TREATMENT FOR RELAPSING PLATINUM SENSITIVE EPITHELIAL OVARIAN CANCER

TREATMENT FOR RELAPSING PLATINUM SENSITIVE EPITHELIAL OVARIAN CANCER Sandro Pignata, MD, PhD Sabrina Chiara Cecere, MD Uro-Gynecological Department, Division of Medical Oncology, IRCCS National Cancer Institute Fondazione G. Pascale, Naples, Italy

OVARIAN CANCER (OC) RELAPSE Despite the best upfront treatment, ovarian cancer has a high incidence of relapse About 70 80% of FIGO stage III-IV ovarian cancer patients develop a disease relapse within 5 years Yang JC, et al. N Engl J Med. 2003; 349:427-34. Adapted from: Piccart MJ, et al. Randomised Intergroup Trial of Cisplatin Paclitaxel Versus Cisplatin Cyclophosphamide in Women With Advanced Epithelial Ovarian Cancer: Three-Year Results, J Natl Cancer Inst, 2000, 92, 9, 699 708, by permission of Oxford University Press

RECURRENT OVARIAN CANCER (ROC): POPULATION CHARACTERISTICS Response to Platinum Time to Recurrence Response to Further Platinum Platinum-sensitive 12 mos 30-60% Platinum-partially sensitive 6-12 mos 25-30% Platinum-resistant <6 mos <10% Platinum-refractory No initial response N/A

THE PLATINUM-FREE INTERVAL (PFI) TO CLASSIFY OC RELAPSE Breaking the old and arbitrary categorisation of relapsed OC P R I M A R Y T H E R A P Y 0 3 6 12 18 24 Refractory Resistant Partially Sensitive Fully Sensitive months Pisano C, et al. Ther Clin Risk Manag. 2009;5:421-426; Gadducci A, et al. Anticancer Res. 2001;21:3525-3533.

Survival (days) Response rate (%) THE PLATINUM-FREE INTERVAL (PFI) TO CLASSIFY OC RELAPSE Breaking the old and arbitrary categorisation of relapsed OC 1000 100 Overall survival 800 80 600 60 Response rate 400 200 0 40 20 366 217 32 9 90 166 0 3/Pr 0 3 3 6 6 9 9 12 TFI (months) 12 18 18 PFS Platinum sensitivity is a continous variable Adapted from Pujade-Lauraine E, et al. Proc Am Soc Clin Oncol. 2002;21: Abstract 829.

PFI IS NOT THE ONLY FACTOR TO CONSIDER IN THE TREATMENT CHOICE Fifth Ovarian Cancer Consensus Conference of the Gynaecologic Cancer InterGroup: recurrent disease From the Tokyo GCIG OC consensus conference PFI revisited Wilson MK, et al. Ann Oncol 2017;2(4):727 32 Treatment-free Interval (TFI) vs. Platinum-free Interval (PFI) Leary AF, et al. Ann Oncol. 2017 Apr 1;28(4):718-726.

«ONE SIZE DOSE DOES NOT FIT ALL» Breaking the old and arbitrary categorisation of relapsed OC Comorbidities Performance status Residual toxicities Symptoms gbrca Patient Tumour Histology Molecular characterisation sbrca HRD status (?) Surgery Previous treatments (type, number) Target maintenance therapy TFI Availability of treatments Treatment

Fifth Ovarian Cancer Consensus Conference of the Gynaecologic Cancer InterGroup: recurrent disease What has to be considered for platinum-sensitive relapse: Is there a role for surgery at relapse? Is a platinum-based therapy an option? Wilson MK, et al. Ann Oncol 2017;2(4):727 32

Fifth Ovarian Cancer Consensus Conference of the Gynaecologic Cancer InterGroup: recurrent disease What has to be considered for platinum-sensitive relapse: The role of surgery at relapse Non platinum-based therapy as an option Platinum-based therapy as an option Wilson MK, et al. Ann Oncol 2017;2(4):727 32

