1. Management of advanced hormone-sensitive and castration-resistant prostate cancer
Matthew D. Galsky, MD
Director, GU Medical Oncology
Tisch Cancer Institute
Icahn School of Medicine at Mount Sinai
New York, NY

2. Overview
Early chemotherapy in patients with metastatic hormone-sensitive prostate cancer
New generation “hormonal” therapies for castration-resistant disease
Integration of immunotherapy and radiopharmaceuticals

3. New Drug Approvals in Prostate Cancer
Galsky et al, CA: A Cancer Journal for Clinicians, 2012

4. Early chemotherapy in patients with metastatic hormone-naïve disease4

5. Huggins: ADT for Prostate Cancer
To put this problem into some historical context, ADT has been recognized as an effective treatment for metastatic prostate cancer since the seminal studies of Huggins and his colleagues in the 1940s. Dr. Huggins was awarded the Nobel Prize for Medicine for his observations that metastatic prostate cancer is dependent on androgen for growth, and that surgical or medical castration can induce significant and prolonged regressions of prostate cancer.

6. Docetaxel in Prostate Cancer
The standard of care for CRPC changed from mitoxantrone/prednisone to docetaxel/prednisone based on SWOG and TAX-327 studies
SWOG 99-16
TAX-327
HR: 0.83, P=0.03
The standard of care for CRPC was recently changed from mitoxantrone-based chemotherapy to docetaxel-based chemotherapy based on the results of the TAX-327 and SWOG trials.1,2
In the SWOG trial, docetaxel/estramustine therapy improved median survival by 2 months compared to mitoxantrone/prednisone therapy. The graphs on the left highlights overall survival rates in both treatment arms. As you can see, docetaxel/estramustine resulted in fewer deaths than mitoxantrone/prednisone.1
In the TAX-327 trial, researchers found that docetaxel therapy led to improved survival and rates of response in terms of pain, PSA level, and quality of life compared to mitoxanthrone/prednisone therapy. The graph on the right demonstrates probability of overall survival among the three treatment arms. In this study, docetaxel (every 3 weeks) was superior to weekly docetaxel or mitoxantrone/prednisone therapy.2
References:
Petrylack DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxanthrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:
Tannock TF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:
Petrylak N Engl J Med. 2004
Tannock, N Engl J Med. 2004

7. Early Chemotherapy +ADT for metastatic prostate cancer?
Attack de-novo testosterone independent clones early - allow ADT to keep PrCa in remission longer
Some patients at the time of progression are too frail for chemo.
Con
ADT will take cells out of cycle and be less responsive to cytotoxics
Some patients respond for a long time and never need chemotherapy
Androgen Deprivation Therapy
Regression Re-emergence
Sweeney et al, ASCO, 2014

8. E3805 – CHAARTED Treatment
Stratification
Extent of Mets
High vs Low
Age
≥70 vs < 70yo
ECOG PS
- 0-1 vs 2
CAB> 30 days
-Yes vs No
SRE Prevention
Prior Adjuvant ADT
≤12 vs > 12 months
Evaluate every 3 weeks while receiving docetaxel and at week 24 then every 12 weeks
ARM A:
ADT + Docetaxel 75mg/m2 every 21 days for maximum 6 cycles
RANDOMIZe
Follow for time to progression and overall survival
Chemotherapy at investigator’s discretion at progression
ARM B:
ADT (androgen deprivation therapy alone)
Evaluate every 12 weeks
ADT allowed up to 120 days prior to randomization.
Intermittent ADT dosing was not allowed
Standard dexamethasone premedication but no daily prednisone
High volume: visceral metastases and/or 4 or more bone metastases
(at least 1 beyond pelvis and vertebral column)

9. Primary endpoint: Overall survival
HR=0.61 ( ) p=0.0003
Median OS:
ADT + D: 57.6 months
ADT alone: 44.0 months
Sweeney et al, ASCO, 2014

10. OS by extent of metastatic disease at start of ADT
High volume
Low volume
p=0.0006
HR=0.60 ( )
Median OS:
ADT + D: 49.2 months
ADT alone: 32.2 months
p=0.1398
HR=0.63 ( )
Median OS:
ADT + D: Not reached
ADT alone: Not reached
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
Sweeney et al, ASCO, 2014

11. Clinical States of Prostate Cancer
Clinically
localized
“Rising PSA”
state
Non-metastatic,
hormone- sensitive
Non-metastatic
CRPC
Metastatic,
hormone-sensitive
Metastatic
CRPC
This flow chart shows the clinical states of prostate cancer. Progression from clinically localized disease to metastatic AIPC generally spans years or more.
Death from prostate cancer
Death from other causes
10-15 years + 11

