Module 2:

Data on Sequencing Drugs in mCRPC

Optimizing Outcomes in Advanced Prostate Cancer

Kala S. Sridhar MD, MSc, FRCPC

Medical Oncologist, Princess Margaret Hospital

Head, GU Medical Oncology Site Group

Associate Professor, University of Toronto

Conflict of Interest Disclosures

• Advisory board: Astellas, Pfizer, Johnson & Johnson, Sanofi

• Honoraria: Astellas, Pfizer, Janssen, Sanofi Aventis

Learning Objectives

• Review the phase III clinical trial data on current treatment options for mCRPC

• Review the current studies on sequencing of drugs in mCRPC

• Discuss the role of biomarkers in prostate cancer

A major challenge in 2015 is not a lack of treatment options but rather knowing which drug and when they should be used for an

individual patient

Trials in Metastatic Prostate Cancer

*Not a head-to-head comparison

Study Regimen Patients HR Survival (p-value)Difference (Months)

TROPIC1 Cabazitaxel vs Mitoxantrone

CRPC, post-Docetaxel

0.70 15.1 vs 12.7P<0.0001

2.4

TAX 3272 Docetaxel Q3W, Mitoxantrone

CRPC 0.76 18.9 vs 16.4P=0.009

2.4

COU-AA-3013 Abiraterone vs placebo

CRPC, post-Docetaxel

0.74 15.8 vs 11.2P<0.0001

4.6

COU-AA-3024 Abiraterone vs Prednisone

CRPC, chemo-naive

0.81 34.7 vs 30.3P=0.0033

4.4

AFFIRM5 Enzalutamide vs placebo

CRPC,post-Docetaxel

0.63 18.4 vs 13.6P<0.001

4.8

PREVAIL6 Enzalutamide vs Placebo

CRPC, chemo-naive

0.71 32.4 vs 30.2P<0.0001

2.2

ALSYMPCA7 Radium-223 vs placebo

CRPC, post/unfit/ for Docetaxel

0.70 14.9 vs 11.3P<0.001

3.6

1. de Bono JS, et al. Lancet 2010, 2. Tannock et al. NEJM 2004, 3. Fizazi et al. Lancet Oncol 2012, 4. Ryan et al. ESMO 2014 Abstract 7530, 5. Scher et al. NEJM2012, 6. Beer et al. NEJM 2014, 7. Parker et al. NEJM 2013

Question

•What are treatment options for a 65 year old man with mCRPC progressing following both Enzalutamide and Abiraterone? CT shows bone metastases, questionable lung, liver lesions. ECOG PS 1. Referred for Radium 223.

a) Docetaxel

b) Radium

c) Clinical trial

d) Cabazitaxel

Question

•What are treatment options for a 65 year old man with mCRPC progressing following both Enzalutamide and Abiraterone? CT shows bone metastases, questionable lung, liver lesions. ECOG PS 1. Referred for Radium 223.

a) Docetaxel

b) Radium

c) Clinical trial

d) Cabazitaxel

Taxanes

• In 2004, based on TAX 327 Docetaxel became the standard for patients refractory to all hormonal options

• In 2010, another taxane – Cabazitaxel showed an OS benefit over Mitoxantrone in the ‘post-Docetaxel’ space

Tannock et al NEJM 2004; de Bono Lancet 2010

Post Docetaxel Hormonal Agents

• 2012 Abiraterone and Enzalutamide when tested ‘post-Docetaxel’ showed improved OS

• Led to the change in name from hormone refractory to castrate-resistant

Fizazi et al. Lancet Oncol 2012; Scher et al NEJM 2012

Sipuleucel - T

• Autologous cellular immunotherapy against prostatic acid phosphatase

• IMPACT trial

• Patients were asymptomatic/minimally symptomatic without visceral metastases

• Post- or pre-Docetaxel (*mostly pre-)

