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Module 3:Focus on Recent CRPC Guidelines and Advanced

Hormone-Sensitive Disease

Optimizing Outcomes in Advanced Prostate Cancer

Sébastien J. Hotte, MD, MSc (HRM), FRCPC

Medical Oncologist and Head, Phase I Program,

Juravinski Cancer Centre, Hamilton, Ontario

Associate Professor, Dept Of Oncology, McMaster University

Co-Chair, GU DSG CCO-PEBC

Conflict of Interest Disclosures

• Research funding: Oncogenex, Novartis, GSK, Amgen, Roche, Astellas, Janssen, Sanofi, Bayer

• Consultant/Honoraria: Novartis, Janssen, Astellas, Pfizer, GSK, Sanofi, Bayer

Learning Objectives

• Review the most recent ASCO and CUA- CUOG guidelines on the management of CRPC

• Discuss the recent clinical trial data on the optimal management of newly diagnosed metastatic hormone-sensitive prostate cancer

• Discuss the role of early chemotherapy for high risk non-metastatic hormone-sensitive prostate cancer

Prostate Cancer: Recent CRPC Guidelines

Androgen-Deprivation Therapy:

• Continuous androgen deprivation (pharmaceutical or surgical) should be continued indefinitely regardless of additional therapies

• Benefit: Moderate• Harm: Moderate• Evidence strength: Weak• Recommendation strength: Moderate

Therapies in Addition to ADT with Demonstrated Survival & Quality-of-Life

Benefits:

• Abiraterone acetate and Prednisone should be offered

• Enzalutamide should be offered

• Benefit: Moderate• Harm: Low• Evidence strength: Strong• Recommendation strength: Strong


Benefits:

• Radium-223 should be offered to men with bone metastases

• Benefit: Moderate• Harm: Low• Evidence strength: Strong• Recommendation strength: Strong


Benefits:

• Docetaxel and Prednisone should be offered

• Benefit: Moderate• Harm: Moderate• Evidence strength: Strong• Recommendation strength: Moderate

Therapies with demonstrated survival benefit and unclear quality-of-life benefit:

• Cabazitaxel and Prednisone may be offered to men who experience progression with Docetaxel

• Benefit: Moderate• Harm: Moderate to high• Evidence strength: Strong• Recommendation strength: Moderate

Therapies with quality-of-life benefit without demonstrated survival benefit:

•Mitoxantrone plus Prednisone may be offered

• Benefit: Low• Harm: High• Evidence strength: Weak• Recommendation strength: Weak

Therapies with biologic activity and unknown survival or quality-of-life benefit:

• Antiandrogens (eg, Bicalutamide, Flutamide, Nilutamide) may be offered.(Benefit: low; harm: low; evidence strength: weak; recommendation strength: weak)

• Ketoconazole may be offered.(Benefit: low; harm: moderate; evidence strength: weak; recommendation strength: weak)

• Low-dose corticosteroid monotherapy may be offered.(Benefit: low; harm: low; evidence strength: weak; recommendation strength: weak)

Palliative Care Services

• Palliative care should be offered to all patients, particularly to those exhibiting symptoms or quality-of-life (QOL) decrements, regardless of treatment type

• Benefit: Moderate• Harm: None• Evidence strength: Moderate• Recommendation strength: Strong

2015 CUA-CUOG GuidelineManagement of CRPC

•What is Castration-Resistant Prostate Cancer?• “disease progression despite castrate levels of testosterone and

may present as either a continuous rise in serum PSA levels, progression of pre-existing disease, and/or the appearance of new metastases

•What does it encompass?• “from pts without metastases or symptoms with rising PSA despite

ADT to pts with metastases and significant debilitation due to cancer symptoms”

2015 CUA-CUOG Guideline

Asymptomatic or minimally symptomatic:

“pain that is relieved by acetaminophen or a non-steroidal anti-inflammatory”

Symptomatic:

“require regular pain medication opioid/narcotics)* treatment”


NON-MET CRPC

• There is no standard of care and no approved regimen in M0 CRPC

• Detection of mets• Pts with PSADT < 8 mos: image every 3-6 mos• Pts with PSADT > 12 mos: image every 6-12 mos

• Imaging• Commonly with bone scans, abdominal/pelvic CT and chest X-ray• MRI and PET still unclear


MET CRPC (asymptomatic or minimally symptomatic)

• Anti-androgen (AA) should be discontinued

• Introduction of, or changes to, 1st generation AA or use of Corticosteroids with or without Ketoconazole may be considered

• Abiraterone acetate 1000 mg/day plus Prednisone 5 mg/twice daily is recommended as first-line therapy (Level 1, Grade A).