PLATINUM-SENSITIVE OC RELAPSE AGO DESKTOP III (ENGOT-ov20; NCT01166737): Surgery at relapse Study Design 80 centres in 12 countries Recruitment 9/2010 3/2015 407 of 409 pts evaluated (2 screening failures) Patients with: 1 st relapse PSROC AGO Score +ve R Cytoreductive surgery with max. effort for complete resection n=408 No OP PFS by Surgical Outcome Platinum-based combination therapy strongly recommended Immediate platinum-based combination therapy strongly recommended OP allowed 3 rd line Median PFS (mos) ΔPFS (mos) HR (95% CI) P-value Wald-test No surgery 14.0-1 - Surgery but with 0.98 13.7-0.3 residual tumour (0.71-1.35) 0.8952 Surgery with complete 0.56 21.2 +7.2 resection (0.43-0.72) <0.0001 du Bois A, et al. J Clin Oncol 35, 2017 (suppl; abstract 5501). Presented at ASCO Annual Meeting 2017. Courtesy of Prof A. du Bois.

PLATINUM-SENSITIVE OC RELAPSE Surgery at relapse: The new reality GOG-0213 trial design Women with recurrent ovarian, peritoneal primary or fallopian tube cancer and a treatment free interval 6 months Surgical candidate YES N=107 NO N=567 R Surgery No surgery R Regimen I Carboplatin AUC 5 Paclitaxel 175 mg/m 2 q 21 days n=674 Regimen II Carboplatin AUC 5 Paclitaxel 175 mg/m 2 Bevacizumab 15 mg/kg q 21 days Maintenance Bevacizumab 15 mg/kg q 21 days until progression or toxicity precludes further treatment Coleman L, et al. J Clin Oncol 36, 2018 (suppl; abstr 5501). Presented at ASCO Annual Meeting 2018.

PLATINUM-SENSITIVE OC RELAPSE Surgery at relapse: The new reality Coleman L, et al. J Clin Oncol 36, 2018 (suppl; abstr 5501). Presented at ASCO Annual Meeting 2018. Courtesy of Prof L. Coleman.

WHEN PLATINUM IS NOT AN OPTION Platinum hypersensitivity Progressed or relapsed OC during last platinum Residual toxicity (e.g. neurotoxicity, ) Wilson MK, et al. Ann Oncol 2017;2(4):727 32

WHEN PLATINUM IS NOT AN OPTION Hypersensitivity, incidence and development Incidence seems to be correlated with increased number of cycles of carboplatin administered, occurring in less than 1% of the patients during primary treatment but in 8 44% of patients during 2 nd or 3 rd line 1,2 The risk of hypersensitivity reactions rises with a longer platinum-free interval 3 Particular caution is advised in patients receiving: 4 More than eight courses of carboplatin Second platinum dose after reintroduction in second-line chemotherapy 1. Sliesoraitis S, Chikhale PJ. Int J Gynecol Cancer. 2005;15:13-8; 2. Gadducci A, et al. Int J Gynecol Cancer. 2008;18(4):615-20; 3. O Cearbhaill R, et al. Gynecol Oncol. 2011;116(3):326-31; 4. Markman M, et al. J Clin Oncol.1999;17(4):1141-5.

WHEN PLATINUM IS NOT AN OPTION: TFIP 6 12 MONTHS OVA-301 trial An open-label, multi-centre, randomised Phase 3 study comparing the combination of PLD and Trabectedin with PLD alone in patients with advanced relapsed ovarian cancer (ROC) PFS 1 OS 2,3 1. Poveda A, et al. Ann Oncol 2011;22(1):39 48, by permission of Oxford University Press on behalf of the European Society for Medical Oncology (ESMO) ; 2. Reprinted from Eur J Cancer, 2012; 48, Monk BJ, et al. Trabectedin plus pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer: Overall survival analysis, 2361 8; Copyright 2012, with permission from Elsevier. 3. Poveda A, et al. Cancer Treat Rev 2014;40:366 75.

