1. Sequencing Considerations After Progression Following Initial Therapy for mCRPC
mCRPC, metastatic castration-resistant prostate cancer.

2. About These Slides
Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients
When using our slides, please retain the source attribution:
These slides may not be published, posted online, or used in commercial presentations without permission. Please contact for details
Slide credit: clinicaloptions.com
Disclaimer: The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. Faculty Tanya B. Dorff, MD Assistant Professor of Clinical Medicine
Division of Medical Oncology
Department of Medicine USC Keck School of Medicine/Norris Comprehensive Cancer Center
Los Angeles, California
Tanya B. Dorff, MD, has disclosed that she has received consulting fees from Bayer, Dendreon, Genentech, and Pfizer and speaker fees from Astellas and Dendreon.

4. mCRPC: Defining “Meaningful” OS Improvement
Summary of OS by baseline PSA (ng/mL) in mCRPC trials
mCRPC, metastatic castration-resistant prostate cancer; PSA, prostate-specific antigen.
Med OS difference in lowest quartile was 13 months compared to 7 months for PSA and 5.4 months for 3rd quartile; minimal benefit in highest quartile
Schellhammer PF, et al. Urology. 2013;81:

5. mCRPC: Abiraterone Following Disease Progression on Enzalutamide and Vice Versa
Abiraterone response after prior treatment with enzalutamide1
Enzalutamide versus docetaxel in men with CRPC progressing after abiraterone2
CRPC, castration-resistant prostate cancer; PSA, prostate-specific antigen.
Retrospective reports such as that by Loriot and colleagues indicate that we see far fewer responses to abiraterone in patients who have been treated with enzalutamide than we had seen in the registrational trials, in which prior therapy was excluded. Similarly, Schrader and colleagues presented a relatively disappointing experience with enzalutamide after abiraterone pre-treatment. Interestingly, with the overlapped waterfall plots, one can see that there are responses in both abi – responsive and abi-nonresponsive patient populations. One can almost see 4 subgroups of patients here.
1. Loriot Y, et al. Ann Oncol 2013;24: Suzman DL, et al. Prostate. 2014; 74:

6. mCRPC: Enzalutamide Following Disease Progression on Abiraterone and Docetaxel
Enzalutamide response after prior tx with abiraterone and docetaxel
mCRPC, metastatic castration-resistant prostate cancer; tx, treatment.
Schrader AJ, et al. Eur Urol. 2014;65:30-36.

7. ARV7: Androgen Receptor Splice Variant Without Ligand Binding Domain
May predict lack of response to abiraterone and enzalutamide1
Not associated with lack of response to docetaxel2
Taxane-Treated Patients
AR, androgen receptor.
1. Antonarakis ES, et al. N Engl J Med. 2014;371:
2. Antonarakis ES, et al. ASCO GU Cancer Symposium Abstract 138.

8. A Standard of Care for mCRPC
Docetaxel:
A Standard of Care for mCRPC
Docetaxel
TAX 3272
SWOG
mCRPC, metastatic castration-resistant prostate cancer.
Median TTP mitoxantrone 3-4 months vs 6 months taxotere & OS 18.9 months vs 16.5 months
1. Petrylak DP, et al. N Engl J Med. 2004;351:
2. Tannock IF, et al. N Engl J Med. 2004; 351:

9. TROPIC: OS (ITT) for Prednisone + Cabazitaxel 0r Mitoxantrone in mCRPC
30% reduction in risk of death for CBZP vs MP MP
CBZP
Median OS, mos
12.7
15.1 HR
0.70
95% CI
P value
< .0001
Combined median follow-up, mos
12.8
CBZP, cabazitaxel; ITT, intent to treat; mCRPC, metastatic castration-resistant prostate cancer; MP, mitoxantrone.
Points on curve represent censored observations.
De Bono JS, et al. Lancet. 2010;376:

10. ALSYMPCA (Radium-223): Overall Survival
100
HR = 0.70 (95% CI, ) P = < .001 90 80 70 60
Survival (%) 50
Radium-223, n = 614
Median OS: 14.9 months 40 30 20
Placebo, n = 307
Median OS: 11.3 months 10 3 6 9 12 15 18 21 24 27 30 33 36 39
Mos
Parker C, et al. N Engl J Med. 2013;369:

