Current role of chemotherapy in hormone-naïve patients Elena Castro

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1 Current role of chemotherapy in hormone-naïve patients Elena Castro Spanish National Cancer Research Centre Lugano, 17 October 2017

2 Siegel, Ca Cancer J Clin,2017 Buzzoni, Eur Urol, Aprox 15-20% of new PrCa diagnosis present with advanced disease: - 4-5% distant metastasis EU, USA - Prevalence of metastasis at diagnosis varies geographically, depending on screening programs, access to health system, etc % patients with metastatic disease will present it after recurrence following treatment for localized disease. 20% Metastatic Disease M1 CPRC_M1 80% Local DIsease M0 Recurrence M1 CPRC_M1

-ADT may induce biochemical and clinical responses in 90% of patients - After 24-36 months progression to Castration Resistance Prostate Cancer ocurrs

3 -ADT may induce biochemical and clinical responses in 90% of patients - After months progression to Castration Resistance Prostate Cancer ocurrs -ADT may induce adaptation of hormone-sensitive cells and/or selection of ARindependent clones Hellerstdet, CA Cancer J Clin, 2002 Zong, Nat Rev Urol, 2013

Docetaxel TAX-327 Metastatic No Chemo ECOG 2 n=1006 Docetaxel 75mg/m 2 q3w +

N=33 4 Mitoxantrone 12mg/m 2 q3w + Prednisone 5 mg /12h N=33 7 Study

response Improved OS (18.9m vs 16.5 m, p<0.

4 Docetaxel TAX-327 Metastatic No Chemo ECOG 2 n=1006 Docetaxel 75mg/m 2 q3w + Prednisone 5 mg /12h N=33 5 Docetaxel 30 mg/m 2 1w + Prednisone 5 mg /12h N=33 4 Mitoxantrone 12mg/m 2 q3w + Prednisone 5 mg /12h N=33 7 Study endpoints: Primary: OS Secondary: Pain reduction, QoL, 50% decline, tumour response Improved OS (18.9m vs 16.5 m, p<0.001) 50% PSA decline (45% vs 32 %, p<0.001) Reduction in pain: 35 % vs 22 % (p=0.01) QoL:22% vs 13% (p=0.009) Tannock, NEJM, 2004

5 Would the adition of docetaxel to ADT for M1 hormone-sensitive PrCa delay the progression to mcrpc and improve survival?

GETUG 15 study M1 HSPC Stratification - Previous TT -Glass risk group

<or >8 Docetaxel 75mg/m 2 q3w (No prednisone) up to 9 cycles + ADT N=19 3 ADT

endpoints: Primary: OS Secondary: Clinical and PSA Progression Free Survival

6 GETUG 15 study M1 HSPC Stratification - Previous TT -Glass risk group -Apendicular vs axial disese -Performance status -PSA < or > 65ng/dL -Gleason <or >8 Docetaxel 75mg/m 2 q3w (No prednisone) up to 9 cycles + ADT N=19 3 ADT alone 72% de novo M1 Median follow-up: 50 months Median 8 cycles N=19 2 Study endpoints: Primary: OS Secondary: Clinical and PSA Progression Free Survival Median OS: 58.4 vs 52.2 months, p=0.955) 3y OS: 64.2% vs 62.9% Gravis, Lancet Oncol, 2013

7 bpfs: 22.9 vs 12.9, HR 0.72, p=0.005 cpfs: 20.5 vs 15.4, HR 0.75, p=0.015

CHAARTED study M1 HSPC Stratification -Low vs High volume

-Adjuvant ADT <12 vs<12 months 73% de novo M1 27%

up to 6 cycles + ADT N=39 7 ADT alone N=39 3 ADT allowed

9 months Study endpoints: Primary: OS Secondary: Time to

6 vs 44 months (HR 0.61, p<0.001) cpfs: 33 vs 19.

8 CHAARTED study M1 HSPC Stratification -Low vs High volume - Age <70 vs >70 yrs -MAB <30 vs >30 days -SER prevention -Adjuvant ADT <12 vs<12 months 73% de novo M1 27% recurrent disease Docetaxel 75mg/m 2 q3w (No prednisone) up to 6 cycles + ADT N=39 7 ADT alone N=39 3 ADT allowed up to 120 days prior to randomization Median follow-up: 28.9 months Study endpoints: Primary: OS Secondary: Time to CRPC andto clinical progression Improved OS: 57.6 vs 44 months (HR 0.61, p<0.001) cpfs: 33 vs 19.8 monts (HR, 0.49 p<0.001) Time to CRPC: 20.2 vs 11.7 months (HR 0.56,p<0.001) Seeney,NEJMl, 2015

9 ADT + docetaxel was beneficial in all subgroups Seeney,NEJMl, 2015

10 STAMPEDE: Docetaxel +Pred + ADT vs ADT Recruitment: Oct-2005 to Mar-2013 Patients: 1184 SOC 592 SOC+DocP Allocation ratio:2:1 Courtesy of Dr Sydes

