Combining PARP Inhibition and Immunotherapy for Ovarian Cancer Oliver Dorigo, MD, PhD

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1 Combining PARP Inhibition and Immunotherapy for Ovarian Cancer Oliver Dorigo, MD, PhD Director and Associate Professor, Division Gynecologic Oncology Director Mary Lake Polan Gynecologic Oncology Research Laboratory Director Clinical Research Group Gynecologic Cancer Trials Director Gynecologic Oncology Fellowship Stanford Department of Obstetrics and Gynecology, Hong Kong International Oncology Forum September 8 h, 2018

2 Combining PARP Inhibition and Immunotherapy for Ovarian Cancer 1. Defects in DNA Repair Mechanisms in Ovarian Cancer 2. Clinical efficacy of either PARPi or Immunotherapy in Ovarian Cancer 3. Rationale for combining PARPi and Immunotherapy 4. Clinical efficacy of PARPi and Immune Checkpoint Inhibition

3 Epithelial Ovarian Cancer Subtypes Are Associated With Different Mutations and Molecular Aberrations Epithelial ovarian cancer can be characterized as a heterogeneous disease, not only histologically, but through the identification of distinct molecular pathway alterations Epithelial High-grade serous Low-grade serous Mucinous Clear cell Endometrioid TP53 BRCA1 and BRCA2 NF1 RB1 CDK12 Homologous Recombination repair genes* BRAF KRAS NRAS ERBB2 KRAS HER2 amplification ARID1A PIK3CA PTEN CTNNB1 PPP2R1 ARID1A PIK3CA PTEN PPP2R1 MMR deficiency * CHK2, BARD1, BRIP1, PALB2, RAD50, RAD51C, ATM, ATR, EMSY, and Fanconi anemia genes. HER2, human epidermal growth factor receptor 2; MMR, mismatch repair. Banerjee S, Kaye SB. Clin Cancer Res. 2013;19(5):961-8.

4 Approximately Half of HGSOCs Have Alterations in HR Repair Genes HR repair genes may have mutations, deletions, amplifications, or promoter methylation OTHER (some may be HR deficient via upregulation of mirnas or other mechanisms) Other 21% BRCA1 germline mutations 8% HR DEFICIENT BRCA1 somatic mutations 3% BRCA2 germline mutations 6% BRCA2 somatic mutations 3% NER mutations 4-8% BRCA1 promoter methylation 10% MMR mutations 3% CDK12 mutations 3% RAD51C promoter methylation 2% FA gene mutations 2% Cyclin E1 amplification 15% Core RAD gene mutations 1.5% HR PROFICIENT PTEN homozygous loss 7% EMSY amplification 6% POSSIBLY HR DEFICIENT HR DNA-damage gene mutations 2% FA, Fanconi anemia; HGSOC, high-grade serous epithelial ovarian cancer; HR, homologous recombination; mirna, microrna; MMR, mismatched repair; NER, nucleotide excision repair. Konstantinopoulos PA, et al. Cancer Discov. 2015;5(11):

5 DNA Repair involves a Complex Protein Network Poly (ADP) Ribose Polymerase Annunziata CM, O'Shaughnessy J. Poly (ADP-ribose) polymerase as a novel therapeutic target in cancer. Clin Cancer Res Sep 15;16(18):

6 Mutations and Defects in DNA Repair Genes Are Associated With Hereditary Ovarian Cancer Hereditary Breast and Ovarian Cancer Syndrome 1 BRCA1 BRCA2 Fanconi Anemia Pathway 1 RAD51C RAD51D RAD50 BRIP1 BARD1 CHEK2 MRE11A NBN PALB2 Lynch Syndrome 2 and Mismatch Repair 1 MLH1 MSH2 MSH6 PMS2 Defects in mismatch repair may be measured by assessing microsatellite instability Mutations in TP53 are also frequently associated with ovarian cancer 1. Frey MK, Pothuri B. Gynecol Oncol Res Pract. 2017;4:4. 2. National Institutes of Health. Genetic Home Resource. Lynch syndrome. Accessed October 29, 2017.

