Clinically node positive newly diagnosed prostate cancer Nicholas - PowerPoint PPT Presentation

Clinically node positive newly diagnosed prostate cancer Nicholas James @Prof_Nick_James 1

Disclosures • Trial funding from: • Cancer Research UK • Medical Research Council • Astellas • Janssen • Novartis • Pfizer • Sanofi-Aventis • Speaking fees and Advisory Boards • Astellas, Janssen, Novartis, Pfizer, Sanofi-Aventis, Bayer, Clovis, Merck, Ferring, Astra Zeneca

Focus of talk • I will focus on newly diagnosed clinically node positive (cN+) hormone sensitive prostate cancer (mHSPC) with no prior therapy • Treatment of the primary • Which treatments can we combine?

cN+ HSPC: what do we know? • Androgen deprivation therapy remains a fixed part of therapy • Radiotherapy improves survival in low volume TxNxM1 and TxN0M0 disease implying benefit in N+M0

Which combinations in M0 HSPC? • Combinations with good evidence • ADT + RT • ADT + docetaxel • ADT + abiraterone • Combinations with limited evidence ADT + docetaxel + RT • ADT + abiraterone + RT • • Combinations with no evidence ADT + docetaxel + androgen receptor targeting (ART) • + RT

TREATING THE PRIMARY

Radiotherapy as a Standard of Care 7 MRC CTU at UCL 31-Aug- 19

The effect is consistent with HORRAD Overall survival MRC CTU at UCL Boeve et al. Eur Urol (2018)

Summary Prostate radiotherapy did not improve survival for unselected patients u (HR=0 · 92, 95%CI 0 · 80-1 · 06; p=0.266) Prostate radiotherapy did improve survival (from 73% to 81% at 3 years) in u those with a low metastatic burden (HR=0 · 68, 95%CI 0 · 52-0 · 90; p=0 · 007). Test for interaction: p=0.0098 Mirrors benefit seen in HORRAD trial u Implies potential benefit in cN+M0 disease taken with known survival gain u with radiotherapy in N0M0 disease Burdett S, Boeve LM, Ingleby FC, et al: Prostate Radiotherapy for Metastatic Hormone-sensitive Prostate Cancer: A STOPCAP Systematic Review and Meta-analysis. Eur Urol, 2019 Parker CC, James ND, Brawley CD, et al: Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 MRC CTU at UCL trial. Lancet 392:2353-2366, 2018

WHAT WE KNOW ABOUT M0 HSPC - DOCETAXEL

What is the current evidence for docetaxel or bisphosphonates in men with hormone sensitive prostate cancer? A systematic review and meta-analyses Claire Vale MRC Clinical Trials Unit at UCL Systemic Treatment Options for Cancer of the Prostate Working Group: Rydzewska LH, Tierney JF, Albiges L, Clarke NW, Fisher D, Fizazi K, James ND, Mason MD, Parmar MKB, Sweeney CJ, Sydes MR, Tombal B and Burdett S Vale CL, Burdett S, Rydzewska LH, et al: Lancet Oncol 17:243-56, 2016

M1 docetaxel: Failure-free survival Results based on 2993 men / 2198 events Trial name CHAARTED GETUG-15 STAMPEDE (SOC +/- Doc) STAMPEDE (SOC+ZA +/- Doc) HR=0.64 (0.58, 0.70); p<0.0001 Overall .5 1 2 Favours SOC + docetaxel Favours SOC Heterogeneity: c 2 =1.66, df=3, p=0.646, I 2 =0% 15% absolute reduction in failure (from 80% to 65%) at 4 years Vale CL, Burdett S, Rydzewska LH, et al: Lancet Oncol 17:243-56, 2016

M0 docetaxel: Failure free survival Results based on 2348 men / 842 events Trial name GETUG 12 RTOG 0521 STAMPEDE (SOC +/- Doc) STAMPEDE (SOC+ZA +/- Doc) TAX 3501 (Immediate ADT) TAX 3501 (Delayed ADT) Overall HR=0.70 (0.61, 0.81), p<0.0001 .5 1 2 Favours SOC Favours SOC + docetaxel Heterogeneity: c 2 =2.63, df=5, p=0.757, I 2 =0% 8% absolute reduction in failure (from 70% to 62%) at 4 years Vale CL, Burdett S, Rydzewska LH, et al: Lancet Oncol 17:243-56, 2016

M1 docetaxel: Survival Results based on 2993 men / 1254 deaths Trial name CHAARTED GETUG15 STAMPEDE (SOC +/- Doc) STAMPEDE (SOC+ZA +/- Doc) Overall HR=0.77 (0.68, 0.87) p<0.0001 .5 1 2 Favours SOC + docetaxel Favours SOC Heterogeneity: c 2 =4.80, df=3, p=0.187, I 2 = 37.5% 10% absolute improvement in survival (from 40% to 50%) at 4 years Vale CL, Burdett S, Rydzewska LH, et al: Lancet Oncol 17:243-56, 2016

M0 docetaxel: Survival Results based on 2120 men / 346 deaths Trial name GETUG 12 RTOG 0521 STAMPEDE (SOC +/- Doc) STAMPEDE (SOC+ZA +/- Doc) Overall HR= 0.87 (0.69, 1.09) p=0.218 .5 1 2 Favours SOC + docetaxel Favours SOC Heterogeneity: c 2 =1.80, df=3, p=0.614, I 2 =0% 5% potential improvement in survival (from 80 to 85%) at 4 years Vale CL, Burdett S, Rydzewska LH, et al: Lancet Oncol 17:243-56, 2016

Conclusions – docetaxel in M0 disease • Consistent effect on failure free survival with docetaxel – hazard ratio around 0.7 • Individual trials underpowered with respect to overall survival • Trend to an OS benefit seen in the meta-analysis – HR 0.87 (CI: 0.69-1.09) Vale CL, Burdett S, Rydzewska LH, et al: Lancet Oncol 17:243-56, 2016

Question: docetaxel in M0 disease • What is the interaction with radiotherapy and docetaxel – is there dual benefit?

