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How to Sequence the many novel agents for CRPC

Charles J Ryan, MDProfessor of Clinical Medicine and Urology

Helen Diller Family Comprehensive Cancer CenterUniversity of California, San Francisco

The Challenge of this “Abundance”

• What to give?

• What to give when?

• What is the impact of prior treatment?

• What can guide us?

Therapeutic Goals in mCRPC

Baseline PSA

ProgressionTumor/Bone Progression

Pain

Death

Adapted from Halabi S. J Clin Oncol. 2009;27: 2766-2771.

Chemotherapy

ECOG PS Decline

Delay, Prevent, Preserve, Survive

ECOG PS= Eastern Cooperative Oncology Group Performance Status.

24-48 months

What Anti-Tumor Therapies are Available?

• Immunotherapy– Sipuleucel T

• AR directed therapies– Abiraterone– Enzalutamide

• Chemotherapy– Docetaxel– Cabazitaxel– Mitoxantrone

• Radioisotope– Alpharadin

Immunotherapy

• Consensus– SOC in pre-chemotherapy indolent low volume disease. – Uptake slower than anticipated. – Patients enthusiastic about receiving it

• Challenge– Patients want “remission” and they don’t get it from

Sipuleucel-T. – Cost/Perception

• Opportunity– Earlier metastatic detection may increase use. – “Remission induction”

Survival “Delta” may peak b/w 2-3 years: Ideal time to use may be “EARLY CRPC”

1*Kaplan-Meier estimates with 95% confidence interval and number at risk.†(Percent Sipuleucel-T – percent control)/percent control.

Sipuleucel T

Sipul T

Targeting AR in mCRPC• Consensus

– SOC in pre-chemotherapy– Many patients get abi who would not have gotten chemotherapy– Both asymptomatic and symptomatic patients. – No comparison data of Abi vs Enz

• Challenge– Primary resistance –

• Opportunity– Regulatory space created by “Abiraterone/Enzalutamide refractory,

chemotherapy naive”?– Combination studies underway

AR Amplification

(30%)

Intratumor Androgen Production/conversion/sequestration

Persistent Serum Androgens (e.g.

adrenals)

The Persistent Relevance of Androgens – The Biological Foundation of Secondary Hormonal Therapy

CRPC

Enzalutamide and Abiraterone – Different points, one Pathway

Androgen Production

AR Binding

Signaling Event Intervention

Conversion to DHT

Androgen Transport/

Circulation/Uptake

SCC Inhibitors

CYP 17 Inihibitors

Block Transport

5-Alpha Reductase inhibitors

AbirateroneOrteronelKetoconazole

Drugs

EnzalutamideARN-509Tok-001

Novel AR Inhibitors

Pre

-Rec

epto

r R

ecep

tor

Intracrine Production

Polymorphisms

Amplified 5 Alpha Reductase

Amplified ARSplice Variant AR

Aberration

Two very active agents

Abiraterone/Pred vs Prednisone Enzalutamide Vs Placebo

Beer et al, Proc GU ASCO 2014Ryan et al, NEJM 2012

Baseline Features: Prevail and 302

Ryan et al, Proc ASCO 2012, LBA4518

Beer et al, Proc GU ASCO 2014

Abiraterone Doubled the Maximal Decline in PSA (≥ 50%) Relative to Prednisone Alone

12

• 29% of patients on the prednisone control arm had a decline in PSA by ≥ 50%• 69% of patients on the abiraterone arm had a decline in PSA by ≥ 50%

-25

Max

imal

Dec

line

From

Bas

elin

e (%

)

-50

-75

-100

0

25

50

75

100

Abiraterone + Prednisone Placebo + Prednisone

IA3 data. A negative percent indicates a decline in PSA. A positive percent indicates that the subject never has a decline in PSA.

Sandhu GU ASCO 2014Noonen et al Proc ESMO 2012

Is “Sequencing” of Abiraterone and Enzalutamide Worth it?