• Enzalutamide 160 mg/day is recommended as first-line therapy (Level 1, Grade A).

• Treatment with Docetaxel 75 mg/m2 every 3 weeks plus 5 mg oral Prednisone twice daily can be offered (Level 1, Grade A).


Met CRPC (with symptoms)

• Treatment with Docetaxel 75 mg/m2 every 3 weeks plus 5 mg oral Prednisone twice daily is recommended (Level 1, Grade A).

• Radium-223 every 4 weeks for 6 cycles is recommended in patients with pain due to bone metastases and who do not have visceral metastases (Level 1, Grade A).

• Abiraterone acetate 1000 mg/day plus Prednisone 5 mg twice daily or Enzalutamide 160 mg/day may be considered as first-line therapy in patients who cannot receive or refused Docetaxel (Expert opinion).


Met CRPC (who progress after Docetaxel-based chemo)

• Options with survival benefit• Cabazitaxel (25 mg/m2) plus Prednisone (5 mg/day) (Level 1,

Grade A)

• Abiraterone acetate (1000 mg per day) plus Prednisone (5 mg twice daily) (Level 1, Grade A)

• Enzalutamide (160 mg/day) (Level 1, Grade A)

• Radium-223 q 4 weeks for 6 cycles (Level 1 Grade A)

• Options with unknown survival benefit• Docetaxel plus Prednisone re-exposure in patients who have had a

previous favorable response to Docetaxel may be reasonable

• (Expert Opinion). Mitoxantrone plus Prednisone may be offered for palliative pain relief (Grade C).


CRPC with Bone mets (includes pre/post chemo settings)

• Denosumab (120 mg subcutaneous) or Zoledronic acid (4 mg intravenous) every 4 weeks, along with daily calcium and vitamin D supplementation, is recommended to prevent disease-related skeletal complications (Level 1, Grade A).

• Treatment with Zoledronic acid should not be used in men with baseline creatinine clearance <30 mL/min.

• Optimal duration of Zoledronic acid and Denosumab in men with CRPC and bone metastases is undefined. The risk of ONJ appears to be related to time on bone-targeted therapy; therefore caution should be taken in using these agents more than 2 years.

Prostate Cancer: HSPC

Question

Which of the following non-CRPC prostate cancer patients are candidates for Docetaxel therapy?

a) 68 year old man with localized, Gl 9 prostate cancer and PSA of 34 being treated with IMRT and ADT

b) 71 year old man with newly diagnosed metastatic prostate cancer with 2 bone metastases on bone scan

c) 63 year old man with newly diagnosed metastatic prostate cancer with liver metastases

d) All of the above

e) 2 and 3

f) 3 only

ECOG 3805 (CHAARTED):Chemo-Hormonal vs Androgen Ablation Randomized Trial in Extensive Disease

3-year OS: 69.0% vs. 52.5%3-year OS in pts with a high extent of metastatic disease: 63.4% vs. 43.9%

“Patients with a high extent of metastatic disease accounted for most of the benefit in the OS from Docetaxel plus ADT”

NEJM August 20 2015 373;(8): 737-46

Primary Endpoint: Overall Survival

n engl j med 373;8 nejm.org August 20, 2015742

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

tive (rather than palliative) intent. Among pa-tients who started ADT before randomization, the median time from the start of ADT to ran-domization was 1.2 months (range, 0 to 3.9) in the combination group and 1.3 months (range, 0 to 3.9) in the ADT-alone group.

SurvivalThe median overall survival was 13.6 months longer with the addition to ADT of early docetax-el than with ADT alone (57.6 months vs. 44.0 months; hazard ratio for death in the combina-tion group, 0.61; 95% confidence interval [CI], 0.47 to 0.80; P<0.001) (Fig. 1A). There were 85 prostate-cancer deaths in the combination group and 114 prostate-cancer deaths in the ADT-alone group (Table S1 in the Supplementary Appen-dix). The benefit at the last analysis was more apparent in the subgroup with high-volume dis-ease than in the overall study population (Fig. 1B), with a median overall survival that was 17.0 months longer in the combination group than in the ADT-alone group (49.2 months vs. 32.2 months; hazard ratio for death, 0.60; 95% CI, 0.45 to 0.81; P<0.001). The median survival at the time of the analysis had not been reached in the subgroup with low-volume disease in ei-ther study group (Fig. 1C). A benefit of docetax-el treatment was detected in all the subgroups analyzed (Fig. 2).

