ovarian cancer NCCN 1 Genetic counseling and testing should be considered in women with a history of ovarian carcinoma, fallopian tube or primary peritoneal cancer SGO 2 Women diagnosed with epithelial ovarian, tubal, and peritoneal cancers should receive genetic counseling and be offered genetic testing, even in the absence of family history ASCO 3 Genetic counseling and testing should be considered in women with epithelial ovarian, fallopian tube or primary peritoneal cancer even in the absence of family history NCCN, National Comprehensive Cancer Network; SGO, The Society of Gynecologic Oncology; ASCO; American Society of Clinical Onc ology. 1. NCCN Guidelines for Breast and/or Ovarian Genetic Assessment V Accessed April 30, Lancaster et al. Gynecol Oncol. 2015;136(1): Lu et al. J Clin Oncol. 2014;32(8):

18 Clinical Value: WHY Should Genetic Testing Be Performed? Germline BRCA or other high risk mutation identified No germline mutation 1. SGO Clinical Practice Statement: Genetic Testing for Ovarian Cancer. Available at: Accessed August 1, Lancaster et al. Gynecol Oncol. 2015;136(1):3-7.

19 What to test? Mutations Can Be Germline or Somatic Germline Mutations Inherited and present in every cell in the body 1 Somatic Mutations Acquired and found only within tumor cells 2 BRCA mutated cells BRCA intact cells 1. Petrucelli et al. BRCA2 Hereditary Breast and Ovarian Cancer. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. Seattle (WA): University of Washington, Seattle; [cited 01 Aug 2016]. [about p 56]. Accessed from: 2. Moschetta et al. Ann Oncol. 2016;27(8):

20 How to Test? Clinical Utility of Multigene Panel Testing Use next-generation sequencing (NGS) Detect gene mutations other beyond BRCA1/2 Assess multiple genes simultaneously rather than in sequence saves time and enhances efficiency Results may be more complex Variants of uncertain significance Genes of uncertain significance Increased probability of detecting mutations of uncertain significance Increased anxiety and/or confusion Potential for misinterpretation of results ie. Inappropriate surgery or screening 1. SGO Clinical Practice Statement: Genetic Testing for Ovarian Cancer. Available at: Accessed August 1, Lancaster et al. Gynecol Oncol. 2015;136(1):3-7.

21 Why Does BRCA status Matter? Prognostic Bolton JAMA 2012

22 Proportion of patients progressionfree Why Does BRCA status Matter? PFS by BRCAm status Number at risk Olaparib BRCAm Placebo BRCAm Olaparib BRCAm Placebo BRCAm Time from randomization (months) BRCAm (n=136) Olaparib Placebo Events: total pts (%) 26:74 (35.1) 46:62 (74.2) Median PFS, months % reduction in risk of disease progression or death with olaparib Predictive HR= % CI (0.11, 0.31); P< Ledermann, J. ESMO/ECC 2013

23 Ledermann J, et al. Lancet Oncol. 2014;15: Khanna KK. Nat Genet. 2001;27: Sanchez-Perez I. Clin Transl Oncol.2006;8: Kennedy RD. J Clin Oncol. 2006;24: TARGETING BRCA1/2 MUTATIONS PARP & Base Excision Repair Therapeutic DNA damage NAD+ PARP PARP recruitment poly(adp-ribose) PARP PARP activation and assembly of repair factors PARG PARP PAR degradation via PARG XRCC1 LigIII pol β PNK 1 LigIII XRCC1 PNK 1 End processing, gap filling, and ligation

24 Chemical structure of PARP inhibitors Rucaparib Veliparib Olaparib Niraparib Jones et al, J of Medicinal Chemistry 2015

25 PARP Inhibitors Overview PARP Status Company Comments Olaparib Rucaparib Approved: > 3 L- FDA Study-42 Study-19 EMA Approved ARIEL-2 AZ SOLO trials (1, 2, 3) Capsules to tablets Cedarinib Ph III Plat-S & R PAOLO- with Bev Clovis FM-1 Comp Dx Breakthrough FDA 4/15 ARIEL 3-Plat-S maint ARIEL 4- Recurrent Veliparib Phase III- GOG AbbVie 1 st L Maint HG serous-3 arms Niraparib Approved NOVA Tesaro Talazoparib Phase III BioMarin Medivation Myriad HRD- genomic scarring (42 = cut-off) QUADRA-Recurrent PRIMA- 1 st L maint Only in Br Ca currently