7 Genomic Instability Status Measured Using HRD Testing May Identify More Potential for Intervention Loss of HR Error-prone repair of DNA Genomic instability LOH 1 Large-scale genomic loss of heterozygosity TAI 2 Telomeric allelic imbalance LST 3 Large-scale state transitions HR, homologous recombination; HRD, HR deficiency. 1. Abkevich V, et al. Br J Cancer. 2012;107(10): Birkbak NJ, et al. Cancer Discov. 2012;2(4): Popova T, et al. Cancer Res. 2012;72(21):

8 Deficient DNA-Repair Mechanisms in Cancer Cells lead to Cell Death after Induction of Double stranded DNA Breaks Chemotherapy Double-stranded break Radiation Normal cell Cancer cell with defective repair Repair of DNA BRCA deficient or deficiency of other HR proteins No repair (No HR pathway) Survival Cell death Exploits inherent weakness of cancer cells that have defective DNA repair

9 Poly (ADP) Ribose Polymerase Inhibition blocks DNA Repair and Induces Synthetic Lethality 1. Platinum chemotherapy Inflicts DNA damage via adducts and DNA crosslinking Poly (ADP) Ribose Polymerase PARP1 2. PARP1 upregulations Base-excision repair of DNA damage PARP1 PARP1 PARP inhibitor 3. Inhibition of PARP1 Disables DNA base-excision repair 4. Replication fork collapse Double-strand DNA break Cell Survival BRCA-1 BRCA-2 Cell Death O Shaughnessy J, et al. ASCO

10 Summary of FDA-Approved PARP Inhibitors Drug Olaparib 1 Registrational Clinical Trials Study 42 SOLO-2 Study 19 Indications Treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for olaparib. 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. Rucaparib 2 Study 10 ARIEL 2 Monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for rucaparib. Niraparib 3 NOVA Maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. FDA, US Food and Drug Administration; PARP, poly ADP ribose polymerase. 1. Olaparib package insert. AstraZeneca LP; Rucaparib package insert. Clovis Oncology, Inc; Niraparib package insert. TESARO, Inc; 2017.

11 PARP Inhibition as Maintenance Therapy and Treatment for Patients with Recurrent Ovarian Cancer

12 Maintenance Therapy for Ovarian Cancer to Increase Progression Free Survival and Prevent Recurent Disease 2L 3L Median PFS* 10.2 mo ( ) 4L 5L Median PFS* 6.4 mo ( ) Median PFS* 5.6 mo ( ) Median PFS* 4.4 mo ( ) 6L Median PFS* 4.1 mo ( ) 7L FIRST RECURRENCE RECURRENCE RECURRENCE RECURRENCE RECURRENCE RECURRENCE *PFS was calculated from the day of randomization (day of first cycle of chemotherapy) to the first disease progression. PFS = progression-free survival; L = line. Hanker LC, et al. Ann Onc. 2012;23: Lorusso D, et al. Int J Surg Oncol. 2012;2012:

13 Few Initial Attempts at Maintenance Therapy Have Proven Effective Until Recently Maintenance beneficial? Strategy No Yes Prolonged initial therapy 1-2 Short duration / non cross-resistant chemotherapy 3 High-dose chemotherapy 4 Intraperitoneal 5 Interferon- 6 Oregovomab 7 Erlotinib 8 Tanomastat 9 Abagovomab 10 Paclitaxel (6 months) 11 Paclitaxel (12 months) 12 Extended chemotherapy is often associated with increased AEs such as neurotoxicity Lambert HE, et al. Ann Oncol. 1997;8: Bertelsen K, et al. Gynecol Oncol. 1993;49: De Placido S, et al. J Clin Oncol. 2004;22(13): Chan JK, et al. N Engl J Med. 2016;374: Barakat RR, et al. J Clin Oncol. 2002;20: Hall GD, et al. Br J Cancer. 2004;91: Berek J, et al. J Clin Oncol. 2009;27: Vergote IB, et al. J Clin Oncol. 2014;32: Hirte H, et al. Gynecol Oncol. 2006;102(2): Sabbatini P, et al. J Clin Oncol. 2013;31: Conte PF, et al. J Clin Oncol. 2007;25(18s):275s. 12. Markman M, et al. J Clin Oncol. 2003;21:

14 Five Phase III Maintenance Studies of 2,570 women are changing the paradigm of Ovarian Cancer Treatment

15 Progression-free survival (%) SOLO2: Olaparib Maintenance Improves PFS in BRCA mutant Ovarian Cancer PFS by Investigator Assessment Oaparaib (n=196) Olaparib Placebo (n=99) Events (%) 107 (54.6) 80 (80.8) Median PFS, mo HR % CI: p< Placebo Months since randomization No. at risk: Olaparib Placebo