• Improved OS, thought no improvement in standard indices

Kantoff, P et al NEJM 2010

Radium

• A bone-seeking alpha emitter

• ALSYMPCA Trial

•mCRPC w/ bone mets (no visceral disease, or nodes > 3cm) and symptomatic (taking analgesics for pain or palliative RT to bones)

• Post-docetaxel or refused/unfit for Docetaxel

• Improved OS regardless of prior Docetaxel

Parker, C et al, NEJM 2013

Pre-Docetaxel - Hormonal Agents

• 2013-14 Abiraterone and Enzalutamide both showed improvements in PFS and OS

• Both approved in the pre-chemotherapy setting

Ryan C et al NEJM 2013; Beer T et al NEJM 2014

Current mCRPC Options

Sartor O et al, Asian J Andro 2014

Question

•What is the best treatment option for a minimally symptomatic 72 year old man with mCRPC with involvement of 9 bony sites?

a) Docetaxel

b) Enzalutamide

c) Abiraterone

d) Radium 223

e) Not sure

Question

•What is the best treatment option for a minimally symptomatic 72 year old man with mCRPC with involvement of 9 bony sites?

a) Docetaxel

b) Enzalutamide

c) Abiraterone

d) Radium 223

e) Not sure

Current Challenges

• Post-Docetaxel is a not a biological definition

• Newer agents not compared head to head

• Control group considered sub-optimal now

•Mixed patient populations

• Reporting of endpoints not standardized

• Second line pts have more advanced disease, more negative prognostic factors

• Single institution studies have a risk of bias in patient selection and follow-up

Sequencing Trials (1st, 2nd, 3rd line)

Sartor O et al, Asian J Andro 2014

Docetaxel First: Sequencing (DAE)

Docetaxel -> Abiraterone -> Enzalutamide Response to Enzalutamide Therapy

Study N Sequence PSA Response to Abi(≥50%)

PSA Response(≥50%)

Median PFS

Bianchini 2014 39 Docet-Abi-Enza 38.4% 13% 2.8 months

Schrader 2014 35 Docet-Abi-Enza 45.7% 29% -

Badrising 2014 61 Docet-Abi-Enza - 21% 3 months

Bournakis 2013 25 Docet-Abi/TAK700-Enza

Abi/TAK700-resistant 40% -

Schmid 2014 35 Docet-Abi-Enza - 10% 3.1 months

Thomson 2014 23 Docet-Abi-Enza - 39% 2.8 months

Singh 2014 23 Docet-Abi-Enza - 17% -

Vera-Badillo 2014 26 Docet-Abi-Enza - 27% -

Cheng 2014 183 Docet-Abi-Enza - 19% -

Scholz 2014 63 Docet-Abi-Enza - 29% -

Azad 2014b 68 Docet-Abi-Enza 49% 22% -

Brasso 2014 137 Docet-Abi-Enza 45.6% 18% -

Docetaxel First: Sequencing (DAE)

• Enzalutamide PSA RR 13-40% vs. 38-45% AFFIRM

• Non-PSA responders: 49% vs. 17%

•Median TTP: 2.8 mo vs. 8.3 mo on AFFIRM

• Non-PSA responders with response to Enza 21%

Docetaxel First: Sequencing (DEA)

Abiraterone PSA RR: 3-13% vs. 29-51%PFS 2-4 months vs. 5.6 mo (COU301)Non-PSA responders: 63-78% vs. 11%

DAE may be marginally superior to DEA however formal prospective randomized studies are needed

Docetaxel -> Enzalutamide -> Abiraterone Response to Abiraterone Therapy

Study N Sequence PSA Response to Enza(≥50%)

PSA Response (≥50%)

Median PFS

Ileana 2012 24 Docet-Enza-Abi - 13% 2.4 months

Noonan 2013 30 Docet-Enza-Abi 60% 3% 3.9 months

Loriot 2013 38 Docet-Enza-Abi - 8% 2.7 months

Docetaxel First: Sequencing DAC, DCA

• French/UK study of DAC suggested Cabazitaxel activity similar to TROPIC

• Israeli study showed a PSA RR of 30% vs. TROPIC 39%

• Dutch study showed shorter biochemical PFS (4mo) in DAC vs. 6.4 mo in TROPIC

• DCA (m OS 18.2 mo) vs. DAC (mOS 11.8mo)