26 PARP inhibitors: Indications and Efficacy Olaparib Rucaparib Niraparib Current FDA approval Trial Name Study Design, Population Monotherapy for gbrca+ with 3+ prior therapies Study 42 Label SOLO-2 - Efficacy Phase III Maint olaparib vs placebo, PSOC > 2 priors, response, BRCA+(germline) Monotherapy for somatic or gbrca+ after 2 prior chemotherapies ARIEL2 Phase II Open-label rucaparib, 1+ prior; PSOC, PROC; measurable; BRCA + (g58.2%; s 17.2%, unk 24.6%) RR PSOC: 70% PROC: 25% Maintenance for recurrent PSOC after chemotherapy NOVA Phase III Maint niraparib vs placebo, PSOC > 2 priors, response, BRCA+(g 36.7%; s 8.5%) or BRCA WT PFS 19.1 vs 5.5m; HR=0.3 PSOC: 12.7m PROC: 7.3m gbrca+: 21 vs 5.5 m; HR=0.27 Non-gBRCA: 9.3 vs 3.9m; HR=0.45

27 PARP inhibitors: Indications and Toxicity Olaparib Rucaparib Niraparib Current FDA approval Monotherapy for gbrca+ with 3+ prior therapies Monotherapy for somatic or gbrca+ after 2 prior chemotherapies Maintenance for recurrent PSOC after chemotherapy Trial Name Study 42 Label SOLO-2 - Toxicity Phase III ARIEL2 Phase II NOVA Phase III Grade 3-4 Toxicity 19.5% anemia 10% neutropenia 2.6% nausea 4.1% fatigue 29% anemia 10% increase LFTs 7% thrombocytopenia 33.8% thrombocytopenia 25% anemia 19.6% neutropenia 8.2% fatigue 8.2% hypertension All Grades Toxicity 75.9% nausea 65.6% fatigue 78% nausea 78% fatigue

28 Kaufman B, et al. JC Single Agent, Many Tumor Types

29 Mirza, MR N Engl J Med. 2016

30 NOVA Trial: PFS Results stratified by BRCA and HRD Status Niraparib n=138 gbrcam n=203 Placebo n=65 Non-gBRCAm, HRD+ N=162 Niraparib n=106 Placebo n=56 Overall nongbrcam N=350 Niraparib n=234 Placebo n=116 PFS Median, Months (95% CI) 21.0 (12.9, NR) 5.5 ( ) 12.9 ( ) 3.8 ( ) 9.3 ( ) 3.9 ( ) Hazard Ratio, p value HR, 0.27 P < HR, 0.38 P < HR, 0.45 P < Mirza, MR N Engl J Med. 2016

31 Swisher, EM Lancet Oncology. 2017

32 ARIEL 2 ARIEL 2: Presented by R. Kristeleit at 2015 ECCO Meeting

33 Current treatments for ovarian cancer

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

(1978) Altretamine (1990) Objective response (RR) Clinical benefit (RR, no PFS, no OS) Clinical benefit (no PFS, no OS*, OS^) Clinical benefit (RR, PFS, no OS) Clinical benefit (RR,

34 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 Gemcitabine Carboplatin PlSOC (2006) Olaparib > 3L BRCAm (2014); Carboplatin Paclitaxel PLD-Acc Rucaparib- Acc (1989) (1992, 1998) ROC ROC (2016) (1999)* Cisplatin (1978) Altretamine (1990) Objective response (RR) Clinical benefit (RR, no PFS, no OS) Clinical benefit (no PFS, no OS*, OS^) Clinical benefit (RR, PFS, no OS) Clinical benefit (RR, PFS, OS) Clinical benefit (PFS, no OS) Topotecan ROC (1996) PLD- Full ROC (2005) ^ (2006) Chemo + Bevacizumab (2014) PlROC Chemo + Bevacizumab PlSOC (2016) Niraparib- PsROC Maint (2017)

35 EOC, epithelial ovarian cancer; IV, intravenous; IP, intraperitoneal. Image curtesy of Dr. Robert Coleman 1. Ledermann et al. Ann Oncol. 2013;24 Suppl 6:vi du Bois. Cancer. 2009;115(6): cytoreduction of all macroscopic visible disease 1

36 Emerging new multiplex classification system Histology Molecular signature Treatmentfree interval Number of prior chemotherapy regimens 1. HGSC/ endometrioid 2. Other, specify 1. BRCA mutation 2. BRCA-like 3. Other, specify 1. <3 months months 3. >12 months 1. 3 or fewer 2. >3 Alvarez et al. Gynecol Oncol. 2016;141(3):405-9.