WHEN PLATINUM IS NOT AN OPTION The post hoc analysis of the OVA-301 trial: TFIP 6-12 months T+PLD a valid option in BRCA mutated ROC BRCA1-mutated patients treated with T+PLD showed longer PFS and OS compared to PLD BRCA1 mut may predict improved outcome to T + PLD treatment Monk BJ, et al. Effect of BRCA1 and XPG mutations on treatment response to trabectedin and pegylated liposomal doxorubicin in patients with advanced ovarian cancer: exploratory analysis of the phase 3 OVA-301 study. Ann Oncol 2015;26(5):914 20. by permission of Oxford University Press on behalf of The European Society for Medical Oncology (ESMO).

WHEN PLATINUM IS AN OPTION Platinum-based combination Platinum-based combination PARP inhibitors Carboplatin + gemcitabine + bevacizumab bevacizumab maintenance (for bevacizumab naïve) Platinum-based combination + bevacizumab bevacizumab maintenance (for bevacizumab pre-treated in first line)

WHEN PLATINUM IS AN OPTION All the platinum based combinations are equivalent in terms of efficacy, with different toxicity profiles ICON 4/AGO OV 2.2 GEICO 0104 CARBO AUC5 + TAX 175 mg/m² q21d Alopecia, neurotoxicity, haematologic toxicity, hypersensibility AGO OV 2.5 CARBO AUC4 d1+ GEM 1000 mg/m² d1,8 q21d Haematologic toxicity, hypersensibility CALYPSO/ AGO OV 2.9 CARBO AUC5 + PLD 30 mg/m² Palmoplantar erythrodysesthesia, mucositis, thrombocytopenia

META-ANALYSIS COMBINATION THERAPY VS. MONOTHERAPY Carbo/paclitaxel, carbo/pld, carbo/gemcitabine Endpoint Odds ratio combo/mono (95% CI) P value ORR (n=1730, 8 studies) 1.42 (1.1601.74) 0.001 PFS at 2 years (n=2234, 7 studies) 0.67 (0.52-0.89) 0.004 PFS at 1 year 0.69 (0.57-0.84) 0.000 OS at 2 years (n=2315, 8 studies) 0.80 (0.067-0.95) 0.012* Combination chemotherapy appears to improve ORR, PFS, and OS when compared to monotherapy in the management of ROC Orlando M, et al. ASCO 2007, Abstract 5524; Pfisterer J, et al. J Clin Oncol. 24: 4699-4707, 2006; Parmar MK, et al. Lancet 361: 2099-2106, 2003.

WHEN PLATINUM IS AN OPTION Platinum-based combination Platinum-based combination PARP inhibitors Carboplatin + Gemcitabine + bevacizumab bevacizumab maintenance (for bevacizumab naïve) platinum-based combination + bevacizumab bevacizumab maintenance (for bevacizumab pre-treated in first line)

SOLO2/ENGOT-OV21: STUDY DESIGN Patients BRCA1/2 mutation Platinum-sensitive relapsed ovarian cancer At least 2 prior lines of platinum therapy CR or PR to most recent platinum therapy R 2:1 Olaparib tablets 300 mg bid n=196 Placebo n=99 Primary endpoint Investigator-assessed PFS Sensitivity analysis: PFS by blinded independent central review (BICR) Key secondary endpoints: Time to first subsequent therapy or death (TFST), time to second progression (PFS2), time to second subsequent therapy or death (TSST), overall survival (OS) Safety, health-related quality of life (HRQoL*) *Primary endpoint for HRQoL was trial outcome index (TOI) of the FACT-O (Functional Assessment of Cancer Therapy Ovarian) Presented by Pujade-Lauraine E, at SGO 2017 Annual Meeting.