• DCA may be better because patients receive more cycles of C (4 vs. 6)

Sartor O et al, Asian J Andro 2014; Sonpavde G et al Clin Genit Cancer 2015

Abiraterone First – Sequencing Studies

Study Type of analysis/ Data set

N

Median treatment duration (mos)

PSA decline ≥ 50% (%)

Median OS (mo)

Sequence of Abiraterone-Enzalutamide (A-E)

Azad et al. [64] Retro MC Cohort 47 4.6 25.5 8.6

Smith et al. [89] Phase III post-hoc 33 5 - --

Suzman et al. [90] Retro SC Cohort 30 -- 34 --

Cheng et al. [73] Retro MC Cohort 28 -- 36 --

Sequence of Abiraterone-Abiraterone (A-A)

Smith et al. [89] Phase III post-hoc 55 4 44 --

Sequence of Abiraterone –Docetaxel (A-D)

de Bono et al. [95] Phase III post-hoc 265 3 47 --

Azad et al. [86] Retro MC Cohort 37 -- 32 --

Zafeiriou et al. [91] Retro SC Cohort 37 -- -- --

Mezynski [92] Retro SC Cohort 35 5 26 12.5

Suzman et al. [90] Retro SC Cohort 31 -- 40 --

Schweizer et al. [93] Retro SC Cohort 24 -- 38 --

Aggarwal et al. [94] Retro SC Cohort 23 4.3 48 12.4

Chi K et at, Ann Oncol 2015

Abiraterone First Sequences

• A-E– PSA RR 26-36%, m OS 8.6

• Trend towards decreased response to sequential hormonal therapy, consistent with post D setting, and possibly due to similar mechanisms of cross resistance

• A-D– PSA RR 26-48% m OS 12.5.

• Number of cycles of D less than in first line setting

• D has activity after A

• Again a formal trial needs to be done

Chi K et at, Ann Oncol 2014

Enzalutamide First

• Given positive PREVAIL data, and recent access program use of Enzalutamide in first line has gone up

• Sequencing studies are awaited for this and other newer agents such as Radium

Sequencing Studies Overview

• Small studies

• Retrospective

• Not rigorously controlled

• Unclear if lower response rates in sequential therapy is due to another line of treatment or actual cross resistance

• And, is this the same in all patients?

• Highlights the need for biomarkers

Potential Biomarkers

• Prostate cancer significantly lags behind other solid tumors in this regard

• No validated assay for evaluation of androgen receptor profiles for optimal treatment selection

Question

• Is current research focusing on biomarkers to predict

a) Response to a certain treatment?

b) Resistance to a certain treatment?

c) Both

Question

• Is current research focusing on biomarkers to predict

a) Response to a certain treatment?

b) Resistance to a certain treatment?

c) Both

Biomarkers and response or resistance to androgen axis-targeting agents

CATEGORY BIOMARKER

Favorable outcome during androgen axis-targeted therapy

• Tumor expression of CYP17 combined with intense nuclear AR expression (for Abiraterone and Enzalutamide)

• High AR expression, expression of androgen-regulated genes and CYP17 cofactors (for Abiraterone)

• ERG gene rearrangement in tumor tissue or circulating tumor cells (CTCs)

• Post-treatment CTC level (<5/7.5 mL), and AR-regulated gene expression in CTCs

• C-terminal AR loss – galeterone improved PSA response in patients with C-terminal AR loss, suggesting activity in patients with AR-Vs

Resistance to androgen axis-targeted therapy

• AR-V7 in tumor tissue (for Enzalutamide) or CTCs (for Abiraterone and Enzalutamide)