37 Individualized/Personalized Medicine for Ovarian Cancer

38 Individualized Cancer Therapy

39 Confluence of Multiple Advances Pharmacogenomics Bioinformatics Personalized Medicine Translational Genomics Molecular bio Pharmacometabonomics Companion Diagnostics

40 Improved Efficacy Overcoming drug resistance Enhanced tumor delivery Tumor specificity Intellectual Appeal Rational Targets New era Numerous molecular aberrancies Altered Toxicities < Myelosuppression < Alopecia < Neuropathy > Hemorrhage > DVT Challenges Assessing Activity Defining relevant targets Costs

41 Underlying Molecular Biology of High- Grade Serous Ovarian Cancer TCGA Ovarian - TCGA GBM - TCGA Lung - TSP

Non-HRD HRD Approximately 20-25% of ovarian cancer patient have a deleterious germline or somatic mutation in the BRCA1 or BRCA2 gene BRCA 1 and 2

42 Non-HRD HRD Approximately 20-25% of ovarian cancer patient have a deleterious germline or somatic mutation in the BRCA1 or BRCA2 gene BRCA 1 and 2 mutations 16-18% germline 6-7% somatic TCGA, Molecular profiling of serous ovarian cancer 2011 Pennington et al. Clin Cancer Res. 2014;20(3):

43 NOVA Trial: PFS Results HRD Positive Stratified by BRCA Status HRD Positive BRCAwt N=115 HR=0.38 ( ) P<0.001 HRD Positive sbrcam N=47 HR=0.27 ( ) P=0.02 Non gbrcam - HRD Negative N=134 HR=0.58 ( ) P=0.02

44 Summary Rucaparib: Overall Response Rate and Duration of Response for Study 10 and ARIEL2 Study 10 ARIEL2 RECIST ORR% RECIST + CA125 PFI 6-12 months Median PFS (mo) (90% CI) gbrcam BRCAm (g + s) BRCA-like Biomarker Negative 65% 1 75% 3 30% 2 13% 2 81% 1 82% 2 45% 2 21% 2 88% (9.0, NR) (5.2, 7.6) (3.5, 7.1) Presented By 1. R. Shapira-Frommer R, 2015 ASCO Annual Meeting. Abstract Iain McNeish at 2015 ASCO Annual Meeting. 3. R. Kristeleit at 2015 ECCO Meeting.

45 Clinical Trials Biologic Therapies for Rare Epithelial Ovarian Cancers Herzog et al. FDA Workshop; 2015

47 18 studies with 977 cases Frequency of the MSI-H phenotype in unselected ovarian cancer ~12% Range 0-37% More common in mucinous and endometrioid subtypes Pal, T Clin Cancer Res 2008

48 Molecular Analysis for Therapy Choice: NCI MATCH 03/13/ 54

NCI-MATCH Objective To determine whether matching certain drugs or drug combinations in adults whose tumors have specific gene abnormalities will effectively

49 NCI-MATCH Objective To determine whether matching certain drugs or drug combinations in adults whose tumors have specific gene abnormalities will effectively treat their cancer, regardless of the cancer type This is a signal-finding trial treatments that show promise can advance to larger, more definitive trials 03/13/ 56

50 NCI-MATCH Overall Match Rate as of 03/13/2017 Around 20% of patients have a gene abnormalit y matching one being studied 03/13/ 57

51 Future of Ovarian Cancer Treatment

52 Blockade of PD-1/PD-L1 or CTLA-4 Signaling CTLA4 Tumor PD1/PD-L1 Ipilimumab* Tremelimumab * FDA-approved Adapted from Ribas A. N Engl J Med. 2012;366(26): Nivolumab* Pembrolizumab* Atezolizumab* Avelumab Durvalumab