Progression-free survival (%) PFS BY INVESTIGATOR ASSESSMENT Olaparib (n=196) Placebo (n=99) Events (%) 107 (54.6) 80 (80.8) Median PFS, months 19.1 5.5 Months since randomisation Median follow-up was 22.1 months in the olaparib group and 22.2 months for placebo Reprinted from The Lancet Oncol, 18(9), Pujade-Lauraine E, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial, 1274 84. Copyright 2017, with permission from Elsevier.

NOVA STUDY Phase III trial of maintenance therapy with Niraparib in recurrent platinum-sensitive high-grade serous ovarian cancer Patient stratification Relapsed high-grade serous histology or known gbrca mut 2 prior regimens of platinum-based chemotherapy Responded to last platinum regimen; remains in response and enrolled within 8 weeks of completion of last platinum regimen No measurable lesion >2 cm Non-gBRCA mut gbrca mut Time to disease progression on penultimate platinum-based therapy Bevacizumab with last or penultimate chemotherapy CR/PR during last platinum regimen Mirza MR, et al. N Engl J Med 2016;375:2154 2164. N=553 R 2:1 R 2:1 Niraparib 300 mg QD N=234 Placebo N=116 Niraparib 300 mg QD N=138 Placebo N=65 Primary endpoint BICR-assessed PFS in 3 predefined cohorts gbrca Overall Non-gBRCA Non-gBRCA HRD+ Key secondary endpoints PRO, chemotherapy-free interval; time to first subsequent treatment; PFS2; time to second subsequent treatment; OS; safety Exploratory analysis Non-gBRCA mut cohort: PFS stratified by HRD/BRCA status HRD positive, sbrca mut HRD-positive BRCA wt HRD-negative

NOVA TRIAL: MAINTENANCE NIRAPARIB IN PLATINUM-SENSITIVE HGOC 1º Endpoint: BICR assessed PFS Niraparib (n=138) Placebo (n=65) Median PFS, months 21.0 5.5 HR=0.27 95% CI 0.17, 0.41 P<0.001 Niraparib (n=234) Placebo (n=116) Median PFS, months 9.3 3.9 HR=0.45 95% CI 0.34, 0.61 P<0.001 From N Engl J Med, Mirza MR, et al, Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer, 375, 2154 64. Copyright 2016, Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Progression-free survival (%) Progression-free survival (%) Progression-free survival (%) NOVA EXPLORATORY ANALYSIS PFS in non-gbrca mut subgroups HRD positive HRD negative sbrca mut (n=47) BRCA wt (n=115) (n=134) Niraparib (n=35) Placebo (n=12) Niraparib (n=71) Placebo (n=44) Niraparib (n=92) Placebo (n=42) PFS median (95% CI) (Months) 20.9 (9.7 NR) 11.0 (2.0 NR) PFS median (95% CI) (Months) 9.3 (5.8 15.4) 3.7 (3.3 5.6) PFS median (95% CI) (Months) 6.9 (5.6 9.6) 3.8 (3.7 5.6) Hazard ratio (95% CI); P value 0.27 (0.081 0.903); P=0.0248 Hazard ratio (95% CI); P value 0.38 (0.231 0.628); P=0.0001 Hazard ratio (95% CI); P value 0.58 (0.361 0.922); P=0.0226 % of patients without progression or death at 12 mo 62% 19% % of patients without progression or death at 12 mo 45% 11% % of patients without progression or death at 12 mo 27% 7% % of patients without progression or death at 18 mo 52% 19% % of patients without progression or death at 18 mo 27% 6% % of patients without progression or death at 18 mo 19% 7% 100 75 Hazard ratio 0.27 (95% CI 0.08 0.90) P=0.02 100 75 Hazard ratio 0.38 (95% CI 0.23 0.63) P<0.001 100 75 Hazard ratio 0.58 (95% CI 0.36 0.92) P=0.02 Niraparib 50 50 50 25 Placebo 0 0 2 4 6 8 10 12 14 16 18 20 22 24 No. at Risk Months since randomisation Niraparib 35 32 29 26 23 21 19 17 9 8 7 2 1 Placebo 12 9 7 4 4 3 1 1 1 1 1 1 1 Niraparib 25 25 Niraparib Placebo Placebo 0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 No. at Risk No. at Risk 0 2 4 6 8 10 12 14 16 18 20 22 24 Months since randomisation Months since randomisation Niraparib 71 58 46 38 29 25 21 12 7 6 4 2 1 Niraparib 92 73 54 35 26 22 11 8 3 3 3 2 1 Placebo 44 32 19 12 7 6 3 2 0 Placebo 42 35 19 11 7 6 2 2 0 From N Engl J Med, Mirza MR, et al., Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer, 375, 2154 64. Copyright 2016, Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society; Mirza MR, et al. Ann Oncol. 2016;27(Suppl 6): Abstract LBA3_PR.

