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

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

May 29, 2023 265 likes •665 views

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

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Clinically node positive newly diagnosed prostate cancer

Nicholas James

@Prof_Nick_James

1

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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

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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?
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cN+ HSPC: what do we know?

  • Androgen deprivation therapy remains a fixed part
  • f therapy
  • Radiotherapy improves survival in low volume

TxNxM1 and TxN0M0 disease implying benefit in N+M0

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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

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TREATING THE PRIMARY

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MRC CTU at UCL

31-Aug- 19

7

Radiotherapy as a Standard of Care

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MRC CTU at UCL

The effect is consistent with HORRAD

Boeve et al. Eur Urol (2018) Overall survival

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MRC CTU at UCL

Summary

u

Prostate radiotherapy did not improve survival for unselected patients (HR=0·92, 95%CI 0·80-1·06; p=0.266)

u

Prostate radiotherapy did improve survival (from 73% to 81% at 3 years) in those with a low metastatic burden (HR=0·68, 95%CI 0·52-0·90; p=0·007). Test for interaction: p=0.0098

u

Mirrors benefit seen in HORRAD trial

u

Implies potential benefit in cN+M0 disease taken with known survival gain 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

  • trial. Lancet 392:2353-2366, 2018
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WHAT WE KNOW ABOUT M0 HSPC - DOCETAXEL

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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

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M1 docetaxel: Failure-free survival

Favours SOC + docetaxel Favours SOC Trial name Overall STAMPEDE (SOC+ZA +/- Doc) STAMPEDE (SOC +/- Doc) GETUG-15 CHAARTED HR=0.64 (0.58, 0.70); p<0.0001

1 2 .5

Heterogeneity:c2=1.66, df=3, p=0.646, I2=0%

Results based on 2993 men / 2198 events

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

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M0 docetaxel: Failure free survival

Results based on 2348 men / 842 events

Trial name Overall TAX 3501 (Delayed ADT) TAX 3501 (Immediate ADT) STAMPEDE (SOC+ZA +/- Doc) STAMPEDE (SOC +/- Doc) RTOG 0521 GETUG 12 HR=0.70 (0.61, 0.81), p<0.0001

.5 1 2

8% absolute reduction in failure (from 70% to 62%) at 4 years

Favours SOC + docetaxel Favours SOC Heterogeneity:c2=2.63, df=5, p=0.757, I2=0%

Vale CL, Burdett S, Rydzewska LH, et al: Lancet Oncol 17:243-56, 2016

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M1 docetaxel: Survival

Results based on 2993 men / 1254 deaths

10% absolute improvement in survival (from 40% to 50%) at 4 years

Trial name Overall STAMPEDE (SOC+ZA +/- Doc) STAMPEDE (SOC +/- Doc) GETUG15 CHAARTED HR=0.77 (0.68, 0.87) p<0.0001

.5 1 2

Heterogeneity:c2=4.80, df=3, p=0.187, I2 = 37.5% Favours SOC + docetaxel Favours SOC Vale CL, Burdett S, Rydzewska LH, et al: Lancet Oncol 17:243-56, 2016

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M0 docetaxel: Survival

Results based on 2120 men / 346 deaths

5% potential improvement in survival (from 80 to 85%) at 4 years

Trial name Overall STAMPEDE (SOC+ZA +/- Doc) STAMPEDE (SOC +/- Doc) RTOG 0521 GETUG 12 HR= 0.87 (0.69, 1.09) p=0.218

.5 1 2

Heterogeneity:c2=1.80, df=3, p=0.614, I2=0% Favours SOC + docetaxel Favours SOC Vale CL, Burdett S, Rydzewska LH, et al: Lancet Oncol 17:243-56, 2016

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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

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Question: docetaxel in M0 disease

  • What is the interaction with radiotherapy and

docetaxel – is there dual benefit?

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

STAMPEDE docetaxel subgroup analysis

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Docetaxel and radiotherapy in M0

  • Suggests interaction between RT and

docetaxel – only benefit in patients not getting radiotherapy

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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
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ADT + RT + ABIRATERONE

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Abiraterone in high-risk M0 prostate cancer

  • Prognosis of newly-diagnosed high-risk M0 disease
  • Cohort selection:

Non-metastatic N=915 Metastatic N=1002 N+M0 N=384 N0M0 N=530 Randomised by Jan-2014 N=1,917 No RT N=70 RT N=314 RT 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

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Failure-free survival

Events 535 Control | 248 Abiraterone No good evidence of heterogeneity by stratification factors

status Mets Overall M1 M0 Dths/N SOC-only 218/502 44/455 Dths/N SOC+AAP 150/500 34/460 (95% CI)

  • Haz. Ratio

0.63 (0.52, 0.76) 0.61 (0.49, 0.75) 0.75 (0.48, 1.18) Favours: abiraterone SOC-only .2 .4 .6 .8 1 1.2 1.4

SOC vs SOC+AAP

status Mets Overall M1 M0 FFS/N SOC-only 393/502 142/455 FFS/N SOC+AAP 210/500 38/460 (95% CI)

  • Haz. Ratio

0.29 (0.25, 0.34) 0.31 (0.26, 0.37) 0.21 (0.15, 0.31) Favours: abiraterone SOC-only .2 .4 .6 .8 1 1.2 1.4

SOC vs SOC+AAP

Mets * treatment interaction P-value = 0.085

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

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Failure-free survival

SOC vs SOC+AAP SOC vs SOC+AAP

Is radiotherapy planned? RT planned No RT planned 110/396 425/561 24/396 224/564 0.023 0.18 (0.12, 0.28) 0.31 (0.26, 0.36) Overall 0.29 (0.25, 0.34) Favours: abiraterone SOC-only .2 .4 .6 .8 1 1.21.4

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

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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

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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

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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

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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

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CAN WE CHOOSE BETWEEN DOCETAXEL AND ART?