Secondary End Points and Toxic EffectsThe proportion of patients who had a decrease in the PSA level to less than 0.2 ng per milliliter at 12 months was 27.7% in the combination group, as compared with 16.8% in the ADT-alone group (P<0.001) (Table 2). The median time to the development of castration-resistant prostate cancer (biochemical, symptomatic, or radiographic) was 20.2 months with combina-tion therapy, as compared with 11.7 months with ADT alone (hazard ratio in the combina-tion group, 0.61; 95% CI, 0.51 to 0.72; P<0.001)

Patie

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00 12 24 36 48 7260 84

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B Patients with High-Volume Disease

A All PatientsHazard ratio for death with ADT+docetaxel,0.61 (95% CI, 0.47–0.80) P<0.001

No. at RiskADT+docetaxelADT alone

397393

333318

8971

189168

4627

53

21

00

ADT+docetaxel(median overall survival, 57.6 mo)

ADT alone(median overall

survival, 44.0 mo)

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Hazard ratio for death with ADT+docetaxel,0.60 (95% CI, 0.45–0.81) P<0.001


263250

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survival, 32.2 mo)

C Patients with Low-Volume Disease

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Hazard ratio for death with ADT+docetaxel,0.60 (95% CI, 0.32–1.13) P=0.11


134143

120125

3331

6676

1513

00

ADT+docetaxel(median overall survival, NR)


survival, NR)

Figure 1. Kaplan–Meier Estimates of Overall Survival.

The median duration of follow-up was 28.9 months among all patients (Panel A), 29.2 months among pa-tients with high-volume disease (Panel B), and 27.6 months among patients with low-volume disease (Pan-el C). ADT denotes androgen-deprivation therapy, and NR not reached.

The New England Journal of Medicine Downloaded from nejm.org at MCMASTER UNIVERSITY HEALTH SCI LIB on September 2, 2015. For personal use only. No other uses without permission.

Copyright © 2015 Massachusetts Medical Society. All rights reserved.

OS by Extent of Metastatic Disease at Start of ADT






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397393

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survival, 44.0 mo)

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263250

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survival, 32.2 mo)


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134143

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survival, NR)










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397393

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survival, 44.0 mo)

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Surv

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g (%

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100

80

60

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00 12 24 36 48 7260 84

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263250

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survival, 32.2 mo)


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134143

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survival, NR)





High Volume Low Volume

In patients with high volume metastatic disease, there is a 17 month improvement in median overall survival from 32.2 months to 49.2 months. We projected 33 months alone in the ADT alone arm with collaborations of SWOG9346 team.

Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

High Volume Disease

• ≥4 bone lesions and

• ≥1 lesion in any bony structure beyond the spine/pelvis

OR

• Visceral disease

GETUG-AFU 15 TRIAL DESIGN

RANDOMIZATION

ADT + Docetaxel

ADT alone

Stratification : - Prior systemic TT- Glass risk group

Arm A

Arm B

D: 75 mg/m2 q3 up to 9 cycles

ADT: - LHRH agonist- or maximum androgen blockade- or orchiectomy

Lancet Oncology February 2013 14(2);149-58

OVERALL SURVIVAL

•Median follow-up 81.3 months [69.2-83.7]

Median OSADT alone: NR [61.8- NR]ADT + D: 83.1 [ 69.5- NR]HR: 1.0 [0.6-1.5]p=0.87

Median OSADT alone: 35.1 [29.9- 44.2]ADT + D: 39 [ 28- 52.6]HR: 0.8 [0.6-1.2]p=0.35

High VolumeLow Volume

Comparison of GETUG 15 & ECOG 3805

GETUG ECOG

Total Sample Size 385 790

High Volume dz 183 (47.5%) 514 (65%)

Median F/U 83 months 29 months

Received Post-Protocol Docetaxel

ADT only Arm: 80%ADT-Doce Arm: 45%


Received Post-Protocol Abi or Enz

ADT only Arm: NRADT-Doce Arm: NR


Presented by Eric J. Small, MD – Genitourinary Cancers Symposium

CONCLUSIONS (GETUG)

• PFS improved by Docetaxel in mHSPC (GETUG 15 and CHAARTED)