ARIEL-3 Phase 3, randomised, double-blind study of rucaparib vs. placebo following response to platinum-based chemotherapy for recurrent ovarian carcinoma study design Patient eligibility Stratification High-grade serous or endometrioid epithelial OC, primary peritoneal, or fallopian tube cancers Sensitive to penultimate platinum Responding to most recent platinum (CR or PR)* Excludes patients without assessable disease following second surgery CA-125 within normal range No restriction on size of residual tumour ECOG PS 1 No prior PARP inhibitors R 2:1 HRR gene mutation status by NGS analysis: BRCA1 or BRCA2 Non-BRCA HRR gene None of the above Response to recent platinum CR PR Progression-free interval after penultimate platinum 6 to 12 months >12 months Rucaparib 600 mg BID n=375 Placebo BID n=189 *CR (defined by RECIST) or PR (defined by RECIST and/or a GCIG CA-125 response [CA-125 within normal range]) maintained until entry to ARIEL3 ( 8 weeks of last dose of chemotherapy). ATM, ATR, ATRX, BARD1, BLM, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L, RPA1.,BID.

ARIEL3 Investigator-Assessed Progression-Free Survival BRCA mutant Median HRD Median ITT Rucaparib (n=130) Placebo (n=66) (months) 95% CI 16.6 13.4 22.9 5.4 3.4 6.7 HR, 0.23; 95% CI, 0.16 0.34; P<0.0001 Rucaparib (n=236) Placebo (n=118) (months) 95% CI 13.6 10.9 16.2 5.4 5.1 5.6 HR, 0.32; 95% CI, 0.24 0.42; P<0.0001 Rucaparib (n=375) Placebo (n=189) Median (months) 95% CI 10.8 8.3 11.4 5.4 5.3 5.5 HR, 0.36; 95% CI, 0.30 0.45; P<0.0001 At risk (events) Rucaparib 130 (0) 93 (23) 63 (46) 35 (58) 15 (64) 3 (67) 0 (67) Placebo 66 (0) 24 (37) 6 (53) 3 (55) 1 (56) 0 (56) Rucaparib, 48% censored Placebo, 15% censored At risk (events) Rucaparib 236 (0) 161 (55) 96 (104) 54 (122) 21 (129) 5 (134) 0 (134) Placebo 118 (0) 40 (68) 11 (95) 6 (98) 1 (101) 0 (101) Rucaparib, 43% censored Placebo, 14% censored Rucaparib 375 (0) 228 (111) At risk (events) 128 (186) 65 (217) 26 (226) 5 (234) 0 (234) Placebo 189 (0) 63 (114) 13 (160) 7 (164) 2 (167) 1 (167) 0 (167) Rucaparib, 38% censored Placebo, 12% censored Reprinted from The Lancet, Vol.390, Nº10106, Coleman RL, et al., The Lancet,, Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial, p1949-1961. Copyright 2017, with permission from Elsevier.

