SOLO-1. Dott.ssa Elisabetta Sanna U.O.C. Ginecologia Oncologica- AOB Cagliari Direttore: Dott. Antonio Macciò

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2 SOLO-1 maintenance therapy in patients with newly diagnosed advanced ovarian cancer following platinum-based chemotherapy Dott.ssa Elisabetta Sanna U.O.C. Ginecologia Oncologica- AOB Cagliari Direttore: Dott. Antonio Macciò

3 There remains a significant unmet need for newly diagnosed ovarian cancer 1 Platinum-based chemotherapy Bevacizumab 1-18 months Median progression-free survival 2,3,4 ~7% 38% of women relapse within 3 5-year survival rate 5 years of first line treatment 1 There is a significant need for better frontline treatment to improve outcomes for women with ovarian cancer Ledermann, J. A. et al. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 24 Suppl 6, vi24-32 (213) 2. Bookman, M. A. et al. J. Clin. Oncol. 27, (29); 3. Burger, R. A. et al. N. Engl. J. Med. 365, (211); 4. Perren, T. J. et al. N. Engl. J. Med. 365, (211); 5. de Angelis R et al. Lancet Oncol 214;15:23-34.

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5 The majority of patients receive multiple lines of cytotoxic chemotherapy which is associated with cumulative toxicity and decreasing periods of remission 1-4 CA 125 level 1 ST LINE 2 ND LINE 3 RD LINE 4 TH LINE 5 TH LINE PFS PFS PFS PFS PFS 18.2 months 1.2 months 6.4 months 5.6 months 4.4 months Surgery * Bowel obstruction Symptoms Time PFS = progression-free survival; CA-125 = cancer antigen 125; = Common indicator of fatality 1. Markman, M. et al. The Oncologist. 2;5(1):26 35; 2. Hanker LC, et al. Ann Oncol. 212;23(1): ; 3. Armstrong, D. K. The Oncologist 7, 2 28 (22); 4.Fotopoulou, C. Eur. J. Cancer Suppl. 12, (214) 5

6 Woman responding no or very little (%) Women responding yes (%) Disease recurrence leads to a decrease in patient reported physical and emotional wellbeing Relapse (N=116) No relapse (N=57) ,5 8, ,7 15, ,6 21, ,5 15,8 66,4 26,3 Severe limitations in moderate activity Very limited ability to climb several flights of stairs Able to less than desired Limited in work and other activities Did less than wanted to Problems with concentration at work and home Colombo N et al. Int J Gynecol Cancer. 217;27(6);

7 maintenance treatment improves PFS in patients with platinum sensitive relapsed ovarian cancer 1-3 Study 19 Phase II study 1,2 Recurrent ovarian cancer after two or more prior lines of platinum therapy (N=265) Maintenance in patients achieving a CR/PR on platinum therapy capsules po 4mg bid significantly prolonged PFS compared with placebo (HR.35; 95% CI.25 to.49; p<.1) Trend towards benefit for overall survival (HR.73; 95% CI.55 to.95; nominal p=.21; statistical significance not reached) 11 vs 4 months Phase III study 3 Recurrent BRCAm ovarian cancer after two prior lines of platinum therapy (N=295) Maintenance in patients achieving a CR/PR on platinum therapy tablets po 3mg bid significantly prolonged PFS compared with placebo (HR.3; 95% CI.22 to.41; p<.1) 3 vs 5.5 months PFS = progression-free survival; CR = complete response; PR = partial response; po = per oral; bid = twice a day; HR = hazard ratio; CI = confidence interval 1. Ledermann J, et al. N Engl J Med. 212;366(15): ; 2. Gourley C, et al. J Clin Oncol 217;35(suppl); poster related to abstr 5533; 3. Pujade-Lauraine et al., Lancet Oncol. 217 Sep;18(9):

8 Treatment considerations 15% still alive, disease free, at 1 years First-line treatment Recurrent disease Cure Goal Palliation High Toxicity acceptance Low Less important Convenience More important When a women is diagnosed with advanced epithelial ovarian cancer, the goal of firstline treatment is to achieve a cure