16 Probability of PFS Probability of PFS Probability of PFS ARIEL3: Investigator-assessed PFS (Primary Endpoint) BRCA mutant HRD ITT Median (mo) 95% CI Median (mo) 95% CI Median (mo) 95% CI 1.0 Rucaparib (n=130) Rucaparib (n=236) Rucaparib (n=375) Placebo (n=66) HR 0.23; 95% CI: ; p< Placebo (n=118) HR 0.32; 95% CI: ; p< Placebo (n=189) HR 0.36; 95% CI: ; p< No. at risk Rucaparib Placebo Months At risk Rucaparib Placebo Months Months At risk (events) Rucaparib Placebo Rucaparib, 48% censored Placebo, 15% censored Rucaparib, 43% censored Placebo, 14% censored Rucaparib, 38% censored Placebo, 12% censored CI, confidence interval; HR, hazard ratio; HRD, homologous recombinant deficiency; ITT, intent-to-treat; PFS, progression-free survival..

17 Niraparib Significantly Increased PFS vs Placebo in gbrcamut Cohort Progression-Free Survival, % Niraparib Placebo 100 PFS Median 21.0 mos (95% CI) (12.9, NR) 5.5 mos (3.8, 7.2) 75 Niraparib 74% Reduction in Risk of Progression or Death HR (95% CI) 0.26 (0.17, 0.41) Estimated 24 Month PFS Niraparib: 42% Placebo: 16% Placebo Number at Risk: Time Since Randomization (months) Niraparib Placebo CI = confidence interval; gbrca = germline breast cancer susceptibility gene; gbrcamut = gbrca mutation; HR = hazard ratio; NR = not reached; PFS = progression-free survival. ZEJULA (niraparib) capsules [prescribing information]. Waltham MA: TESARO, Inc.; Matulonis UA, et al. ASCO Annual Meeting, Lord R, Mirza MR, Woelber L, et al. SGO Annual Meeting (Abstract 20: Oral Presentation).

18 Progression-free Survival (%) Progression-free Survival (%) Progression-free Survival (%) NOVA Exploratory Analysis Showed PFS Improvement Across Subgroups of Non-gBRCAmut Cohort HRD-positive 1 HRD-negative 1 sbrcamut HR (95% CI): 0.27 (0.08, 0.90) P= BRCAwt HR (95% CI): 0.38 (0.23, 0.63) P= HR (95% CI): 0.58 (0.36, 0.92) P= Niraparib Placebo 100 Niraparib Placebo 100 Niraparib Placebo Time Since Randomization (months) Estimated 24 mo PFS mo 20.9 mo mo 9.3 mo Time Since Randomization (months) HRD-positive HRD-negative Niraparib 31% 19% Placebo 9% 7% mo 6.9 mo Time Since Randomization (months) BRCA = breast cancer susceptibility gene; BRCAwt = BRCA wild-type; CI = confidence interval; HRD = homologous recombination deficiency; NR = not reached; PFS = progression-free survival; sbrcamut = somatic BRCA mutation. 1. Mirza MR, et al. N Engl J Med. 2016;375(suppl): Mirza MR. Oral Presentation at ESMO Matulonis UA, et al. ASCO Annual Meeting, 2017

19 Study 42: FDA Approval for Olaparib as Treatment for Patients with Ovarian Cancer, gbrca Mutation, and 3 Prior Lines of Chemotherapy Study 42 (NCT ) N 298 Design Phase II Patients Treatment Results Safety: Most common grade 3 AEs Recurrent cancers with gbrca (ovarian, breast, pancreatic, prostate) and progression after 3 prior therapies Ovarian cancer cohort (N=193): platinum-resistant epithelial ovarian, primary peritoneal, or fallopian tube cancer Olaparib 400 mg BID ORR (all patients): 26% ORR (patients with ovarian cancer): 31% Fatigue (6.4%) Anemia (17.4%) Abdominal pain (5.7%) Kauffman JC et al. J Clin Oncol. 2015;33(3):