WHEN PLATINUM IS AN OPTION Bevacizumab in platinum-sensitive relapsed OC: the OCEANS trial CBDCA AUC 4 GEM 1000 mg/m 2 d1, 8 Platinum-sensitive recurrent OC Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior bevacizumab n=484 CG + placebo CG + bevacizumab Placebo q3w until progression CBDCA AUC 4 GEM 1000 mg/m 2 d1, 8 Bevacizumab 15 mg/kg q3w until progression Stratification variables: Platinum-free interval (6-12 vs. >12 months) Cytoreductive surgery for recurrent disease (yes vs. no) CG for 6 (up to 10) cycles Epithelial ovarian, primary peritoneal, or fallopian tube cancer. Aghajanian C, et al. J Clin Oncol 30(17), 2012:2039 45

WHEN PLATINUM IS AN OPTION OCEANS trial: PFS and OS results Primary analysis of PFS 1 Final OS 2 1. Aghajanian C, et al. J Clin Oncol, 30(17), 2012:2039 45. Reprinted with permission. 2012 American Society of Clinical Oncology; 2. Reprinted from Gynecol Oncol 139(1), Aghajanian C, et al. Final overall survival and safety analysis of OCEANS, a phase 3 trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent ovarian cancer, 10 6. Copyright 2015, with permission from Elsevier.

x6-8 cycles WHEN PLATINUM IS AN OPTION Bevacizumab beyond progression in platinum-sensitive bevacizumab pre-treated relapsed OC: the MITO-16/MaNGO OV-2 trial design CG + placebo Carboplatin PLD or gemcitabine or paclitaxel Stage IIIB-IV EOC, FT or PPC progressing or recurring at least 6 months after front-line chemotherapy plus avastin (n 400) 1:1 Carboplatin PLD or gemcitabine or paclitaxel CG + bevacizumab Avastin 15 mg/kg q3w Primary endpoint PFS Until PD

WHEN PLATINUM IS AN OPTION MITO-16B/MaNGO OV-2B trial: PFS results PFS Investigator assessed (Primary endpoint) Standard Experimental Log Rank P No. of events 161 143 Median PFS 8.8 months 11.8 months <0.001 HR* (95% CI) 0.51 (0.41-0.65) *Adjusted by: Age, PS, centre size, bevacizumab at relapse, chemo backbone, residual disease at initial surgery Pignata S, et al. J Clin Oncol 36, 2018 (suppl; abstr 5506). Presented at ASCO Annual Meeting 2018.

WHEN PLATINUM IS AN OPTION Treatment algorithm BRCA mutated or WT Platinum based treatment Radiologic CR or PR Olaparib/ niraparib Platinum based ct If TFIp 6-12 months consider Pld + trabectedin Platinum based treatment Carbo-gem + bevacizumab Bevacizumab Platinum based treatment Olaparib/ niraparib TFIp 6-12 months Pld + trabectedin Platinum based ct SECOND LINE MAINTENANCE THIRD LINE FOURTH LINE

CONCLUSIONS Platinum free interval is not the only parameter to be considered to select treatment for recurrence. Other parameters including biology, pathology and previous target maintenance therapy need to be taken into account. Recurrent OC patients are classified for being candidate or not to a platinum re-treatment. Indication for surgery must be assessed although final results of trials are still pending. Platinum combination chemotherapy is more effective than single agent platinum. In patients who respond to a platinum based therapy, PARP-i maintenance is effective in prolonging PFS, with higher effect in BRCA mutated patients. Platinum based therapy plus bevacizumab prolongs PFS compared to chemo alone, both in patients who are bevacizumab naive or bevacizumab pre-treated. Bev-containing regimens given in preference to patients at high risk of quick progression and large bulk of disease. In patients with TFI between 6 12 months, not candidate for platinum, trabectedine-pld should be considered.

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