STAMPEDE docetaxel subgroup analysis The Lancet 2016 387, 1163-1177DOI: (10.1016/S0140-6736(15)01037-5)

Docetaxel and radiotherapy in M0 • Suggests interaction between RT and docetaxel – only benefit in patients not getting radiotherapy

Docetaxel and radiotherapy and survival in M0 HSPC • Suggests interaction between RT and docetaxel – only benefit in patients not getting radiotherapy • Further data to be presented at ESMO 2019

ADT + RT + ABIRATERONE

Abiraterone in high-risk M0 prostate cancer • Prognosis of newly-diagnosed high-risk M0 disease • Cohort selection: Randomised by Jan-2014 N=1,917 Metastatic Non-metastatic N=1002 N=915 N0M0 N+M0 N=384 N=530 RT No RT RT N=314 N=70 N=519 James N, De Bono JS, Spears M, et al: Adding abiraterone for patients (pts) with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Outcomes in non-metastatic (M0) patients from STAMPEDE (NCT00268476). Proc ESMO Annals of Oncology, 2017

Failure-free survival Events 535 Control | 248 Abiraterone Mets * treatment interaction P-value = 0.085 SOC vs SOC+AAP SOC vs SOC+AAP Mets Mets SOC-only SOC-only SOC+AAP SOC+AAP Haz. Ratio Haz. Ratio status status Dths/N FFS/N Dths/N FFS/N (95% CI) (95% CI) No good evidence of M0 M0 142/455 44/455 34/460 38/460 0.75 (0.48, 1.18) 0.21 (0.15, 0.31) heterogeneity by M1 M1 393/502 218/502 210/500 150/500 0.61 (0.49, 0.75) 0.31 (0.26, 0.37) stratification factors Overall Overall 0.63 (0.52, 0.76) 0.29 (0.25, 0.34) .2 .2 .4 .4 .6 .6 .8 .8 1 1.2 1.4 1 1.2 1.4 Favours: abiraterone Favours: abiraterone SOC-only SOC-only James N, De Bono JS, Spears M, et al: Adding abiraterone for patients (pts) with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Outcomes in non-metastatic (M0) patients from STAMPEDE (NCT00268476). Proc ESMO Annals of Oncology, 2017

Failure-free survival SOC vs SOC+AAP SOC vs SOC+AAP Is radiotherapy planned? No RT planned 425/561 224/564 0.023 0.31 (0.26, 0.36) RT planned 110/396 24/396 0.18 (0.12, 0.28) Overall 0.29 (0.25, 0.34) .2 .4 .6 .8 1 1.21.4 Favours: abiraterone SOC-only James N, De Bono JS, Spears M, et al: Adding abiraterone for patients (pts) with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Outcomes in non-metastatic (M0) patients from STAMPEDE (NCT00268476). Proc ESMO Annals of Oncology, 2017

Failure-free survival in M0 subgroup ADT +/- Abi James N, De Bono JS, Spears M, et al: Adding abiraterone for patients (pts) with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Outcomes in non-metastatic (M0) patients from STAMPEDE (NCT00268476). Proc ESMO Annals of Oncology, 2017

Metastasis-free survival in M0 subgroup ADT +/- Abi James N, De Bono JS, Spears M, et al: Adding abiraterone for patients (pts) with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Outcomes in non-metastatic (M0) patients from STAMPEDE (NCT00268476). Proc ESMO Annals of Oncology, 2017

Overall survival in M0 subgroup ADT +/- Abi James N, De Bono JS, Spears M, et al: Adding abiraterone for patients (pts) with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Outcomes in non-metastatic (M0) patients from STAMPEDE (NCT00268476). Proc ESMO Annals of Oncology, 2017

Abiraterone in M0 HSPC • Evidence of failure free and metastasis free survival benefit from ADT + abiraterone vs. ADT alone for 2 years • Strong suggestion of synergy with radiotherapy James N, De Bono JS, Spears M, et al: Adding abiraterone for patients (pts) with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Outcomes in non-metastatic (M0) patients from STAMPEDE (NCT00268476). Proc ESMO Annals of Oncology, 2017

CAN WE CHOOSE BETWEEN DOCETAXEL AND ART?

STAMPEDE: SOC+DocP vs SOC SOC+DOC SOC HR (95%CI) 0.78 (0.66, 0.93) P-value 0.006 Recruitment: Oct-2005 to Mar-2013 Patients: 1184 SOC 592 SOC+DocP Reported: ASCO 2015 Published: Lancet 2016 Allocation ratio: 2:1

STAMPEDE: SOC+AAP vs SOC SOC+AAP SOC HR (95%CI) 0.63 (0.52, 0.76) P-value 0.00000115 Recruitment: Nov-2011 to Jan-2014 Patients: 957 SOC 960 SOC+AAP Reported: ASCO 2017 Published: NEJM 2017 Allocation ratio: 1:1