11. Concurrent Radium-223 With Abiraterone/Ezalutamide Appears to be Safe
ALSYMPCA1,2
EAP2
Tulane/CCF3
MI/Ind4
Median # doses (% pts receiving 6 doses)
6 (63)
5 (44)
5 (39)
4 (38)
Treatment emergent AE, %
Grade 3/4
Grade 5 43 16 36 4
7.8 NR
11.5
Pts with SSE*, % 33 10
Confirmed PSA decline > 50%, % 8 6 25
(> 30% decline)
Confirmed alk phos decline > 30%, % 47 51
Median OS, mos
14.9 17 11
Secondary malignancy, %
< 1 2
Concurrent abi/enza, %
None 22
AE, adverse event; SSE, symptomatic skeletal event
* SSE, symptomatic skeletal event
1. Parker C, et al. ASCO GU Abstract Vogelzang NJ, et al. ASCO GU Abstract 247.
3. Emamekhoo H, et al. ASCO GU Abstract Modi D, et al. ASCO GU Abstract 275.

12. Combination of Abiraterone + Radium-223 Associated with Improved PFS and OS
36% of pts had nodal/visceral involvement
N=110 but 36% had nodal and/or visceral involvement – that could explain why they did better with concurrent abiraterone.
Formal ongoing trials will define benefit
Etchebehere EC, et al.
Eur J Nucl Med Mol Imaging. 2016;43:8-20.

13. Ongoing Trials Will Inform Optimal Treatment Paradigms in mCRPC
NCT : PRIMCAB, Cabazitaxel vs AR Switch
NCT : Radium-223 ± abiraterone OR enzalutamide
NCT : Abiraterone ± Radium-223

14. Novel Therapies in Development for mCRPC
Immunotherapy
Multiple immune agents combined
Combining with radiation
AR-targeted
Galeterone
“Bipolar “ tx
Non-AR targets
PARP inhibitors
PI3K/AKT
Ab Conjugates (eg, J591)
AR, androgen receptor; mCRPC, metastatic castration-resistant prostate cancer; PARP, poly ADP ribose polymerase; tx, treatment.
Antonarakis ES, et al. Prostate Cancer Prostatic Dis. 2011;14:

15. Immunotherapy in Prostate Cancer: Mixed Success
GVAX:
Vital 2: docetaxel +/- GVAX, neg
Vital 1: terminated
Ipilimumab:
post docetaxel: ipi and RT vs placebo, neg
Pre-docetaxel: pending
Tasquinomod vs placebo, neg
Prostate cancer vaccine (PSAtricom): pending
JNJ : ongoing
PD1 inhibitors: ??
PSA-
targeted
poxviral
vaccine
mCRPC, metastatic castration-resistant prostate cancer.
As introduction to combination strategies, let’s look at what players have come before and how they have been studied.
PSA TRICOM is PSA with 3 boosters. Vaccinia vector, fowlpox
Kwon ED, et al. Lancet Oncol. 2014;15:
Kantoff PW, et al. J Clin Oncol. 2010;28:

16. Ipilimumab in mCRPC: Promising…But Didn’t Meet OS
Screening
Ipilimumab in mCRPC: Promising…But Didn’t Meet OS
14 months
mCRPC, metastatic castration-resistant prostate cancer.
Kwon ED, et al. Lancet Oncol. 2014;15: 16

17. Radiation and Immunotherapy
Radiation therapy induced tumor cell death and immunogenic modulation may enhance immunotherapy
Clinical Trials:
Sipuleucel-T ± radium-223 (NCT )
Radium atezolizumab
Gameiro SR, et al. Oncoimmunology. 2014;3:e28643.

18. Sipuleucel-T Combined With Other Immune Activators
NCT : Sipuleucel-T + immediate vs delayed ipilimumab
NCT : Sipuleucel-T + pidilizumab + cyclophosphamide
NCT : Sipuleucel-T followed by CYT107 (IL7 SQ)

19. Galeterone: Selective, Multitargeted, Small Molecule for Treatment of CRPC
Mechanism of action
CYP17 lyase inhibitor – blocks androgen synthesis
AR antagonist – blocks androgen binding; limit nuclear translocation
Enhances degradation of AR
Well tolerated safety profile: No mineralocorticoid excess (ME), no prednisone required, no seizures seen to date
Preclinical activity seen in lines containing multiple AR mutations including AR-V7, AR-T878A and AR-F876L
AR, androgen receptor; CRPC, castration-resistant prostate cancer.
Montgomery RB, et al. ASCO Abstract 5029.