20 Rucaparib Is Approved for Treatment of Ovarian Cancer With a Germline or Somatic BRCA Mutations Study 10 (NCT ) 1 ARIEL2 (NCT ) 2 Part 1 Part 2 BRCA mut sbrca mut BRCA wt, LOH high BRCA wt, LOH low N Phase I dose Design Phase II expansion Phase II escalation Patients Treatment Advanced solid tumor, progressed on treatment Rucaparib mg QD or BID (3+3) Platinum-sensitive, HGSOC, with gbrca1/2, 2 4 prior regimens Rucaparib 600 mg BID Platinum-sensitive, HGSOC, 1 prior platinum Part 2 (ongoing): platinum-sensitive, -resistant, or -refractory; 3 4 prior chemotherapies Rucaparib 600 mg BID Results RP2D: 600 mg BID ORR: 59.5% PFS: 12.8 mo Confirmed ORR: 74% PFS: 5.7 mo PFS: 5.2 mo Safety: Most common grade 3 AEs Fatigue (26.2%) Anemia (38.1%) Liver enzymes increased (14.3%) Anemia (22%) Liver enzymes increased (12%) The FDA also approved a companion diagnostic to test for BRCA mutation status (developed by Foundation Medicine Inc.) in conjunction with the rucaparib approval AE, adverse event; BID, twice daily; FDA, US Food and Drug Administration; gbrca, germline BRCA; HGSOC, high-grade serous ovarian cancer; LOH, loss of heterozygosity; L, line of treatment; mut, mutation; ORR, objective response rate; QD, once daily; RP2D, recommended phase II dose; sbrca, somatic BRCA; wt, wild-type. 1. Kristeleit R, et al. Clin Cancer Res. 2017;23(15): Swisher E, et al. Lancet Oncol. 2017;18(1):75-87.

21 QUADRA (NCT ): A Phase 2, Open-Label, Single-Arm Study to Evaluate the Safety and Efficacy of Niraparib in Patients with Advanced, Relapsed, High- Grade Serous Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Kathleen N. Moore, Angeles A. Secord, Melissa Geller, David S. Miller, Noelle G. Cloven, Gini F. Fleming, Andrea E. Wahner Hendrickson, Masoud Azodi, Paul DiSilvestro, Amit Oza, Mihaela Cristea, Jonathan S. Berek, John K. Chan, Yong Li, Katarina Luptakova, Romnee Clark, Ursula A. Matulonis, Bradley J. Monk ASCO 2018, Poster 5514

22 Engineering The Anti-tumor Cancer Immunity Immunity to Cycle Treat Cancer with Cell based Therapies Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity Jul 25;39(1):1-10

23 CD8 T -lymphocytes and PD-L1 Expression Ovarian Cancer Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med Jan 16;348(3): Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N, Honjo T, Fujii S. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A Feb 27;104(9):

24 Clinical Evidence for the Potential of Ovarian Cancer Immunotherapy Study Patients Treatment # Patients Response Survival Vald, Edwards Cancer Immunol Immunother 2010 Recurrent, platinum resistant ovarian Cancer Interleukin-2 i.p. 6 x 10 5 IU/ml weekly x CR: 4 PR: 2 SD: 7 Median Survival: Non-Responder: 1.5 years Responders: not reached ( months) Hodi, Dranoff PNAS 2008 Recurrent metastatic ovarian cancer CTLA-4 Blockade: Ipilupimab i.v. 3mg/kg q 2 3 months 9 CR: 0 PR: 1 SD: 3 Duration of Response: SD: 2,4,6+ Months PR: 35+ Months Diefenbach, Dupont Clin Cancer Res 2008 High Risk ovarian cancer after surgery and 1 st line chemo NY-ESO-1b peptide (position ; 100 μg) ml Montanide ISA-51 s.c. q 3 weeks x 5 9 NA Median PFS: 13 months 6/9 patients recurred 3 patient disease free after 25, 38, and 52 Fujita,Tanaka Clin Cancer Research 1995 NED after surgery and 1 st line chemo x 10 9 TIL after 1 st line chemo 13 TIL 11 Control NA 3-year DFS: TIL: 82.1% Control:54.5% 3-year DFS, residual disease after surgery TIL: 76.2% Control:33.3% Chester C, Dorigo O, Berek JS, Kohrt H. Immunotherapeutic approaches to ovarian cancer treatment. J Immunother Cancer Mar 24;3:7 Kandalaft LE, Powell DJ Jr, Singh N, Coukos G. Immunotherapy for ovarian cancer: what's next? J Clin Oncol Mar 1;29(7):

25 Targeting the PD-L1/PD-1 Immune Checkpoint in Ovarian Cancer Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer Mar 22;12(4):252-64

26 Complete Response to Nivolumab Platinum Resistant Ovarian Cancer Hamanishi J, et al.. Safety and Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer. J Clin Oncol Sep 8