9 SOLO-1 is the first Phase III trial to investigate maintenance therapy with a PARP inhibitor in newly diagnosed ovarian cancer SOLO-1 is a global randomised multicentre placebo controlled Phase III study Newly diagnosed, FIGO stage III IV, high-grade serous or endometrioid ovarian, primary peritoneal or fallopian tube cancer Germline or somatic BRCAm ECOG performance status 1 Cytoreductive surgery* In clinical complete response or partial response after platinumbased chemotherapy 3 mg bid (N=26) 2:1 randomisation Stratified by response to platinum-based chemotherapy (N=131) Study treatment continued until disease progression Patients with no evidence of disease at 2 years stopped treatment Patients with a partial response at 2 years could continue treatment 2 years treatment if no evidence of disease Primary endpoint Investigator-assessed PFS (modified RECIST 1.1) Secondary endpoints PFS using BICR PFS2 Overall survival Time from randomisation to first subsequent therapy or death Time from randomisation to second subsequent therapy or death HRQoL (FACT-O TOI score) *Upfront or interval attempt at optimal cytoreductive surgery for stage III disease and either biopsy and/or upfront or interval cytoreductive surgery for stage IV disease BICR = blinded independent central review; ECOG = Eastern Cooperative Oncology Group; FACT-O = Functional Assessment of Cancer Therapy Ovarian Cancer; FIGO = International Federation of Gynecology and Obstetrics; HRQoL = health-related quality of life; PFS = progression-free survival; PFS2 = time to second progression or death; RECIST = Response Evaluation Criteria in Solid Tumours; TOI = Trial Outcome Index; PARP = poly (ADP-ribose) polymerase; BRCAm = BRCA gene mutation (accessed October 218)

10 Patients in SOLO-1 had a minimum follow-up of 3 years Analysis Prespecified analysis at 26 PFS events 9% power at a two-sided significance level of 5% Target HR for PFS of.62 (median of 21 months [olaparib] vs. 13 months [placebo]) Protocol amended due to slower than projected event rate primary PFS analysis conducted after 196 events OR last patient randomised had the opportunity to be on study for 36 months First patient in: 3 Sep 213 Last patient in: 6 Mar 215 Data cut-off: 17 May 218 Minimum follow-up period of 3 years HR = hazard ratio; PFS = progression-free survival Moore K et al. Oral presentation LBA7_PR, ESMO (218)

11 Baseline characteristics were well balanced between treatment groups Characteristic (N=26) (N=131) Median age, years (range) 53. (29 82) 53. (31 84) Response after platinum-based chemotherapy, N (%) Clinical complete response* 213 (81.9) Partial response 47 (18.1) ECOG performance status, N (%) 1 Missing Primary tumour location, N (%) Ovary Fallopian tubes Primary peritoneal Other FIGO stage, N (%) III IV 2 (76.9) 6 (23.1) 22 (84.6) 22 (8.5) 15 (5.8) 3 (1.2) 22 (84.6) 4 (15.4) 17 (81.7) 24 (18.3) 15 (8.2) 25 (19.1) 1 (.8) 113 (86.3) 11 (8.4) 7 (5.3) 15 (8.2) 26 (19.8) *Clinical complete response was defined as no evidence of (RECIST) measurable or non-measurable disease on the post-treatment scan and a normal CA-125 level. Partial response was defined as a 3% reduction in tumour volume from the start to the end of chemotherapy or no evidence of disease on the post-treatment scan, but with a CA-125 level which had not decreased to within the normal range Other includes ovary, fallopian tube, peritoneum, and omentum (N=1), ovary and peritoneum (N=1) and tubo-ovary (N=1) ECOG = Eastern Cooperative Oncology Group; FIGO = International Federation of Gynecology and Obstetrics Moore K et al. N. Engl. J. Med. (218) epub ahead of print 11

12 Baseline characteristics were well balanced between treatment groups Characteristic (N=26) (N=131) Baseline CA-125 level, N (%) ULN >ULN Missing Histology, N (%) Serous Endometrioid Mixed serous/endometrioid BRCA mutation, N (%) BRCA1 BRCA2 Both BRCA1 and BRCA2 247 (95.) 13 (5.) 246 (94.6) 9 (3.5) 5 (1.9) 191 (73.5) 66 (25.4) 3 (1.2) 123 (93.9) 7 (5.3) 1 (.8) 13 (99.2) 1 (.8) 91 (69.5) 4 (3.5) Myriad/BGI or locally reported; the five patients from China had germline BRCA mutation testing performed within China, using the BGI test. Central germline testing confirmed that 388/391 patients had a BRCA1/2 mutation, 1 patient had a BRCA variant of uncertain significance, and 2 patients were BRCA wild-type. Foundation Medicine testing confirmed that the two germline BRCA wild-type patients had somatic BRCA mutations ULN = upper limit of normal per institutional standard. Moore K et al. N. Engl. J. Med. (218) epub ahead of print 12