Post Enz Abi response rate =11%PSA PFS= 15 weeks

PSA declines are common on ENZ post ABISustained declines and clinical benefit

<20%

Ryan Proc GU ASCO 2013

Combination Phase III: Alliance: A031201 - PI Michael Morris

Total of 616 deaths, log-rank statistic 90% power (one sided type I error rate of 0.025) to detect HR of 0.77 in favor of arm B

Stratification factor: prior chemo

Arm A:Enzalutamide

Arm B:

EnzalutamideAbirateronePrednisone

Chemotherapy• Consensus

– Overall use declining? – Still very useful in aggressive disease/symptom control and visceral

metastases– More “debulking” pre Enzalutamide or Abi?

• Challenge– Perception– Urology practices– Still no viable combinations.

• Opportunity– Cabazitaxel front line. – combinations?– Novel delivery?

Treatments for CRPC by Symptoms and Presence of Visceral Disease

Symptomatic Asymptomatic Visceral Non-VisceralDocetaxel √ √ √Sipuleucel-T √* √ √Abiraterone acetate

√ √ √ √Enzalutamide √ √ √ √Cabazitaxel √ √ √ √Mitoxantrone √ √ √Radium-223 √ √

*Mild symptoms.

Mohler JL, et al. J Natl Compr Canc Netw. 2013;11:1471-1479.

Be aware of Phenotypic Change….

CRPC

ASI or ARTTherapy

Primary Resistance(Non-

response)

Response

Acquired Resistance:

(compensatory /adaptive)

Death Non-PC Cause

Resistance with Phenotypic Change:e.g. Neuro-endocrine

ASI= Androgen Synthesis InhibitorART = AR Targeted Therapy

Ryan Proc GU ASCO 2013

Docetaxel Probably as effective post Abiraterone/Enza

Maximal PSA Decline on Docetaxel Following Prior Abiraterone Therapy

Aggarwal Proc ASCO 2012

Radio-Isotopes• Consensus

– OS advantage is real– Alsympca trial was in very ill patients – in whom docetaxel had

failed or would be too toxic.

• Challenge– Clinical data is lacking from the phase III trial.– How to “use” it once you have started.– No real data on integrated/subsequent use of other active therapies

(abi and enza etc)• Opportunity

– May be easily combine-able with Abiraterone/Enzalutamide and chemotherapy

ALSYMPCA Overall Survival (Updated Analysis)

Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39Radium-223 614 578 504 369 274 178 105 60 41 18 7 1 0 0

Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 0

Radium-223 Dichloride, n = 614Median OS: 14.9 months

Placebo, n = 307Median OS: 11.3 months

HR = 0.69595% CI, 0.581, 0.832P = 0.000070

10

20

30

40

50

60

70

80

90

100

%

Parker C, et al. NEJM. 2013; 369(3):213-223.

May 2013, Radium-223 was FDA approved for patients with castrate- resistant prostate cancer who have bone metastases and no known visceral metastases

ALSYMPCA: Adverse EventsAll Grades Grades 3 or 4

Radium-223n = 600n (%)

Placebon = 301

n (%)

Radium-223n = 600

n (%)

Placebo n = 301

n (%)Hematologic Anemia 187 (31) 92 (31) 77 (13) 39 (13) Neutropenia 30 (5) 3 (1) 13 (2) 2 (1) Thrombocytopenia 69 (12) 17 (6) 38 (6) 6 (2)Nonhematologic Bone pain 300 (50) 187 (62) 125 (21) 77 (26) Diarrhea 151 (25) 45 (15) 9 (2) 5 (2) Nausea 213 (36) 104 (35) 10 (2) 5 (2) Vomiting 111 (19) 41 (14) 10 (2) 7 (2) Constipation 108 (18) 64 (21) 6 (1) 4 (1)

Parker C, et al. N Engl J Med. 2013;369(3):213-223. Nilsson S, et al. J Clin Oncol. 2014;32(suppl 4): Abstract 9.

• At 1.5 years after the final injection, there were no reports of AML, MDS, or primary bone cancer• Aplastic anemia was reported in 1 patient in the radium-223 arm (considetered treatement-related)• Primary cancers in other organs were identified in 2 Radium-223 treated patients and 3 placebo-treated

patients (deem not study-drug related by investigators)

http://www.onclive.com/publications/obtn/2012/december-2012/sequencing-of-novel-prostate-cancer-agents-is-a-work-in-progress/2

Summary Map of CRPC therapies