53 Ovarian Immune Checkpoint Inhibitors Overview Brand Name Mfg Ipilimumab 1 Nivolumab 2 Pembrolizumab 3 Avelumab 4 Atezolizumab Yervoy BMS Opdivo BMS Keytruda Merck N/A Pfizer Tecentriq Genentech Isotype IgG1 IgG4 IgG4 IgG1 IgG1 Targets CTLA-4 PD-1 PD-1 PD-L1 PD-L1 ADCC Yes 5 No 6 No/Minimal 7 Yes 8 Yes 8 Approved indications (Date) Melanoma (2011) Melanoma (2014), Hodgkin s (2016), RCC (2015), NSCLC (2015) Melanoma (2014), NSCLC (2015) H & N (2016) Merkel cell Pend (2016) Bladder (2016) NSCL (2016) 1. Hodi FS et al. Proc Natl Acad Sci USA. 2008;105: Hamanishi J et al. J Clin Oncol. 2015;33: Varga A et al. Presented at ASCO Abstract Disis ML et al. Presented at ASCO Abstract Romano E et al. Proc Natl Acad Sci U S A. 2015;112(19): Wang C, Thidium KB, Han M, et al. Cancer Immunol Res. 2014;2(9): Homet Moreno B, Ribas A, et al. Br J Cancer. 2015;112(9): Boyerinas B et al. Cancer Immunol Res. 2015;3:

54 Ovarian Immune Checkpoint Inhibitors Ipilimumab 1 Nivolumab 2 Pembrolizumab 3 Avelumab 4 N Patient population Metastatic ovarian carcinoma Platinum-resistant, post-taxane Failure or inability to receive standard Tx; PD-L1+ Recurrent postplatinum Prior therapies NR 4: 55% 4: 80.8% 3: 65.3% (not including adjuvant) PD-L1+ prevalence NR 80% (IC 2/3) 100% ( 1% TC) 77% ( 1% TC) Median follow-up NR 11 months NR 12.4 months TRAE, any 22% 95% 69.2% 66.1% TRAE, Gr 3+ NR 40% 3.8% 6.5% ORR (95% CI) NR 15% ( ) 11.5% ( ) 9.7% ( ) DCR (95% CI) NR 45% (23-69) 34.6% (17-56) 54% (45-63) mpfs NR 3.5 months NR 2.6 months mos NR 20 months NR 10.8 months DCR, disease control rate; NR, not reached; TC, tumor cell; TRAE, treatment-related adverse event. 1. Hodi FS et al. Proc Natl Acad Sci U S A. 2008;105: Hamanishi J et al. J Clin Oncol. 2015;33: Abstract Varga A et al. Presented at ASCO Disis ML et al. Presented at ASCO Abstract 5533.

55 Neoadjuvant therapy 3-4 cycles Resistant/ refractory JAVELIN Ovarian 200 (avelumab) NRG GY-009 (atezolizumab) KEYNOTE 100 (pembrolizumab) Pembrolizumab + bevacizumab EORTC-1508 (atezolizumab) Lack of response or early recurrence (<6 mo) Debulking surgery 1 st -line platinum-based chemotherapy Response 1 st -line maintenance Late recurrence (>6 mo) = platinum sensitive Re-treat with platinum Response 2 nd -line maintenance Re-treat with platinum Response Late recurrence (>6 mo) = platinum sensitive = frontline JAVELIN Ovarian 100 (avelumab) Pembrolizumab + chemotherapy = recurrent = PS = PS recurrence ATALANTE (atezolizumab) KEYNOTE 100 (pembrolizumab) Pembrolizumab + bevacizumab PS, platinum sensitive. 1. NCCN guidelines. Version Clinicaltrials.gov. Accessed October 11,

56 Review ovarian cancer: Incidence, origin, and management Overall ovarian cancer is a rare disease Classification of ovarian cancer patients is evolving as data on molecular signatures emerge Cornerstone of management is surgery and chemotherapy Survival continues to improve Discuss genetic testing: Who, why and what? Importance of genetic testing for all women with ovarian cancer Genetic testing now has treatment implications besides clinical value in prognosis and cascade testing Review current treatments for ovarian cancer PARP inhibitors approved for several indications in ovarian cancer Enhance understanding of Individualized/Personalized Medicine for ovarian cancer Individualization based on histologic subtypes and mutation status Studies of treatment strategies targeting the hallmarks of cancer are ongoing or in development

Practical Guidance and Strategies for PARP Inhibition. Nicoletta Colombo, MD University of Milan-Bicocca European Institute of Oncology Milan, Italy

Practical Guidance and Strategies for PARP Inhibition Nicoletta Colombo, MD University of Milan-Bicocca European Institute of Oncology Milan, Italy Clinical Data Maintenance therapy : BRCA-mutated or all