20. Galeterone in CRPC: Efficacy*
12-week maximal PSA response in treatment-naïve patients (TN-M0 and TN-M1): 82% and 75% reached PSA30 and PSA50
PSA Response: TN-M0 and TN-M1
12-week maximal PSA response in treatment-naïve metastatic patients (TN-M1): 85% and 77% reached PSA30 and PSA50
PSA Response: TN-M1
CRPC, castration-resistant prostate cancer; PSA, prostate-specific antigen.
*Data cut-off May 12, 2014.
Montgomery RB, et al. ASCO Abstract 5029.

21. Galeterone in CRPC: Efficacy (cont.)
PSA response in abi refractory patients*
27% (4/15) had any PSA decline and 13% (2/15) have demonstrated a maximal PSA30
35% (6/17) had stable CTC (change <3) and 35% (6/17) had decreasing (≥3 count) CTC counts
CTC analysis of C-terminal truncation
CTC C-terminal AR loss in the presence
of N-terminal AR positivity in the M0 and
M1 treatment arms at 1 week
Reduction in C-terminal immunoreactivity is potentially consistent with AR splice variant
100% (4/4) maximal PSA reduction >50%
30%
20%
10% 0%
-10%
-20%
-30%
-40%
-50%
-60%
-70%
-80%
-90%
-100%
Equal N- and C-Terminal Immunoreactivity
Little or No C-Terminal Immunoreactivity
Maximal PSA (%)
Abi, abiraterone; AR, androgen receptor; CRPC, castration-resistant prostate cancer; CTC, circulating tumor cells; Enz, enzalutamide; PSA, prostate-specific antigen; PSA30, 30% PSA decline.
*Data cut-0ff May 12, 2014.
Enz refractory patients not evaluable for PSA response.
Montgomery RB, et al. ASCO Abstract 5029.

22. Bipolar Androgen Therapy in Hormone-Sensitive Prostate Cancer
ADT, androgen deprivation therapy; BAT, bipolar androgen therapy.
Theoretically increases AR expression 17/29 men (59%) having a PSA < 4 ng/ml after 2 cycles of BAT. Ten patients receiving BAT had RECIST evaluable disease, and 8 (80%) objective responses were observed (4 complete; 4 partial). Three patients progressed per RECIST criteria and 3 had unconfirmed progression on bone scan. Men treated with 6-months of ADT had improved QOL after the first cycle of BAT
Schweizer MT, et al.
ASCO Genitourinary Cancers Symposium Abstract 236.

23. DNA-Repair Defects and Olaparib in mCRPC
mCRPC, metastatic castration-resistant prostate cancer.
Mateo J, et al. N Engl J Med. 2015;373:

24. Olaparib in mCRPC: PFS & OS
mCRPC, metastatic castration-resistant prostate cancer.
Mateo J, et al. N Engl J Med. 2015;373:

25. Phase II 177Lu-J591 in mCRPC: Efficacy
Best PSA Response1
Cohort 1 (65 mCi/m2)
Cohort 2 (MTD, 70 mCi/m2)
Overall: At least 30% PSA decrease2,3 = 10/32 (31%)
1. Tagawa ST, et al. ASCO Abstract 5140.
2. Petrylak DP, et al. J Natl Cancer Inst. 2006;98:
3. Armstrong AJ, et al. J Clin Oncol. 2007;25:

26. GSK2636771, an Inhibitor of PI3Kβ, in Pts with PTEN-Deficient Tumors
PTEN, phosphatase and tensin homolog.
1. Arkenau HT, et al. ASCO Abstract 2514.

27. Conclusions
AR remains a major target in mCRPC even after progression on abiraterone and/or enzalutamide
Standard options include chemotherapy and radium-223
Novel approaches include immunotherapy, radioimmunoconjugate strategies, and non-AR targeted therapies
Optimal sequencing is not established but will likely be different for each patient as we have better tools/biomarkers for personalizing therapy
AR, androgen receptor; mCRPC, metastatic castration-resistant prostate cancer.
Although what EARLY means has been redefined to some extent, since docetaxel is going to be adminsitered up front to many, based on CHAARTED, and CYP17 inhibition (or better AR targeting) may also move up in the future.
The molecular sub-categorization for now is identifying neuroendocrine and other aggressive variants, which may only lead to choice of chemo over AR targeting tx, or potentially aurora kinase inhib if that pans out from the ongoing trial,

28. Go Online for More CCO Coverage of Prostate Cancer!
Downloadable slidesets of key studies from ASCO 2016 selected by expert faculty Expert Analysis of key presentations from ASCO 2016
clinicaloptions.com/oncology