12. New generation of “hormonal therapies” for castration-resistant disease12

13. What is castration-resistance?
CRPC is NOT Hormone Refractory Cancer,
500 ng/mL
Testosterone
but is frequently Hormone Ultra-Sensitive
PSA
50 ng/mL
Castration Therapy
Castration Resistance

14. T Androgen Deprivation Therapy CRPC selective pressure adaptation
ABERRANT
MODIFICATION
GF, cytokines
Src
Sumo AC P
COFACTOR
PERTURBATION
CoAct gain
CoR loss/dismissal
CoACT
MUTATION
gain of function AR AR
DEREGULATION
amplification
overexpression
INTRACRINE
ANDROGEN
SYNTHESIS T
ALTERN.
SPLICING
RESTORED AR ACTIVITY
(rising PSA)
CRPC

15. T Androgen Deprivation Therapy CRPC selective pressure adaptation
ABERRANT
MODIFICATION
GF, cytokines
Src
Sumo AC P
COFACTOR
PERTURBATION
CoAct gain
CoR loss/dismissal
CoACT
MUTATION
gain of function AR AR
DEREGULATION
amplification
overexpression
INTRACRINE
ANDROGEN
SYNTHESIS T
ALTERN.
SPLICING
RESTORED AR ACTIVITY
(rising PSA)
CRPC

16. Enzalutamide T T Enzalutamide AR Tumor AR Death
Oral drug rationally designed to target AR signaling, impacting multiple steps in AR signaling pathway.
No demonstrated agonist effects in pre-clinical models. T T
Enzalutamide
Inhibits Binding of
Androgens to AR 1 AR
Cell cytoplasm
Inhibits Nuclear
Translocation of AR 2
Cell nucleus
Tumor
Death AR
Inhibits Association
Of AR with DNA 3
Tran et al. Science 2009;324:787–90.
Charles Sawyers & Michael Jung

17. T Androgen Deprivation Therapy CRPC selective pressure adaptation
ABERRANT
MODIFICATION
GF, cytokines
Src
Sumo AC P
COFACTOR
PERTURBATION
CoAct gain
CoR loss/dismissal
CoACT
MUTATION
gain of function AR AR
DEREGULATION
amplification
overexpression
INTRACRINE
ANDROGEN
SYNTHESIS T
ALTERN.
SPLICING
RESTORED AR ACTIVITY
(rising PSA)
CRPC

18. Abiraterone (CYP-17 Inhibitor)
Reduce adrenal androgen synthesis by inhibition of 17α-hydroxylase and C17,20-lyase.
These enzymes are needed to produce the precursors of the sex steroids in both the adrenal cortex and testicles….
and in prostate cancer cells……
Abiraterone is a potent and selective CYP17 inhibitor unlike keto which is a less potent and competitive inhibitor of several CYP enzymes. Cytochrome p17 is a microsomal enzyme that catalyzes two independently regulates steroid reactions key to androgen and estrogen biosynthesis. I should mention that there is also evidence that CYP-17 is expressed in the bone metastases based on an abstract at this years ASCO.
Attard, JCO, 2008

19. Expected Toxicities of CYP17 Inhibition
ACTH increases
DOC and Corticosterone increase
Expected side effect profile  mineralocorticoid excess
Hypokalemia
Hypertension
Fluid overload
The side effects of CYP17 inhibition can be predicted based on what happens in patients with congenital CYP17 deficiency. CYP loss interupts the negative feedback control of ACTH – this results in an increase in DOC and corticosterone and the resulting side effects of mineralocorticoid excess – hypokalemia, hypertension, and fluid overload.
Rise in ACTH blunted with co-administration of steroids
Attard, JCO, 2008

20. Abiraterone and Enzalutamide:
07/12/09
Abiraterone and Enzalutamide:
Four Positive Studies!
mCRPC
Pre-chemotherapy
mCRPC
1st Line
Chemotherapy
mCRPC
Post-chemotherapy
COU-AA-302
COU-AA-301
PREVAIL
AFFIRM
Co-Primary Endpoints: OS, rPFS
Primary Endpoint: OS

21. PREVAIL: Radiographic Progression-Free Survival
Median rPFS: Enzalutamide, not reached
Placebo, 3.9 months
Beer T, et al. J Clin Oncol. 2014;32(suppl 4): Abstract LBA 1.