27 Immune Checkpoint Inhibition in Ovarian Cancer Therapy Study Class Ph N Prior Ther apies Response (n/n) mpfs, mo mos, mo ORR CBR Nivolumab UMIN Anti PD-1 II 20 2 CR: 10 (2/20) PR: 5 (1/20) SD: 30 (6/20) % 45% Pembrolizumab KEYNOTE (NCT ) Anti PD-1 Ib 26 1 CR: 3.8 (1/26) PR: 7.7 (2/26) SD: 23.1 (6/26) ORR: 11.5 (3/26) NA NA 11% 35% Ipilimumab NCT Anti CTLA-4 II 40 4 ORR: % CI: NA NA 10% Avelumab JAVELIN 4 (NCT ) Anti PD-L1 Ib PR: 9.7 (12/124) SD: 44.4 (55/124) % 54% Atezolizumab Expansion Study 5 (NCT ) Anti PD-L1 Ia 12 NA PR: 2 of 9 patients

28 <br />KEYNOTE-100 (NCT ): Phase 2, Two-Cohort Study of Pembrolizumab for Recurrent Advanced Ovarian Cancer<br /> Presented By Ursula Matulonis at 2018 ASCO Annual Meeting

29 <br /> Presented By Ursula Matulonis at 2018 ASCO Annual Meeting

30 Efficacy by PD-L1 Expression: Cohorts B and A + B<br />Confirmed Response Rates Based on RECIST v1.1 per BICR # PD-L1 staining cells (tumor cells, lymphocytes, macrophages) Combined Positive Score (CPS): Total # of viable cancer cells Presented By Ursula Matulonis at 2018 ASCO Annual Meeting

31 Response Predictors to PARPi and Immunotherapy: Cancer Cell Genomics and Tumor Microenvironment Spectrum of Somatic Mutations in Cancer Genomes Tumor Mutational Burden Microsatellite Instability Neoantigen load Homologous Recombination Deficiency Martincorena I, Campbell PJ. Somatic mutation in cancer and normal cells. Science Sep 25;349(6255):1483-9

32 Biological Rationale for Combining PARPi with Immune Checkpoint Inhibition PARPi Sato H, Shibata A. DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells. Nat Commun Nov 24;8(1):1751 Jiao S, Hung MC. PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression. Clin Cancer Res Jul 15;23(14):

33 The Double Stranded Break Repair Pathways regulates PD-L1 Expression Sato H, Shibata A. DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells. Nat Commun Nov 24;8(1):1751 Jiao S, Hung MC. PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression. Clin Cancer Res Jul 15;23(14):

34 BRCA mutated Ovarian Cancers show increased Expression of PD-1 and PD-L1, and higher Neoantigen Load compared to HR-proficient Tumors Strickland, K. C., Howitt, B. E., Shukla, S. A., Rodig, S., Ritterhouse, L. L., Liu, J. F., Konstantinopoulos, P. A. (2016). Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget, 7(12),

35 Slide 4 Presented By Panagiotis Konstantinopoulos at 2018 ASCO Annual Meeting

36 Slide 7 Presented By Panagiotis Konstantinopoulos at 2018 ASCO Annual Meeting

37 Slide 10 Presented By Panagiotis Konstantinopoulos at 2018 ASCO Annual Meeting

38 Slide 11 Presented By Panagiotis Konstantinopoulos at 2018 ASCO Annual Meeting

39 A Phase 1 Study of the Anti-PD-1 Monoclonal Antibody BGB-A317 in Combination with the PARP Inhibitor BGB- 290 in Advanced Solid Tumors Friedlander M 1, Meniawy T 2, Markman B 3, Mileshkin L 4, Harnett P 5, Millward M 2, Lundy J 3, Freimund A 4, Norris C 1, Mu S 6, Wu J 7, Paton V 7, Wang L 8, Gao B 5 1 Prince of Wales Hospital, Randwick, NSW; 2 Linear Clinical Research & Sir Charles Gairdner Hospital, Nedlands, Western Australia; 3 Monash Cancer Centre, Clayton, Melbourne, Australia; 4 Peter MacCallum Cancer Centre, Melbourne, Victoria; 5 Westmead Hospital, Parramatta, NSW; 6 BeiGene USA, Inc., Fort Lee, NJ, USA; 7 BeiGene USA, Inc., Emeryville, CA, USA; 8 BeiGene (Beijing) Co., Ltd, Beijing, China NCT