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STAMPEDE: SOC+DocP vs SOC

HR (95%CI) 0.78 (0.66, 0.93) P-value 0.006

SOC SOC+DOC Recruitment: Oct-2005 to Mar-2013 Reported: ASCO 2015 Published: Lancet 2016 Patients: 1184 SOC 592 SOC+DocP Allocation ratio: 2:1

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STAMPEDE: SOC+AAP vs SOC

SOC SOC+AAP

HR (95%CI) 0.63 (0.52, 0.76) P-value 0.00000115

Recruitment: Nov-2011 to Jan-2014 Reported: ASCO 2017 Published: NEJM 2017 Patients: 957 SOC 960 SOC+AAP Allocation ratio: 1:1

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STAMPEDE: SOC+AAP vs SOC+DocP

AAP and DocP may work in quite different ways Evidence about whether to give both is pending

ESMO 2017

Recruitment: Nov-2011 to Mar-2013 Reported: ESMO 2017 Published: Sydes et al, Annals of Oncology, 2018 Patients: 189 SOC+DocP 377 SOC+AAP

566 patients randomised contemporaneously to either research arm

Sydes MR, Spears MR, Mason MD, et al: Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol. Ann Oncol 29:1235-1248, 2018

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Summary

Strong evidence favouring AAP Toxicity profiles quite different and well known Weak evidence favouring AAP No good evidence of a difference

Cause-specific survival

Head-to-head data in 566 pts

(Nov-2011 to Mar-2013)

à Proportionately different time spent in each disease state

Favours SOC+AAP Favours SOC+DocP Hazard ratio

Metastatic progression-free survival Progression-free survival Failure-free survival Symptomatic skeletal events Cause-specific survival Overall survival

Sydes MR, Spears MR, Mason MD, et al: Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol. Ann Oncol 29:1235-1248, 2018

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Docetaxel vs. AR therapy in mHSPC

  • No evidence of survival difference in STAMPEDE
  • Upfront abiraterone gives longer failure free and

metastasis free benefit than docetaxel

  • but shorter castrate refractory phase
  • Effects on failure free survival may be more

important in M0 disease as lower risk of prostate cancer death

Sydes MR, Spears MR, Mason MD, et al: Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol. Ann Oncol 29:1235-1248, 2018

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DOES FAILURE FREE SURVIVAL MATTER?

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Addition of docetaxel to first-line long-term hormone therapy in prostate cancer (STAMPEDE): long-term survival, quality-adjusted survival and cost-effectiveness analysis.

Nicholas James

  • n behalf of

Beth Woods, Eleftherios Sideris, Matthew Sydes, Melissa Spears, Mark Sculpher and the STAMPEDE Investigators

36

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Impact of docetaxel on Quality Adjusted Life Years (QALYs)

  • All groups show a QALY gain
  • Driven by reduction in relapse therapy and skeletal events

0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 Incremental QALYs (DOC+SOC vs. SOC) M0 Q1 M0 Q2 M0 Q3 M0 Q4 M1 Q1 M1 Q2 M1 Q3 M1 Q4

Non-metastatic Metastatic

Woods BS, Sideris E, Sydes MR, et al: Addition of Docetaxel to First-line Long-term Hormone Therapy in Prostate Cancer (STAMPEDE): Modelling to Estimate Long-term Survival, Quality-adjusted Survival, and Cost-effectiveness. Eur Urol Oncol 1:449-458, 2018

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Conclusion

  • ADT plus 1 drug therapy improves failure free survival &

increases QALYs in M0 HSPC

  • ADT + radiotherapy improves survival in low volume M1

HSPC and TxN0M0 HSPC

  • Available data suggest an either/or effect with docetaxel

and radiotherapy

  • Available data suggest a synergistic effect with

abiraterone and radiotherapy

  • Overall supports ADT + RT + 2 years abiraterone in cN+

prostate cancer

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Key references

  • 1. Vale CL, Burdett S, Rydzewska LH, et al: Addition of docetaxel or bisphosphonates to standard of care in men with

localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate

  • data. Lancet Oncol 17:243-56, 2016
  • 2. James ND, Sydes MR, Clarke NW, et al: Addition of docetaxel, zoledronic acid, or both to first-line long-term

hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 387:1163-77, 2016

  • 3. James ND, de Bono JS, Spears MR, et al: Abiraterone for Prostate Cancer Not Previously Treated with Hormone
  • Therapy. N Engl J Med 377:338-351, 2017
  • 4. 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). Annals of Oncology, 2017

  • 5. 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

  • 6. 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 trial. Lancet 392:2353-2366, 2018

  • 7. Woods BS, Sideris E, Sydes MR, et al: Addition of Docetaxel to First-line Long-term Hormone Therapy in Prostate

Cancer (STAMPEDE): Modelling to Estimate Long-term Survival, Quality-adjusted Survival, and Cost-effectiveness. Eur Urol Oncol 1:449-458, 2018

  • 8. Sydes MR, Spears MR, Mason MD, et al: Adding abiraterone or docetaxel to long-term hormone therapy for

prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol. Ann Oncol 29:1235-1248, 2018