• F876L AR mutation in circulating DNA (for Enzalutamide)

ARV7 Status and Resistance to Abirateroneand Enzalutamide

OBJECTIVE: Association between ARV7 status and PSA response rates, PSA progression-free survival (PSA-PFS), and clinical radiographic PFS

METHODS:

• Quantitative RT-PCR utilized to interrogate CTC for of AR-V7

• 31 Enza-treated patients and 31 Abi-treated patients, of which 38.7% and 19.4% had detectable AR-V7 from CTCs, respectively

RESULTS Xtandi n=31

Zytigan=31

AR-V7 Positive

AR-V7 Negative

AR-V7 Positive

AR-V7 Negative

PSA response rates, %

0 52.6 0 68

P=0.004 P=0.004

Median PSA-PFS(mo)

1.4 5.9 1.3 NR

P<0.001 p<0.001

Median PFS (mo) 2.1 6.1 2.3 NR

P<0.001 P<0.001

CONCLUSIONS:

• Detection of AR-V7 in CTCs is linked to resistance to Abiraterone and Enzalutamide

• AR-V7 status may one day be used as a biomarker to predict resistance to AR-targeting agents, facilitate treatment selection, and fuel the development AR N-terminal domain inhibitors

Antonarakis E et al NEJM 2014

Does ARV7 predict response to docetaxel?

• Early data would suggest that ARV7 mutation may not affect response to Docetaxel.

• ARV7 may indicate a worse prognosis overall

• Data needs to be validated further

• Should these patients get alternate chemotherapy regimens?

• Can they be studied as a group?

Antonarakis E et al ASCO 2015

Outstanding issues with biomarker development

• Is it possible to identify clinically useful biomarkers, such as AR-V7, for androgen axis-targeted therapy

• Based on potential resistance mechanisms, several biomarkers might need to be interrogated and varying biomarker panels might be applicable for various therapies

• Further research required

• Validate preliminary findings and address conflicting data

• Confirm that biomarkers can discriminate between outcomes on androgen axis-targeted therapy versus other treatments

• Tests must be scaled for affordable clinical adoption and practicality

Sequencing Decision Tools in development

• Key Criteria

• Prior treatment and response

• Extent of metastases (none/bone/visceral)

• PSA level/doubling time?

• Symptoms/ECOG status

• Comorbidities – Diabetes, Cardiac

• Drugs and their tolerability and side effects?

What about the costs?

Funding these agents in sequence is expensive

Generic Name(Trade)

mCRPCIndication

OS Benefit

Treatment Duration

Cost/Cycle

Approved Funded

Docetaxel(Taxotere)

All 3.1 mo 10 cycles $218 Yes Yes

Abiraterone Pre-chemo 5.2 mo 15 mo $3448 Yes Yes

Post-chemo 4.6 mo 8 mo $3448 Yes Yes

Enzalutamide Pre-chemo* 2.2 mo 16.6 mo* $3,174.64* Yes* No*

Post-chemo 4.8 mo 8 mo $3448 Yes Yes

Cabazitaxel Post-chemo 2.4 mo 6 cycles $3287 Yes Yes

Radium 223 Unfit/post 3.6 mo 6 cycles $5640/dose Yes Yes

* Data from Ontario, Canada, 2015

Just when we thought we were getting closer…

• CHAARTED study reported that earlier use of chemotherapy in de novo metastatic patients had improved overall survival especially in those with high volume disease...

• Not sure yet how this will impact the sequencing question…

Conclusions

• Novel hormonal agents are being used earlier• Will this change the natural history of the disease?

• Chemotherapy use had been dropping• How will CHAARTED impact on this?

•Without Level 1 data various approaches are being used• A-D-E• E-D-A• Early Radium use since can’t be given with A/E/D• A-D-E-C

• Should pts have exposure to all agents at some point?

• Need some definitive studies to guide our management

Conclusions

•With more treatments comes more questions, but also more hope for future development!