• Overall survival after a median follow-up of 82.9 months:• No improvement in low volume mHSPC (GETUG 15/ CHAARTED)• Discrepancy in OS results for high-volume mHSPC

• Explaining the OS discrepancy:• “Salvage” Docetaxel more frequent in GETUG-15 (80%) ???• GETUG 15 underpowered in high volume mHSPC?• Other trials to come soon (Stampede)

Docetaxel and/or Zoledronic acid for hormone-naïve prostate cancer: First overall survival results from STAMPEDE (NCT00268476)

• STAMPEDE: RCT using novel multi-arm, multi-stage design for men with high-risk locally advanced or metastatic PCa starting on ADT

• 3 comparisons reported: Standard of care (SOC) (ADT for 3+ years), Docetaxel (75mg/m2 plus Pred), Zoledronic acid (ZA) (4mg)

• Primary outcome: Survival

• 2:1:1:1 to SOC:D:Z:D+Z with N=2,962

Presented By Nicholas James at 2015 ASCO Annual Meeting

Inclusion Criteria

Newly Diagnosed:Any of:• Metastatic• Node-positive• ≥2 of:

• Stage T3/4• PSA ≥ 40 ng/ml• Gleason 8-10

All Patients:• Fit for all protocol treatment• Fit for follow-up• WHO performance status 0-2• Written informed consent

Relapsing after previous RP or RT with ≥1 of:• PSA ≥4 ng/ml & rising with doubling

time <6 m• PSA ≥20 ng/ml• Node positive• Metastatic

Full Criteria:• www.stampedetrial.org


Outcome Measures

Primary Outcome Measure:• Overall Survival

FFS Definition:• First line of:

• PSA failure• Local failure• Lymph node failure• Distant metastases• Prostate cancer death

Secondary Outcome Measures:• Failure-free survival• Toxicity• Quality of Life• Skeletal related events• Cost effectiveness

PSA Failure Definition:• PSA failure ≥ 50%

• 24 week nadir + 50% and• >4 ng/ml

• PSA fall of 50%• Failure at t=0



STAMPEDE: All Docetaxel & Zoldronic Acid Comparisons


Patient Characteristics

1% WHO PS 2 [s]

21% WHO PS 1 [s]

65 yr Median Age(min 40, max 84)

[s]

61% Metastatic(85% bony mets)

[s]

15% N+M0

24% N0M0

98% LNRH analogues [s]

29% Planned for RT(72% of N0M0 pts)

[s]

6% Previous local therapy

Balanced by arm[s] Stratification factors + hospital + NSAID/aspirin


Docetaxel: Failure-Free Survival


Docetaxel: Survival


Zoledronic Acid + Docetaxel: Failure-Free Survival


Zoledronic Acid + Docetaxel: Survival


Treatment Effect by Metastatic Status: FFS

Pre-Planned Analysis


Treatment Effect by Metastatic Status: Overall Survival

Pre-Planned Analysis


Docetaxel: Survival – M1 Patients


Grade 3+ Adverse Events Ever Reported


Use of “Life-Prolonging Therapy” for Progression


Conclusions

• Docetaxel improves survival for hormone-naïve prostate cancer

• Zoledronic Acid does not improve survival

• Adding both improves survival but offers no obvious benefit over adding just Docetaxel

•Multi-arm, multi-stage trials are practicable and efficient

• Docetaxel should be:• Considered for routine practice in suitable men with newly-

diagnosed metastatic disease• Considered for selected men with high-risk non-metastatic disease

in view of substantial prolongation of failure-free survival

How Similar are the Men Participating in these Studies?

Median Age % Mets at Presentation % High Risk

GETUG 64 71% 52%

CHAARTED 63 75% 65%

STAMPEDE 65 Most of them Unknown

*”High volume” disease was defined as visceral metastases and/or 4 bone metastases with at least one metastasis beyond the pelvis or vertebral column

These trials DO NOT represent men with slowly progressive disease who develop metastases several years after diagnosis (+/- local treatment)

Presented By Ian Tannock at 2015 ASCO Annual Meeting

Forest Plot of Overall Survival for the 3 Studies

(Thanks to Dr. Eitan Amir)

Recommendation #1

Men with high-risk metastatic prostate cancer, especially those presenting with metastases at or soon after diagnosis,

who are judged fit to receive chemotherapy, should be offered 6 cycles of Docetaxel in addition to ADT