13 Two thirds of patients had upfront surgery History of cytoreductive surgery, N (%) (N=26) (N=131) Upfront surgery Residual macroscopic disease No residual macroscopic disease Unknown Interval cytoreductive surgery Residual macroscopic disease No residual macroscopic disease No surgery 161 (61.9) 37 (23.) 123 (76.4) 1 (.6) 94 (36.2) 18 (19.1) 76 (8.9) 4 (1.5) 85 (64.9) 22 (25.9) 62 (72.9) 1 (1.2) 43 (32.8) 7 (16.3) 36 (83.7) 3 (2.3) Moore K et al. N. Engl. J. Med. (218) epub ahead of print [supplementary appendix] 13

14 The majority of patients received carboplatin and paclitaxel for 6 cycles Characteristic (N=26) (N=131) Agents administered during platinum-based chemotherapy prior to randomisation Bevacizumab Carboplatin Cisplatin Cyclophosphamide Docetaxel Doxorubicin Doxorubicin hydrochloride Gemcitabine Nab-paclitaxel Paclitaxel Number of cycles of platinum-based chemotherapy, N (%) (.4) 241 (92.7) 46 (17.7) 1 (.4) 15 (5.8) 1 (.4) 1 (.4) 2 (.8) 2 (.8) 253 (97.3) 2 (.8) 2 (.8) 198 (76.2) 17 (6.5) 18 (6.9) 23 (8.8) 115 (87.8) 32 (24.4) 7 (5.3) 1 (.8) 13 (99.2) 1 (.8) 16 (8.9) 1 (7.6) 7 (5.3) 7 (5.3) Moore K et al. N. Engl. J. Med. (218) epub ahead of print [supplementary appendix] 14

15 More than 5% of patients in the olaparib arm completed protocoldefined treatment Randomised, N Treated, N Discontinued treatment before 2 years Completed treatment at 2 years per protocol, N (%) Continued treatment beyond 2 years Still receiving treatment at data cut-off, N (%) 111 (42.6) 123 (47.3) 26 (1.) 13 (5.) 92 (7.7) 35 (26.9) 3 (2.3) 1 (.8) Median (mean) total treatment duration (months) 24.6 ( 52.) 13.9 ( ) Median (IQR) duration of follow-up, months 4.7 ( ) 41.2 ( ) DCO: May 218 IQR = interquartile range 1. Moore K et al. N. Engl. J. Med. (218) epub ahead of print; 2. Moore K et al. N. Engl. J. Med. (218) epub ahead of print [supplementary appendix]

16 The most common reason for discontinuation was disease progression Randomised, N Treated, N Discontinued treatment other than protocol defined stopping rule, N (%) Objective disease progression Adverse event Patient decision Other * /unknown reason 124 (47.7) 51 (19.6) 3 (11.5) 22 (8.5) 21 (8.1) 94 (72.3) 78 (6.) 3 (2.3) 2 (1.5) 11 (8.5) * Other includes study-specific discontinuation criteria, severe non-compliance to protocol and lost to follow-up, among other reasons DCO: May 218; Median duration of treatment: olaparib 24.6 months; placebo 13.9 months IQR = interquartile range 1. Moore K et al. N. Engl. J. Med. (218) epub ahead of print; 2. Moore K et al. Oral presentation LBA7_PR, ESMO (218)

17 Investigator-assessed progression-free survival (%) reduced the risk of progression or death by 7% vs. placebo 1 After a median follow-up of 41 months, the median PFS had not been reached in the olaparib arm (vs months in the placebo arm) No. at risk Stima PFS: 49.8 mesi vs 13.8 mesi: 36,7 mesi Months since randomisation Events, N (%) 12 (39.2) 96 (73.3) Median PFS (months) NR 13.8 HR=.3 95% CI:.23,.41 p<.1 Primary endpoint: investigator-assessed PFS DCO: May 218; Median FU: olaparib, 4.7 months placebo, 41.2 months Analysis was performed after 198 progression events had occurred (in 5.6% of patients) PFS = progression-free survival; DCO = data cut-off; HR = hazard ratio; CI = confidence interval 1. Moore K et al. N. Engl. J. Med. (218) epub ahead of print; 2. Moore K et al. Oral presentation LBA7_PR, ESMO (218)

18 Investigator-assessed progression-free survival (%) reduced the risk of progression or death by 7% vs. placebo 1 A 3 anni solo il 4% delle pazienti trattate con olaparib ricade, contro il 7% delle pazienti trattate con placebo No. at risk % progression free at 3 years Months since randomisation % progression free at 3 years Events, N (%) 12 (39.2) 96 (73.3) Median PFS (months) NR 13.8 HR=.3 95% CI:.23,.41 p<.1 Primary endpoint: investigator-assessed PFS DCO: May 218; Median FU: olaparib, 4.7 months placebo, 41.2 months Analysis was performed after 198 progression events had occurred (in 5.6% of patients) PFS = progression-free survival; DCO = data cut-off; HR = hazard ratio; CI = confidence interval 1. Moore K et al. N. Engl. J. Med. (218) epub ahead of print; 2. Moore K et al. Oral presentation LBA7_PR, ESMO (218)

19 Investigator-assessed progression-free survival (%) There was no obvious change in Kaplan-Meier curves after 2 years in the olaparib group, indicating an apparent enduring treatment benefit 1 After a median follow-up of 41 months, the median PFS had not been reached in the olaparib arm (vs months in the placebo arm) No. at risk Months since randomisation Events, N (%) 12 (39.2) 96 (73.3) Median PFS (months) NR 13.8 HR=.3 95% CI:.23,.41 p<.1 Primary endpoint: investigator-assessed PFS DCO: May 218; Median FU: olaparib, 4.7 months placebo, 41.2 months Analysis was performed after 198 progression events had occurred (in 5.6% of patients) PFS = progression-free survival; DCO = data cut-off; HR = hazard ratio; CI = confidence interval 1. Moore K et al. Oral presentation LBA7_PR, ESMO (218); 2. Moore K et al. N. Engl. J. Med. (218) epub ahead of print

20 A consistent benefit was seen across all PFS subgroups 1,2 Subgroup All patients Response to previous chemotherapy Complete response Partial response ECOG performance status at baseline Normal activity Restricted activity Baseline CA-125 value ULN >ULN gbrca mutation type by Myriad testing BRCA1 BRCA2 BRCA1/2 (both) Negative Age <65 years 65 years Stage of disease at initial diagnosis Stage III Stage IV Following debulking surgery prior to study entry Residual macroscopic disease No residual macroscopic disease 3 mg bid 12/26 (39.2) 73/213 (34.3) 29/47 (61.7) 75/2 (37.5) 27/6 (45.) 92/247 (37.2) 1/13 (76.9) 84/188 (44.7) 15/62 (24.2) /3 3/7 (42.9) 85/225 (37.8) 17/35 (48.6) 83/22 (37.7) 19/4 (47.5) 29/55 (52.7) 7/2 (35.) bid Number of patients with events/total number of patients (%) 96/131 (73.3) 73/17 (68.2) 23/24 (95.8) 76/15 (72.4) 2/25 (8.) 89/123 (72.4) 7/7 (1.) 69/91 (75.8) 26/39 (66.7) / 1/1 (1.) 82/112 (73.2) 14/19 (73.7) 79/15 (75.2) 17/26 (65.4) 23/29 (79.3) 69/98 (7.4) HR (95% CI).3 (.23,.41).35 (.26,.49).19 (.11,.34).33 (.24,.46).38 (.21,.68).34 (.25,.46) NC.4 (.29,.56).2 (.1,.38) NC.33 (.24,.45).45 (.22,.92).32 (.24,.44).49 (.25,.94).44 (.25,.77).33 (.23,.46) DCO: May 218; Median FU: olaparib, 4.7 months placebo, 41.2 months ECOG = Eastern Cooperative Oncology Group; ULN = upper limit of normal; PFS = progression-free survival; CA-125 = cancer antigen 125; DCO = data cut-off; HR = hazard ratio 1. Moore K et al. N. Engl. J. Med. (218) epub ahead of print; 2. Moore K et al. Oral presentation LBA7_PR, ESMO (218) better better

21 BICR-assessed progression-free survival (%) BICR analysis of PFS was consistent with the primary endpoint 1 led to a 72% reduction in the risk of disease progression or death vs. placebo Events, N (%) 75 (28.8) 75 (57.3) Median PFS (months) NR 14.1 HR=.28 95% CI:.2,.39; p<.1 No. at risk Months since randomisation DCO: May 218; Median FU: olaparib, 4.7 months placebo, 41.2 months Data maturity at 38.4% BICR = blinded independent centralised review; PFS = progression-free survival; DCO = data cut-off; HR = hazard ratio; CI = confidence interval 1. Moore K et al. N. Engl. J. Med. (218) epub ahead of print; 2. Moore K et al. Oral presentation LBA7_PR, ESMO (218) 21

22 Investigator-assessed progression-free survival (%) A 5% reduction in the risk of second progression or death was observed in SOLO-1 1,2 This demonstrates that olaparib maintenance does not diminish the benefit conferred by subsequent therapy No. at risk Months since randomisation Events, N (%) 69 (26.5) 52 (39.7) Median PFS2 (months) NR 41.9 HR=.5 95% CI:.35,.72; p<.1 In 2 nd line, PARP inhibitor was used in 33/94 (35%) and 1/91 (11%) of patients who received a subsequent therapy in the placebo and olaparib arms respectively DCO: May 218; Median FU: olaparib, 4.7 months placebo, 41.2 months Data maturity at 3.9% PFS2 = progression-free survival 2; DCO = data cut-off; HR = hazard ratio; PARP = poly (ADP-ribose) polymerase 1. Moore K et al. N. Engl. J. Med. (218) epub ahead of print; 2. Moore K et al. Oral presentation LBA7_PR, ESMO (218) 22

23 Adverse events were mostly mild or moderate in the olaparib arm 1,2 Grade 3 AEs occurred in 39% of patients in the olaparib arm vs. 19% in the placebo arm (N=26) (N=13) Median duration of treatment, months (range) 24.6 (-52.) 13.9 ( ) Any AE, N (%) 256 (98.5) 12 (92.3) Any AE of CTCAE Grade 3, N (%) 12 (39.2) 24 (18.5) Any SAE, N (%) 54 (2.8) 16 (12.3) DCO: May 218 A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose. results in death, is life-threatening. requires inpatient hospitalisation or causes prolongation of existing hospitalisation AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; DCO = data cut-off; SAE = serious adverse event 1. Moore K et al. N. Engl. J. Med. (218) epub ahead of print; 2. Moore K et al. Oral presentation LBA7_PR, ESMO (218) 23

24 Most interventions were managed through dose modifications without the need for discontinuation 1,2 11.5% of patients in the olaparib arm discontinued treatment due to an AE (N=26) (N=13) Any AE leading to a dose interruption, N (%) 135 (51.9) 22 (16.9) Any AE leading to a dose reduction, N (%) 74 (28.5) 4 (3.1) Any AE leading to discontinuation of treatment, N (%) 3 (11.5) 3 (2.3) The most common treatment-emergent AEs leading to discontinuation were Nausea (2.3% in the olaparib group vs..8% in the placebo group) Anaemia (2.3% in the olaparib group vs. % in the placebo group) DCO: May 218 AE = adverse event; DCO = data cut-off 1. Moore K et al. N. Engl. J. Med. (218) epub ahead of print [supplementary appendix]; 2. Moore K et al. Oral presentation LBA7_PR, ESMO (218) 24

25 The most common AEs reported in patients on olaparib in SOLO-1 were gastrointestinal disturbances, fatigue and anaemia (N=26) (N=13) Nausea 77,3.8 37,7 Fatigue/asthenia* 63, ,5 Vomiting ,6 Anaemia* 38, Diarrhoea 34, ,6 Constipation Dysgeusia 27,7 26,2 3,8 19,2 All grades (frequency 25%) Grade 3 (frequency 5%) All grades (frequency 25%) Arthralgia 25,4 26,9 Grade 3 (frequency 5%) Neutropenia* 23, , *Grouped term AE = adverse event 1. Moore K et al. Oral presentation LBA7_PR, ESMO (218) Adverse events (%)