STAMPEDE Docetaxel 75mg/m 2 q3w + Prednisone

SOC (ADT+/-RT) N=1184 Metastasis at presentation

11 STAMPEDE Docetaxel 75mg/m 2 q3w + Prednisone 5mg/12h up to 6 cycles + SOC N=592 SOC SOC+DOC OS: 81 vs 71 months, (HR 0.78, p=0.006) 61% M1 and 39% M0 Median follow-up: 43 months SOC (ADT+/-RT) N=1184 Metastasis at presentation OS: 60 vs 45 months (HR 0.76, p=0.005) Study endpoints: Primary: OS Secondary: PFS

13 Do all patients benefit the same? HIGH volume disease -Visceral metastasis or - 4 bone metastasis with 1 beyond vertebral bodies and pelvis Sweeney,NEJMl, 2015

14 CHAARTED_update ESMO Benefit on OS in High Volume - Low Volume: Benefit on time to CRPC: 31 months (ADT+Doce) vs 27monts (ADT), p=0.03

15 GETUG-AFU15 post hoc analysis OS High Volume Disease (48%) OS Low Burden Disease - 20% reduction in the risk of death in the HVD group (No significant) - Patients with LVD did not benefit form early docetaxel.

16 Puente, Ther Adv Me Oncol, 2017

17 METAANALYSIS M patients included -Addition of Docetaxel to ADT improved OS. -HR 0.77 and 9% absolute improvement in survival at 4 years. -Addition of Docetaxel to ADT improved PFS. -HR 0.64 and 15% absolute reduction in failure at 4 years. Overall Survival PFS Vale, Lancet Oncol, 2016

18 METAANALYSIS M0 2121patients included -Addition of Docetaxel to ADT did not improved OS. -HR 0.87, p= Addition of Docetaxel to ADT improved PFS. -HR 0.70 and 8% absolute reduction in failure at 4 years. Overall Survival PFS

19 CONCLUSIONS -Addition of Docetaxel to ADT should be considered standard of care for M1 Hormone- Sensitive Prostate Cancer. - Further evidence on the impact of Docetaxel in survival is needed to recomend the addition of docetaxel to ADT for M0 patients

20 LATITUD trial The addition of abiraterone acetate to ADT significantly increases OS and rpfs in M1 HSPC Fizazi, NEJM, 2017

21 Slide 30 Presented By Nicholas James at 2017 ASCO Annual Meeting

22 Reference OK.SO WHAT SHOULD WE USE?

STAMPEDE: SOC+AAP vs SOC+DocP -Evidence about whether to give both is pending ESMO 2017-566 patients randomised

23 STAMPEDE: SOC+AAP vs SOC+DocP -Evidence about whether to give both is pending ESMO patients randomised contemporaneously to either research arm: Patients: 189 SOC+DocP 377 SOC+AAP Recruitment: Nov2011-Mar2013 Courtesy of Matt Sydes. ESMO 2017

Populations in each comparison SOC+DocP vs SOC M1 61% Age 65 yr median PSA 68 ng/ml median Accrue Oct-2005 to Mar-2013 Freeze May-2015 SOC+DocP vs SOC+AAP M1 60% Age 66 yr median PSA 56

24 Populations in each comparison SOC+DocP vs SOC M1 61% Age 65 yr median PSA 68 ng/ml median Accrue Oct-2005 to Mar-2013 Freeze May-2015 SOC+DocP vs SOC+AAP M1 60% Age 66 yr median PSA 56 ng/ml median Accrue Nov-2011 to Mar-2013 Freeze Mar-2017 SOC+AAP vs SOC M1 52% Age 67 yr median PSA 53 ng/ml median Accrue Nov-2011 to Jan-2014 Freeze Mar-2017 Courtesy of Matt Sydes. ESMO 2017

25 Overall Survival SOC+DocP SOC+AAP HR (95%CI) P-val All 1.16 (0.82 to 1.65) 0.40 M (0.58 to 3.93) 0.40 M (0.77 to 1.66) 0.53 Interact n test 0.69 SOC+DocP SOC+AAP Events Pts Events Pts All Key: HR<1 favours SOC+AAP HR>1 favours SOC+DocP M M Interact n = test for interaction (heterogeneity of treatment effect) Courtesy of Matt Sydes. ESMO 2017

26 Cause-specific survival Status SOC+DocP SOC+AAP N % N % Alive % % Dead 44 23% % Sub-HR (95%CI) P-val All 1.02 (0.70 to 1.49) 0.92 Competing risks approach PCa Death 40 21% 86 23% Other cause 4 2% 19 5% SOC+DocP death: 91% PCa and 9% other SOC+AAP deaths: 82% PCa and 18% other Key: HR<1 favours SOC+AAP HR>1 favours SOC+DocP Courtesy of Matt Sydes. ESMO 2017

27 PSA Failure-free survival SOC+AAP HR (95%CI) P-val Interactn test SOC+DocP All 0.51 (0.39 to 0.67) <0.001 M (0.16 to 0.69) M (0.42 to 0.75) < SOC+DocP SOC+AAP Events Pts Events Pts All Key: HR<1 favours SOC+AAP HR>1 favours SOC+DocP M M Interact n = test for interaction (heterogeneity of treatment effect) Courtesy of Matt Sydes. ESMO 2017