Role of Chemotherapy for Localized High-Risk PC (M0) After Radiation Therapy

Role of chemotherapy for localized high-risk PC (M0) after radiation therapy

• GETUG-12 (Fizazi et al; Lancet Oncol, 2015)• ADT +/- 4 cycles Docetaxel/Estramustine (N=413)

• RFS: 199 events: HR=0.71 (0.54-0.94)

• OS: 91 deaths: too early

• STAMPEDE (Not all M0 men had RT)• ADT +/- 6 cycles Docetaxel/Prednisone (N=689)

• RFS: 229 events; HR=0.57 (0.42-0.76)

• OS: 93 deaths; HR=1.01 but too early

Presented By Howard Sandler at 2015 ASCO Annual Meeting


Top Accruing Sites

Cross Cancer Institute 32

Tom Baker Cancer Centre 32

London Regional Cancer Program 20

McGill University 19

Ottawa Hospital Regional Cancer Centre

17

Peter MacCallum Cancer Centre 15

UT-Southwestern 15

(Others with 10 or more: Fox Chase, Christiana CCOP, Northeast RO Center, Umich, Wash U)


RTOG 0521

Stage Gleason Score

PSA

Any T Stage ≥9 <150

7-‐8 ≥20-‐150

≥T2 8 <20

R

a

n

d

o

m

i

z

e

ARM 1Androgen

Suppression (24 months)+

External RT (8 weeks)

ARM 2Androgen

Suppression (24 months)+

External RT (8 weeks)+

Docetaxel beginning 4 weeks after RT (6 cycles)


Characteristic Arm 1 and Arm 2(N = 563)

Risk Category (stratification) (%)

Gleason ≥9, PSA ≤150, Any T-stage 53

Gleason 8, PSA <20, ≥T2 21

Gleason 8, PSA ≥20-150, Any T-stage 10

Gleason 7, PSA ≥20-150, Any T-stage 16

Gleason Score, no. (%)

7 16

8 31

9-10 53

Serum PSA, ng/ml, Median (Q1-Q3) 15 (7-34)

Age, Median 66

cT3-T4 27%

pN0 33%


Conclusions

• For the first time, improvement in overall survival observed with (tolerable) adjuvant chemotherapy for localized, high-risk, hormone-sensitive prostate cancer• Cumulative incidence of DM reduced

• The potential role of Docetaxel in hormone-sensitive prostate cancer is consistent with and supported by our data and other studies, such as STAMPEDED and CHAARTED.

• This analysis is relatively early and additional follow-up will likely be enlightening.

Role of chemotherapy for localized high-risk PC (M0) after radiation therapy

• GETUG-12 (Fizazi et al; Lancet Oncol, 2015)• ADT +/- 4 cycles Docetaxel/Estramustine (N=413)

• RFS: 199 events: HR=0.71 (0.54-0.94)

• OS: 91 deaths: too early

• STAMPEDE (Not all M0 men had RT)• ADT +/- 6 cycles Docetaxel/Prednisone (N=689)

• RFS: 229 events; HR=0.57 (0.42-0.76)

• OS: 93 deaths; HR=1.01 but too early

• RTOG 0521• ADT +/- 6 cycles Docetaxel/Prednisone (N=563)

• RFS: 221 events: HR=0.76 (0.58-0.99)

• OS: 102 deaths: HR=0.70 (0.51-0.98)

Recommendation #2

Men with localized M0 prostate cancer who are able to receive local treatment with radiotherapy should not be

offered Docetaxel in addition to ADT

This opinion might change with longer follow-up of the GETUG-12, STAMPEDE, and RTOG 0521 trials


Question

The following non-CRPC prostate cancer patients are candidates for Docetaxel therapy:

• 68 year old man with localized, Gl 9 prostate cancer and PSA of 34 being treated with IMRT and ADT

• RTOG 0521: not yet but depends on how early an adopter you are, or the patient in front of you.

• 71 year old man with newly diagnosed metastatic prostate cancer with 2 bone metson BS

• CHAARTED/GETUG suggests YES. STAMPEDE strengthens that.

• 63 year old man with newly diagnosed metastatic prostate cancer with liver mets

• CHAARTED and STAMPEDE say YES.

• All of the above

• MAYBE – see above.

• 2 and 3

• YES as of this ASCO.

• 3 only

• DEFINITELY, but from STAMPEDE, can be less advanced than this and still benefit.

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