26 The most common haematological AEs were anaemia and neutropenia 1,2 This is consistent with previous trials of olaparib in ovarian cancer 3mg bid (N=26) (N=13) Adverse events, % Any grade Grade 3 Any grade Grade 3 Anaemia* Neutropenia* Thrombocytopenia* *Grouped term AE = adverse event 1. Moore K et al. N. Engl. J. Med. (218) epub ahead of print; 2. AstraZeneca data on file (218) 26

27 The safety and tolerability profile for olaparib in SOLO-1 is consistent with previous knowledge despite longer duration of therapy SOLO-1 (newly diagnosed BRCAm) 1 SOLO-2 (PSR BRCAm) 2 tablet (N=26) (N=13) tablet (N=195) (N=99) Adverse events, % All Grades Grade 3 All Grades Grade 3 All Grades Grade 3 All Grades Grade 3 Anaemia* Neutropenia* Thrombocytopenia* Nausea Fatigue/asthenia Vomiting Diarrhoea CTCAE Grade % with AE leading to dose interruption % with AE leading to dose reduction % with AE leading to discontinuation *Grouped term PSR = platinum-sensitive relapse; CTCAE = Common Terminology Criteria for Adverse Events; AE = adverse event 1. Moore K et al. N. Engl. J. Med. (218) epub ahead of print; 2. Pujade-Lauraine E, et al. Lancet Oncol 217:18(9)

28 AEs of special interest were in line with rates seen in previous trials of olaparib 1,2 (N=26) (N=13) MDS/AML,* N (%) 3 (1.2) New primary malignancies, N (%) 5 (1.9) 3 (2.3) Pneumonitis/ILD, N (%) 5 (1.9) *The three cases of MDS/AML occurred months after stopping olaparib (duration of olaparib therapy of months); Including breast cancer (n=3), head and neck cancer (n=1) and thyroid cancer (n=1) in the olaparib group and breast cancer (n=3) in the placebo group AML = acute myeloid leukaemia; MDS = myelodysplastic syndrome; ILD = interstitial lung disease 1. Moore K et al. Oral presentation LBA7_PR, ESMO (218); 2. Moore K et al. N. Engl. J. Med. (218) epub ahead of print 28

29 Change from baseline in TOI score There was no clinically meaningful difference in HRQoL between arms The difference between olaparib and placebo in the mean change from baseline in TOI score over 24 months ( 3.; 95% CI 4.779, 1.216) was not clinically meaningful No. at risk Weeks since randomisation *TOI scores range from to 1, with higher scores indicating better HRQoL and a clinically meaningful difference defined as ±1 points HRQoL = health-related quality of life; TOI = trial outcome index; CI = confidence interval 1. Moore K et al. Oral presentation LBA7_PR, ESMO (218) 29

30 Conclusions Maintenance olaparib led to a substantial, unprecedented improvement in PFS in patients with newly diagnosed, advanced ovarian cancer and a BRCAm, with a difference in median PFS estimated to be in the region of 3 years 1,2 A 7% reduction in risk of disease progression or death was observed for olaparib vs. placebo-treated patients (HR.3; p<.1) 1 After a median follow up of 41 months, median PFS was not reached on the olaparib arm vs months for placebo with PFS at 3 years: 6.4% vs. 26.9% for olaparib vs placebo 1 A reduction in the risk of second progression or death was observed demonstrating that olaparib maintenance does not diminish the benefit conferred by subsequent therapy 1 The safety profile is consistent with previous olaparib data with most AEs being mild or moderate in severity and generally not leading to dose reduction or permanent discontinuation 1 There was no decrease in HRQoL from baseline for olaparib-treated patients over the 24-month treatment period and no clinically important differences in HRQoL compared with placebo-treated patients 1 PFS = progression-free survival; AE = adverse event; HRQoL = health-related quality of life; HR = hazard ratio; BRCAm = BRCA gene mutation 1. Moore K et al. N. Engl. J. Med. (218) epub ahead of print; 2. Moore K et al. Oral presentation LBA7_PR, ESMO (218) 3