28 Progression-free survival SOC+AAP HR (95%CI) P-val Interact n test SOC+DocP All 0.65 (0.48 to 0.88) M (0.17 to 1.05) 0.06 M (0.50 to 0.95) SOC+DocP SOC+AAP Events Pts Events Pts All Key: HR<1 favours SOC+AAP HR>1 favours SOC+DocP Interact n = test for interaction (heterogeneity of treatment effect) M M PFS = FFS ignoring PSA failure Courtesy of Matt Sydes. ESMO 2017

29 Metastatic progression-free survival SOC+AAP SOC+DocP HR (95%CI) P-val All 0.77 (0.57 to 1.03) 0.08 M (0.42 to 2.01) 0.82 M (0.55 to 1.04) 0.09 Interact n test 0.74 SOC+DocP SOC+AAP Events Pts Events Pts All Key: HR<1 favours SOC+AAP HR>1 favours SOC+DocP Interact n = test for interaction (heterogeneity of treatment effect) M M MPFS = new or progression of metastases

30 Symptomatic skeletal events SOC+AAP SOC+DocP HR (95%CI) All 0.83 (0.55 to 1.25) 0.38 P-val Interactn test M (0.24 to 6.67) 0.77 M (0.53 to 1.25) SOC+DocP SOC+AAP Events Pts Events Pts All Key: HR<1 favours SOC+AAP HR>1 favours SOC+DocP M M Interact n = test for interaction (heterogeneity of treatment effect)

31 Exposure to relapse treatments after FFS event Docetaxel started after FFS event AR-targeted therapy started after FFS event SOC+AAP SOC+DocP SOC+DocP SOC+AAP FFS event FFS event Note: Randomisation: Nov-2011 to Jan-2013 Data freeze: Feb-2017 Note: Relapse treatments at investigators discretion Access to relapse treatments may depend on: Metastatic status at event Calendar year of event Suspect under reporting of third-line therapies and onwards

32 PSA Failure-free survival Favours SOC+AAP Favours SOC+DocP Summary Head-to-head data in 566 pts (Nov-2011 to Mar-2013) Progression-free survival Metastatic progression-free survival Symptomatic skeletal events Strong evidence favouring AAP Weak evidence favouring AAP No good evidence of a difference Cause-specific survival Overall survival Hazard ratio Toxicity profiles quite different and well known Courtesy of Matt Sydes. ESMO 2017

33 Adverse events worst toxicity ever Safety population SOC+DocP SOC+AAP Patients included in adverse event analysis 172 (91%) 373 (>99%) Grade 1+ AE 172 (100%) 370 (99%) Grade 3+ AE 86 (50%) 180 (48%) Grade 3+ AEs by category (incl. expected AEs) Endocrine disorder (incl. hot flashes, impotence) 15 (9%) 49 (13%) Febrile neutropenia 29 (17%) 3 (1%) Neutropenia 22 (13%) 4 (1%) Musculoskeletal disorder: 9 (5%) 33 (9%) Cardiovascular (incl. hypertension, MI, cardiac dysrhythmia): 6 (3%) 32 (9%) Gastrointestinal disorder: 9 (5%) 28 (8%) Hepatic disorder (incl. increased AST, increased ALT): 1 (1%) 32 (9%) General disorder (incl. fatigue, oedema): 18 (10%) 21 (6%) Respiratory disorder (incl. breathlessness): 12 (7%) 11 (3%) Renal disorder 5 (3%) 20 (5%) Lab abnormalities (incl. hypokalaemia): 9 (5%) 11 (3%) Courtesy of Matt Sydes. ESMO 2017

34 Adverse events prevalence at 1 year and 2 years 1 year SOC+DocP SOC+AAP Patients in safety dataset Grade 3+ AE 15 (11%) 37 (11%) 2 years SOC+DocP SOC+AAP Patients in safety dataset Grade 3+ AE 11 (11%) 30 (11%) Safety dataset includes patients who: :: started treatment :: with assessment in toxicity window :: without FFS event before window Courtesy of Matt Sydes. ESMO 2017

35 6067 patients included (1921 events) (19.5%) Docetaxel + ADT (391 events) (25.7%) Abiraterone +ADT (353 events) (54.9%) ADT alone (1177 events) Docetaxel +ADT vs ADT Pooled HR for OS HR 0.75 (95%CI ) Abiraterone + ADT vs ADT Pooled HR for OS HR 0.75 (95%CI ) Indirect comparision of Abi + ADT vs Docetaxel + ADT shows no significant difference on OS Wallis, Eur Urol, 2017

36 Choice of Abiraterone or Docetaxel may be driven by factors beyond survival outcomes: - Treatment-associated side effects - Physician patient preferences - Availability - Cost

Hormone sensitive prostate cancer To add abiraterone or docetaxel? Dr Lisa Pickering

> Hormone sensitive prostate cancer To add abiraterone or docetaxel? Dr Lisa Pickering Disclosures Institutional Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific