Don’t miss our upcoming webinars: Subscribe today! In this webinar: The basics of advanced prostate cancer, what it means to have non-metastatic castration resistant prostate cancer, the new treatment options now available for this disease space, and the prognosis for patients in this state of disease. Presented by Dr. Robert Hamilton, urologic oncologist at Princess Margaret Cancer Centre and Associate Professor in the Department of Surgery (Urology) at the University of Toronto, this webinar will provide an overview of this subset of prostate cancer. Dr. Hamilton’s clinical and research interests are in prostate cancer and testicular cancer. Dr. Hamilton trained at the University of Toronto and has completed a Masters of Public Health at The University of North Carolina at Chapel Hill, and a research fellowship at Duke University. He has also completed a fellowship at Memorial Sloan-Kettering Cancer Centre. View the video: https://youtu.be/wE3EVJm5Oo4 To learn more about CCSN, visit us at survivornet.ca Follow CCSN on social media: Twitter - https://twitter.com/survivornetca Facebook - https://www.facebook.com/CanadianSurvivorNet Instagram: https://www.instagram.com/survivornet_ca/ Pinterest - https://www.pinterest.com/survivornetwork

1. What’s New for the Prostate Cancer Patient with Non-
Metastatic Castration Resistant Prostate Cancer
Robert Hamilton, MD MPH FRCSC
Staff Urologist, Princess Margaret Cancer Centre
Assoc. Prof, Dept. of Surgery, University of Toronto

2. Overview
• Background
• Castration resistant prostate cancer (CRPC)
• Natural history of non-metastatic CRPC
• Predictors of time to metastases
• Detecting metastases
• Preventing metastases (the 3 new studies)

3. Prostate Cancer Facts
• Most common cancer among men
– 1 in 9 men diagnosed in their lifetime
– Estimated 22,900 new cases in Canada in 2019
• 3rd leading cause of cancer death among men
– 1 in 29 men will die of prostate cancer

4. Continuum of Prostate Cancer
Symptomatic
Androgen
Deprivation
Death
TumorVolume&Activity
Therapies After LHRH
Agonists
and Antiandrogens
Castration-Sensitive Castration-Resistant
Surgery and
Radiation
Asymptomatic
Premetastatic
Radiographically Metastatic
Chemotherapy
Immunotherapy
7-15 years 3-5 years
Asymptomatic
Hormonal therapies

5. Treatment of advanced disease
• Goals:
1. Reduce testosterone to “castrate” levels
• Testosterone <1.7 nmol/L
2. Block effect of testosterone by blocking the
testosterone (“androgen”) receptor
OR…

6. Some examples of Androgen
Deprivation Therapy
• Antiandrogens
– Non-steroidal
• Bicalutamide (Casodex)
• Niluatmide (Anandron)
• Flutamide (Eulexin)
– Steroidal
• Cyproterone (Androcur)
• LHRH agonists
– Leuprolide (Lupron)
– Luprorelin (Eligard)
– Goserelin (Zoladex)
– Triptorelin (Trelstar)
– Buserelin (Suprefact)
• LHRH antagonists
– Degarelix (Firmagon)

7. Castration-resistant disease
• Growth of prostate cancer (either by PSA or
new/growing metastases) despite castrate
testosterone levels
Androgen
Deprivation
Death
TumorVolume&Activity
Therapies After LHRH
Agonists
and Antiandrogens
Castration-Sensitive Castration-Resistant
Surgery and
Radiation
Premetastatic
Radiographically Metastatic
Chemotherapy
Immunotherapy
Hormonal therapies

8. Castration-resistant disease
• Why does it happen?
– Increased androgen production in the tumor
– Increased androgen receptor levels
– Alterations in androgen receptor (splice-variant; mutations)
– Other pathways (non-androgen dependent)
• Why is it important?
– Signifies accelerated growth of the cancer
– If not yet metastasized, then much greater likelihood of metastases in
near future
– Now enter a time with fairly predictable time to death (3-4 years)

9. Castration-resistant prostate cancer
• Can be “metastatic” or ”non-metastatic”
• Metastatic: development of secondary malignant growths at a distance from a
primary site of cancer.

10. Nonmetastatic CRPC
Rising PSA
while on ADT
Serum
testosterone
levels below
1.7 nmol/L
No evidence
of detectable
metastasis
Nonmetastatic
or nmCRPC

11. Castration-resistant prostate cancer
Metastatic Nonmetastatic
Predictability of survival Predictable Variable
Average Survival Time 36 months 48-60 months
Symptomatic Often Rarely
Consequences Pain, Fracture,
Immobility
Minimal
Treatment options Abiraterone
Enzalutamide
Radium
Docetaxel
Cabazitaxel
Apalutamide
Enzalutamide
Darolutamide

12. What happens to men who are not
metastatic when they become CRPC
%ofpatientswithmets
50% develop metastases
by 3 years

13. Predicting Time To Metastases
• Time to develop metastases
related to:
– Gleason score
– PSA level
– Rate of PSA rise
(PSA Doubling Time)

14. When to image in non-metastatic CRPC
• Based on PSA rise (PSADT)
– Rapid Rise (PSADT < 10 months) or PSA >20
• Imaging every 3-6 months
– Slower Rise (PSADT >10 months)
• Imaging every 6-12 months

15. Detecting metastases
• Conventional imaging:
– CT Scan (Chest, abdomen, Pelvis)
– Bone Scan
– Lacks the sensitivity for detecting small volume
metastases
• Novel Imaging:
– PET scans:
• NaF, PSMA, Axumin, Choline

16. Novel Imaging
• PSMA
– Prostate Specific Membrane
Antigen
– Transmembrane protein
– Actual function unknown
– Significantly overexpressed in
prostate Ca
• Especially advanced disease,
androgen deprivation therapy

17. Preventing metastases in CRPC
• Up until recently:
– No proven way to prevent metastases
– Once PSA started rising….historically tried:
• Adding antiandrogen (e.g. casodex)
• Withdrawing antiandrogen
• Adding ketoconazole
• Adding corticosteroids
– May get PSA response in 30% (short-lived)
– But no proven metastases prevention or survival improvement

18. Preventing metastases in CRPC
• Now have 3 large “Phase III studies”:
– SPARTAN: apalutamide  1207 patients
– PROSPER: enzalutamide  1401 patients
– ARAMIS: darolutamide  1509 patients
• Question:
– Does adding drug “x” to androgen deprivation
therapy prolong the time to metastases

19. Treatment Beyond ADT Provides a ~2-year Increase in
Metastasis-Free Survival (MFS)
1. Smith MR, et al. N Engl J Med 2018.; 2. Hussain M, et al. N Engl J Med 2018.; 3. Fizazi K, et al. N Engl J Med 2019.
Metastasis-FreeSurvival(%)
Metastasis-FreeSurvival(%)
Apalutamide (SPARTAN)1
Enzalutamide (PROSPER)2 Darolutamide (ARAMIS)3
1.0
0.8
0.0
0.2
0.4
0.6
0.9
0.7
0.5
0.3
0.1
0 4 8 12 16 20 24 28 32 40 44 4836
Darolutamide + ADT
Placebo + ADT
SurvivalProbability
Months
No. at Risk
675955 817 18 23768116189262377506
275554 368 0 0412295075117180
DARO + ADT
PBO + ADT
0
0
Hazard ratio, 0.41 (95% CI, 0.34-0.50)
p < 0.001
Median MFS
APA + ADT: 40.5 mo
PBO + ADT: 16.2 mo
Median MFS
DARO + ADT: 40.4 mo
PBO + ADT: 18.4 mo
100
90
80
70
60
50
40
30
20
10
0
APA + ADT 803 713 652 514 398 282 180 96 36 16 3 0
PBO + ADT 401 291 220 153 91 58 34 13 5 1 0 0
4 8 12 2816 20 24 32 36 40 44
No. at Risk
Months
0
Apalutamide + ADT
Placebo + ADT
Hazard ratio, 0.28 (95% Cl, 0.23-0.35)
p < 0.0001
Median MFS
ENZA + ADT: 36.6 mo
PBO + ADT: 14.7 mo
Enzalutamide + ADT
10
0
90
80
70
60
50
40
30
20
10
0
ENZA+ ADT 933 865 759 637 528 431 418 328 237 159 87 77 31 4 0
PBO + ADT 468 420 296 212 157 105 98 64 49 31 16 11 5 1 0
No. at Risk
3 6 9 2112 15 18 24 30 33 36
Months
0 39 42
Hazard ratio, 0.29 (95% CI, 0.24-0.35)
p < 0.0001
27
Placebo + ADT
Too early to know if survival improved…

20. Do metastases matter?
• Ineffective hematopoeisis (low red-cells --> anemia)
• Pain
• Decreased mobility
• Skeletal Related Events (SREs)
– Pathologic fractures
– Spinal cord compression
– Need for surgery/radiotherapy
• Metastases directly associated with survival (see next...slide)
• Pain
• Decreased QOL
• Decreased survival

21. Presented by Matthew Smith ASCO 2018 Chicago.
40
30
20
10
0
MFS(Months)
Pearson’s correlation coefficient = 0.66
p <0.0001
Figure 2. Patient-Level Correlation of MFS and OS Among Patients in the SPARTAN Trial
0 10 20 30 40
OS (Months)
MFS correlates with
overall survival in
SPARTAN trial.

22. MFS by PSA Doubling Time After M0 CRPC
Diagnosis
Time (Months)
Survival
0 12 24 36 48 60 132 156 16884 14412072 96 108
0
0.2
0.4
0.6
0.8
1.0
PSA doubling time
<10 months median MFS 15.2
PSA doubling time
≥10 months median MFS 50.8
Log rank p <0.001
Time (Months)
Survival
0 12 24 36 48 60 132 156 16884 14412072 96 108
0
0.2
0.4
0.6
0.8
1.0
PSA doubling time
<10 months median OS 47.2
PSA doubling time
≥10 months median OS 82.6
Log rank p <0.001
OS by PSA Doubling Time After M0 CRPC
Diagnosis
• MFS has a strong positive association with OS in pts with M0 CRPC
• PSADT <10 months seems to be a poor prognostic factor because it is associated with shorter MFS and OS
• The observed MFS is similar to the control arms of the SPARTAN and PROSPER clinical trials
Aims:
• To determine whether MFS in nmCRPC correlates with OS in a real-world population
• To determine whether a rapid PSADT (<10 months) impacts MFS and OS
Study design:
• Retrospective review of 159 pts with M0 castrate-resistant disease from 2 hospitals in Alberta, Canada

23. Clinical Impact of Treating Patients with CRPC Before the
Disease Metastasizes:
Second Progression-free Survival (PFS2)
Patientswithoutsecondary
progressionordeath(%)
Time from randomization (months)
0 4 528 12 16 20 24 28 32 36 40 44 48
HR, 0.5 (95% CI, 0.39–0.63)
p <0.0001
100
80
60
40
20
0
806 779 760 730 693 637 525 398 289 191 117 44 13 0
401 386 362 331 285 243 182 124 75 45 26 9 1 0
No. at risk
APA
PBO
PBO
PFS1
APA
PFS1
PBO PFS2
Median time to
PFS2 was not
reached (APA) vs.
39.3 months (PBO);
p <0.0001

24. Clinical Impact of Treating Patients with CRPC Before the Disease
Metastasizes: PFS2
Placebo + ADT Switch to approved treatments
Progression
on first
metastatic
therapy
PFS2: Median 39.3 months
Apalutamide + ADT Switch to approved treatments
PFS2: Median not reached
MFS:
Median 16.2 months
MFS:
Median 40.5 months
HR for MFS:
0.28 (95% CI 0.23–0.35), p <0.001
HR for PFS2:
0.5 (95% CI, 0.39–0.63), p <0.0001
Progression
on first
metastatic
therapy
mCRPC
nmCRPC
nmCRPC
mCRPC
Importance of
treating early

25. Updated SPARTAN analysis shows apalutamide
associated with improvement in survival
25% reduction
in the risk of
death

26. PSA Responses in SPARTAN, PROSPER, and ARAMIS
1. Small E, et al AUA 2018 abstract # PD10-11; 2. Hussain M, et al. N Engl J Med 2018.; 3 Sternberg EAU 2018, poster #604 4. Fizazi K,
et al. N Engl J Med 2019. 5. Tamella T, et al EAU 2019. Oral presentation at Breaking News Session 3 BN
Apalutamide
(SPARTAN)1
Enzalutamide
(PROSPER)2,3
Darolutamide
(ARAMIS)4,5
% of patients with
PSA decline ≥50%
93% 76% 84%
% of patients with
PSA decline ≥90%
66% 56% 51%
% of patients with
PSA <0.2 ng/mL
40% 10% N/A
*These are not head-to-head comparisons

27. APA + ADT 787 769 750 732 707 689 657 631 598 486 373 274 179
PBO + ADT 390 382 376 358 339 289 276 255 208 181 99 62 44
No. of patients in each cycle
Placebo + ADT
Leastsquaresmean(SD)change
Frombaseline
2.0
0
-2.0
-4.0
-6.0
2 3 4 5 6 7 9 11 13 17 21 25 29
Apalutamide
+ADT
FACT-P total score (treatment difference in least squares mean
change from baseline)
SPARTAN PROSPER
Study week
No. at risk
ENZA + ADT … 815 718 621 522 427 354
PBO + ADT … 403 329 239 183 139 90
7
6
5
4
3
2
1
0
-1
-2
-3
-4
-5
-6
-7
Leastsquaresmean(95%Cl)
treatmentdifference
Baseline 17 33 49 65 81 97
Favours
enzalutamide+ADT
Favours
placebo+ADT
FACT-P total score (treatment difference in least squares mean change from
baseline)
ARAMIS
1.3 (0.4, 2.1)
Darolutamide
+ ADT
Placebo
+ ADT
FACT-P total score (difference
with placebo)
120
110
90
80
70
60
50
40
30
20
10
0
Health-Related Quality of Life is Maintained

28. Side-effects of Interest in nmCRPC Trials
SPARTAN1 PROSPER2 ARAMIS3
Monitoring schedulea Every 4 weeks Every 16 weeks Every 16 weeks
APA
(n = 803)
PBO
(n = 398)
ENZA
(n = 930)
PBO
(n = 465)
DARO
(n = 954)
PBO
(n = 554)
Median duration of trial regimen
(months)
25.7 11.5 18.4 11.1 14.8 11
Any AEs, n (%) 775 (96.5) 371 (93.2) 808 (87) 360 (77) 794 (83.2) 426 (76.9)
Any serious AEs, n (%) 199 (24.8) 92 (23.1) 226 (24) 85 (18) 237 (24.8) 111 (20.0)
AEs (all grades), %
Fatigue 30.4 21.1 33.0 14.0 12.1 8.7
Hypertension 24.8 19.8 12.0 5.0 6.6 5.2
Rash 23.8 5.5 NR NR 2.9 0.9
Falls 15.6 9.0 11.0 4.0 4.2 4.7
Fractures 11.7 6.5 NR NR 4.2 3.6
Mental impairment disorders 5.1 3.0 5.0 2.0 0.4 0.2

29. Take Home Points
• When on androgen deprivation therapy it is important to:
1. Stay in close contact with your physician to watch for PSA rise to identify CRPC
early
2. Once CRPC: screen for mets with CT & bone scan
1. Soon these will be replaced with PET scans for improved detection
3. If not metastatic, compute rate of rise of PSA (PSADT) to determine risk of
developing mets and frequency of imaging (every 3-6 months vs. every 6-12
months)
4. Report any symptoms (e.g. pain, weakness, fatigue) to your physician as this
may be a sign of metastases

30. Take Home Points
• Historically in non-metastatic CRPC: no proven treatments
• Now have 3 drugs with “Level 1” evidence of benefit for treating
men with rapid (<10 months) PSADT
– Prolong the time to metastases
– May prolong survival (trials need longer follow-up)
• Current status:
Apalutamide Enzalutamide Darolutamide
Health Canada approval? Yes Yes No
Provincial review? Yes Yes No
Provincial funding? No No No
Available via Exceptional Access Program? Yes Yes No

31. Conclusions
• Ensure open dialogue with your physician
about appropriate monitoring of your prostate
cancer
• And to see if you may be a candidate for one
of the new therapies in nmCRPC

32. Canadian Cancer Survivor Network
Contact Info
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Ottawa, ON K2C 2B5
Telephone / Téléphone : 613-898-1871
E-mail: jmanthorne@survivornet.ca or info@survivornet.ca
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