40 A Phase 1 Study of the Anti-PD-1 Monoclonal Antibody BGB-A317 in Combination with the PARP Inhibitor BGB- 290 in Advanced Solid Tumors Tislelizumab (BGB-A317) is a humanized IgG4 monoclonal antibody Minimal Fc gamma receptor binding Targets the PD-1 receptor In development for solid and hematologic malignancies Pamiparib (BGB-290) is a potent, selective PARP 1/2 inhibitor Potent PARP DNA complex trapping Brain penetration in preclinical models Friedlander M 1, Meniawy T 2, Markman B 3, Mileshkin L 4, Harnett P 5, Millward M 2, Lundy J 3, Freimund A 4, Norris C 1, Mu S 6, Wu J 7, Paton V 7, Wang L 8, Gao B 5 Presented by: Dr Linda Mileshkin

41 Best Overall Response Rate RECIST v 1.1 Best Overall Response, n (%) Total (N=43) 31 March 2017 Total (N=49) 31 July 2017 Total (N=49) 4 January 2018 Complete response (CR) 1 (2) 2 (4) 2 (4) Partial response (PR) confirmed 3 (7) 5 (10) 8 (16) Partial response (PR) unconfirmed 7 (16) 7 (14) 4 (8) Objective response rate (CR+PR) 4 (9) 7 (14) 10 (20) Clinical benefit rate (CR+PR+durable SD with 24 weeks) 11 (26) 15 (31) 19 (39) Ovary/Fallopian/Peritoneum N=34 Objective response rate (CR+PR) NC NC 9* (26) Data presented as n (%). NC, not calculated.*3 pts with gbrca mutations. NCT Presented by: Dr Linda Mileshkin

42 Antitumor Activity of Pamiparib/Tislelizumab Combination Treatment across various solid Tumors Clinical Efficacy across various solid tumor types Independent of BRCA status. Ovarian cancer patients with encouraging responses. Data cut-off date: July 31, 2017 NCT Presented by: Dr Linda Mileshkin

43 Olaparib and Durvalumab in Germline BRCA-mutated platinum-sensitive relapsed Ovarian Cancer (MEDIOLA) Trial Design: - gbrcam platinum sensitive, recurrent ovarian cancer - Olaparib 300 mg (tablet) PO BID for 4-weeks, followed by olaparib 300 mg PO BID and durvalumab 1.5 g IV q 4 weeks until progressive disease (PD). - Primary endpoints disease control rate (DCR) at 12 weeks, safety, and tolerability. - Olaparib previously showed a median PFS of 11 months in the OC maintenance setting, and addition of durvalumab was predicted to increase it to 18.3 months, corresponding to a DCR of approximately 90% at 12 weeks. Presented by Y. Drew et al., Annual Meeting of the Society of Gynecologic Oncology New Orleans 2018

44 Olaparib and Durvalumab in Germline BRCA-mutated platinum-sensitive relapsed Ovarian Cancer (MEDIOLA) Results: - Complete Responses: 6/32 (19%), Partial Responses: 14/32 (44%) (ORR of 63%). - Observed DCR at 12 weeks of 81%, - Grade 3 adverse events anemia (9%), increased lipase (9%), increased amylase (6%), and neutropenia (3%). - In patients with 1 2 prior chemotherapies (n = 22), the ORR was 68%, including all 6 patients with CR Conclusion: - This non-chemotherapy combination may provide an clinically effective and well-tolerated treatment option for patients with gbrca, platinum sensitive recurrent ovarian cancer. Presented by Y. Drew et al., Annual Meeting of the Society of Gynecologic Oncology New Orleans 2018

45 Combination Immunotherapy Clinical Trials in Recurrent Ovarian Cancer

46 DNA Damaging Agents/Immunotherapy Combination Trials Brown JS, Sundar R, Lopez J. Combining DNA damaging therapeutics with immunotherapy: more haste, less speed. Br J Cancer Feb 6;118(3):

47 Biomarker-driven Approach to DNA Damaging Agents and Immunotherapy Combination Treatment Brown JS, Sundar R, Lopez J. Combining DNA damaging therapeutics with immunotherapy: more haste, less speed. Br J Cancer Feb 6;118(3):

48 PARP Inhibition and Immunotherapy Can we create Synergy? 1. Proven clinical efficacy of either PARPi or Immunotherapy in recurrent ovarian cancer. 2. PARPi can increase neoantigen expression and induce anti-tumor immune mechanisms in the tumor microenvironment. 3. PARPi combined with immune checkpoint inhibition has shown promising clinical efficacy in initial clinical trials.

49 Stanford Gynecologic Oncology Service Stanford Women s Cancer Center and Stanford Cancer Institute Thank you for your attention!