22. COU-AA-302: Abiraterone Acetate ~Doubles rPFS in Pre-Chemo mCRPC
100
Abiraterone (median, mos):
16.5
Prednisone (median, mos):
8.3
HR (95% CI):
0.53
( )
p Value:
< 80 60
Subjects Without Progression or Death (%) 40 20
Abiraterone
Prednisone 3 6 9 12 15 18 21 24 27 30 33 36
Months From Randomization
Abiraterone
Prednisone
546
542
485
406
389
244
311
176
240
133
195 99
157 78
131 62
117 45 66 20 20 7 4
Rathkopf GU ASCO 2013

23. Time to PSA progression
COU-302 vs PREVAIL
COU-302
PREVAIL
Abiraterone/
Prednisone
Enzalutamide
Placebo
Prednisone Use? Y N
Visceral Disease
Grade 3/4 AE
48%
42%
43%
37%
PSA RR
62%
24%
78% 3%
rPFS
16.5 mo
8.3 mo
15-18 mo
3.9 mo OS
34.7 mo
30.3 mo
32.4 mo
30.2 mo
Time to chemo
25 mo
16.8 mo
28 mo
10.8 mo
Time to PSA progression
11.2 mo
5.6 mo
11.1 mo
2.8 mo
Zhang Expert Opin Pharmacother 2015

24. Substantial (but incomplete) cross-resistance between these therapies
Author
Year N
Median Duration
PSA Decline > 50%
ENZA ABI
Loriot
2013 38
3 mo 3%
Noonan 30
3.2 mo
ABI ENZA
Schrader 35
4.9 mo
29%
Badrising
2014 61
21%
Bianchini 39
2.9 mo
23%
Schmid
2.8 mo
10%
Brasso
137
18%

25. Phase III Enzalutamide +/- Abiraterone Acetate + Prednisone in Treating Patients With Metastatic CRPC R A N D O M I Z E
2:1
Patients with mCRPC with no prior docetaxel
Enzalutamide
160 mg daily
days 1-28
Endpoints
Primary: OS
Key Secondary:
PFS and rPFS
PSA response
Toxicity
Enzalutamide
160 mg daily
Abiraterone Acetate 1000 mg daily
Prednisone 5 mg BID
Enrollment Goal
N = 1224
PI: Michael Morris, MD
Available at

26. Can patients be identified that will not respond to abiraterone and enzalutamide?26

27. T Androgen Deprivation Therapy CRPC selective pressure adaptation
ABERRANT
MODIFICATION
GF, cytokines
Src
Sumo AC P
COFACTOR
PERTURBATION
CoAct gain
CoR loss/dismissal
CoACT
MUTATION
gain of function AR AR
DEREGULATION
amplification
overexpression
INTRACRINE
ANDROGEN
SYNTHESIS T
ALTERN.
SPLICING
RESTORED AR ACTIVITY
(rising PSA)
CRPC

28. Androgen Receptor Splice Variants
Nelson, NEJM, 2014

29. ARV7 is associated with lack of response to enzalutamide and abiraterone
Antonarakis et al, NEJM, 2014

30. Galeterone Decreases AR and AR-V7
LuCaP136 Castration Resistant Xenograft
µM Galeterone (72 hr) 1
2.5 5 AR
AR-V7
b-Actin
–110 kDa
–80 kDa
–45 kDa
Galeterone
Treatment
Initiated
CWR22rv1 Cells
CWR22rv1 cells express wild type AR and AR-V7
Castration (Cx)
Cx + Galeterone 250 mg/kg QD, PO 5x/wk
Taplin et al, 26th EORTC-NCI-AACR Symposium

31. ARMOR2: Galeterone Activity in Patients with AR C-terminal Loss
Time to PSA Progression (PCWG2):
Median 7.3 months (95% CI 2.8–NE)
M0 and M1 Treatment Naïve Arms *
Maximal PSA, %
Exposure (n=7)
Time on treatment:155 to >334 days (ongoing)
Four patients continued into optional extension phase
Taplin et al, 26th EORTC-NCI-AACR Symposium

32. ARMOR3-SV Trial Schematic: Phase 3 Trial
Secondary Endpoints
Overall survival
Skeletal related events
Time to cytotoxic therapy
Primary Endpoint
Radiographic progression free survival
Key Inclusion Criteria
M1 disease
Progressive disease on androgen deprivation therapy based on PCWG2
Detectable AR-V7 from CTCs
ECOG 0 or 1
Key Exclusion Criteria
Prior treatment with second generation antiandrogens (abiraterone, enzalutamide)
Prior treatment with chemotherapy for CRPC
Galeterone
2550 mg/day
Randomize
Enzalutamide
160 mg/day
Other Endpoints
Safety
PSA50
Time to progression and ECOG deterioration
Best overall response by RECIST 1.1
CTC characterization
Pharmacokinetics
Quality of life
Taplin et al, 26th EORTC-NCI-AACR Symposium

33. The role of immunotherapy in metastatic CRPC?33

34. Sipuleucel-T: Autologous APCs Cultured with Antigen Fusion Protein
Recombinant Prostatic Acid Phosphatase (PAP) fusion antigen combines with resting antigen presenting cell (APC)
APC takes up the antigen
Antigen is processed and presented on surface of the APC
Fully activated, the APC is now sipuleucel-T
Inactive T-cell
INFUSE PATIENT
Active T-cell
T-cells proliferate and attack cancer cells
sipuleucel-T activates T-cells in the body

35. Sipuleucel-T Survival Benefit
Sipuleucel-T was approved based on HR (~4 month OS benefit)
Survival curves separate after 6 months
Treatment is done in 5 weeks
Well tolerated
Kantoff NEJM 2010

36. Survival Benefit of Sip-T is Greater When PSA is Lower
7/5/2018
Survival Benefit of Sip-T is Greater When PSA is Lower
IMPACT: Overall Survival by Baseline PSA
Baseline PSA
≤22.1
>22.1–50.1
>50.1–134.1
>134.1 n
128
Median OS, months
-Sipuleucel-T
41.3
27.1
20.4
18.4
-Control
28.3
20.1
15.0
15.6
-Difference
13.0
7.1
5.4
2.8 HR
0.51
(0.31, .85)
0.74
(0.47, 1.17)
0.81
(0.52, 1.24)
0.84
(0.55, 1.29)
Baseline PSA (ng/mL)
41.3
28.3
20.1
15.0
15.6
2.8
HR (95% CI) (0.31, 0.85) (0.47, 1.17) (0.52, 1.24) (0.55, 1.29)
Schellhammer Urology 2013

37. Radium-223 Is For Symptomatic Patients With Bone Mets37

38. Radium-223 Targets Bone Metastases
Radium-223 acts as a calcium mimic
Naturally targets new bone growth in and around bone metastases
Radium-223 is excreted by the small intestine Ca Sr Ba Ra

39. Radium-223 Targets Bone Metastases
Range of alpha-particle
Radium-223
Bone surface
Alpha-particles induce double-strand DNA breaks in adjacent tumour cells
Short penetration of alpha emitters (2-10 cell diameters) = highly localized tumour cell killing and minimal damage to surrounding normal tissue

40. ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design
TREATMENT
6 injections at 4-week intervals
Radium-223 (50 kBq/kg) + Best standard of care
Placebo (saline) + Best standard of care R
A N D
OM I S
E D
2:1
N = 921
PATIENTS
Confirmed symptomatic CRPC
≥ 2 bone metastases
No known visceral metastases
Post-docetaxel or unfit for docetaxel
Total ALP: < 220 U/L vs ≥ 220 U/L
Bisphosphonate use: Yes vs No
Prior docetaxel: Yes vs No
STRATIFICATION

41. ALSYMPCA Updated Analysis Overall Survival
100
HR = 0.695
95% CI, 0.581, P = 90 80 70 60 % 50
Radium-223, n = 614
Median OS: 14.9 months 40 30 20
Placebo, n = 307
Median OS: 11.3 months 10
Month 3 6 9 12 15 18 21 24 27 30 33 36 39
Radium-223
614
578
504
369
274
178
105 60 41 7 1
Placebo
307
288
228
157
103 67 14 4 2

42. Standard Androgen Deprivation Therapy Denosumab, Zoledronic Acid
Treatment Landscape
Standard Androgen Deprivation Therapy
Surgery / Radiation
Denosumab, Zoledronic Acid
Radium-223
Enzalutamide
Abiraterone
Local
Therapy
Androgen
Deprivation
Death
Interventional therapy
Surgery, Radiation, Cryosurgery, Brachytherapy in curative setting, not competition
First-line hormonal therapy
LHRH Agents (Lupron, Zoladex, Firmagon) given to metastatic patients to control PSA, disease progression. Most likely to be continued with Abiraterone however a successful head to head trial or early stage combination trial would have profound positive impact on uptake
Antiandrogens
Casodex given with LHRH in an effort at combined androgen blockade or as a second line agent. Clinical trial efficacy is mixed but embraced by HCPs. Antiandrogen withdrawal can actually lower PSA.
Provenge
Immunotherapy launched in Q Labeled for mild/asymptomatic mCRPC. Should be direct competitor to 302 indication although patients could receive both drugs. Prostvac-VF is similar agent in development
Taxotere
Chemotherapy is standard of care with prednisone. Patent likely to expire in Sandwiched between 301 and 302 indications it is a threat.
Jevtana
Follow-on taxane from sanofi-aventis launched in Q in post Taxotere failures. Use could delay onset of abiraterone usage in 301 setting.
Sipuleucel-T
Docetaxel
Cabazitaxel 42

43. The next few years….. More agents
some will be “me too” drugs?
Increased understanding of the biology of CRPC
Earlier use of therapies
Adjuvant, neoadjuvant, rising PSA, non-mets CRPC
More molecular diagnostics and personalization of prostate cancer subtypes
True “hormone refractory” disease