Prostate cancer advances

1. Systemic Treatment Intensification in Metastatic
Hormone-Sensitive Prostate Cancer
Supported by educational grants from Astellas, Bayer HealthCare Pharmaceuticals Inc.,
Myovant Sciences Ltd., Pfizer, Inc.

2. About These Slides
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Slide credit: clinicaloptions.com

3. Faculty
Alicia K. Morgans, MD, MPH
Genitourinary Medical Oncologist
Dana-Farber Cancer Institute
Boston, Massachusetts
Alicia K. Morgans, MD, MPH, has disclosed that she has received funds for
research support from Bayer, Dendreon, Myovant, Sanofi, and Seattle Genetics
and consulting fees from AAA, AstraZeneca, Astellas, Bayer, Blue Earth, Clovis,
Dendreon, Exelixis, Janssen, Myovant, Myriad, Novartis, Pfizer, Sanofi, and
Seattle Genetics.

4. Guideline Recommendations: 2021 Treatment Options
for mHSPC
ADT
Slide credit: clinicaloptions.com
ADT plus:
Abiraterone
Apalutamide
Enzalutamide
Docetaxel
ADT plus EBRT to primary tumor (for low-volume disease)
NCCN. Clinical practice guidelines in oncology: prostate cancer. v2.2021.

5. Chemohormonal Therapy
 CHAARTED: randomized, open-label phase III
trial of docetaxel + ADT vs ADT alone for
patients with mHSPC with elevated PSA
(N = 790)
 STAMPEDE: randomized, open-label, multiarm,
multistage phase II/III trial (N = 1917)
Sweeney. NEJM. 2015;373:737. James. Lancet. 2016;387:1163. Slide credit: clinicaloptions.com
Randomization for M1 Patients
B Arm A + zoledronic acid
C Arm A + docetaxel
E Arm A + ZA + docetaxel
G Arm A + abiraterone
H Arm A + RT to prostate
A ADT

6. Chemohormonal Therapy: Overall Survival
Sweeney. NEJM. 2015;373:737. James. Lancet. 2016;387:1163. Slide credit: clinicaloptions.com
CHAARTED STAMPEDE
Months
Patients
Surviving
(%)
100
80
60
40
20
0
84
0 12 24 36 48 60 72
No. at Risk
ADT + docetaxel
ADT alone
397
393
333
318
189
168
89
71
46
27
5
3
2
1
0
0
ADT alone
(median OS, 44.0 mo)
ADT + docetaxel
(median OS, 57.6 mo)
HR = 0.61 (95% CI, 0.47-0.80)
Months
Overall
Survival
(%)
100
80
60
40
20
0
84
0 12 24 36 48 60 72
1184
592
1093
545
876
447
538
290
322
181
166
93
87
51
43
20
HR = 0.78 (95% CI 0.66 - 0.93); P = .006
SOC alone
(median OS, 71 mo)
SOC + docetaxel
(median OS, 81 mo)

7. CHAARTED: High-Volume vs Low-Volume Disease
 Median follow-up of 53.7 mo in patients with metastatic hormone-sensitive
prostate cancer randomized to ADT + docetaxel vs ADT alone (N = 790)
Kyriakopoulos. JCO. 2018;36:1080. Slide credit: clinicaloptions.com
High-Volume Disease Low-Volume Disease
Mo
Mo
mOS, Mo
ADT + docetaxel 63.5
ADT alone NR
HR: 1.04 (95% CI: 0.70-1.55; P = .86)
mOS, Mo
ADT + docetaxel 51.2
ADT alone 34.4
HR: 0.63 (95% CI: 0.50-0.79; P <.001)
96
100
80
60
40
20
0
108
0 12 24 36 48 60 72 84
100
80
60
40
20
0
108
0 12 24 36 48 60 72 84 96
OS
(%)

8. STAMPEDE: High-Volume vs Low-Volume Disease
Clarke. Ann Oncol. 2019;30:1992. Slide credit: clinicaloptions.com
High-Burden Disease Low-Burden Disease
Overall
Survival
Overall
Survival
Control (n = 320)
Docetaxel (n = 148)
Control (n = 238)
Docetaxel (n = 124)
Time since randomization (years)
1.00
0.80
0.60
0.40
0.20
0.00
9
0 1 2 3 4 5 6 7 8
HR 0.81 (95% CI 0.64 - 1.02), P = 0.064
1.00
0.80
0.60
0.40
0.20
0.00
9
0 1 2 3 4 5 6 7 8
HR 0.76 (95% CI 0.54 - 1.07), P = 0.107
Time since randomization (years)

9. Abiraterone Acetate: LATITUDE and STAMPEDE Trials in
Advanced Prostate Cancer
 LATITUDE: randomized, double-blind phase III
trial of abiraterone acetate + ADT vs placebo
+ ADT in patients with newly diagnosed
mHSPC (N = 1199)
 High risk = at least 2 of the following 3
features: Gleason score ≥8, measurable
visceral metastasis, ≥3 bone lesions
 STAMPEDE: randomized, open-label, multiarm,
multistage phase II/III trial (N = 1917)
 Newly diagnosed metastatic disease that was
pelvic node–positive or high-risk locally
advanced with ≥2 high-risk features (Gleason
score 8-10, T3-T4, PSA ≥40 ng/mL)
 Relapsing after local therapy with high-risk
features: PSA >4 ng/mL with doubling time
<6 mo, PSA >20 ng/mL, metastatic or nodal
relapse, <12 mo of total ADT including interval
>12 mo without treatment
Fizazi. NEJM. 2017;377:352. James. NEJM. 2017;377:338. Slide credit: clinicaloptions.com

10. Abiraterone Acetate: OS
Fizazi. NEJM. 2017;377:352. James. NEJM. 2017;377:338. Slide credit: clinicaloptions.com
LATITUDE
HR: 0.62 (95% CI: 0.51-0.76; P <.001)
Abiraterone + ADT (n = 597)
Placebo + ADT (n = 602)
Mos
100
90
80
70
60
50
40
30
20
10
0
42
0 6 12 18 24 30 36
OS
(%)
STAMPEDE
Abiraterone + ADT (n = 960)
Placebo + ADT (n = 957)
HR: 0.63 (95% CI: 0.52-0.76; P <.001)
Mos
100
90
80
70
60
50
40
30
20
10
0
54
0 6 12 18 24 30 36
PFS
(%)
42 48

11. Chi. NEJM. 2019;381:13.
TITAN: Apalutamide + ADT vs Placebo + ADT in mHSPC
 International, randomized, double-blind, placebo-controlled phase III trial
 Primary endpoints: OS, radiographic PFS
 Secondary endpoints: time to pain progression, time to SRE, time to chronic opioid use,
time to cytotoxic chemotherapy
 Exploratory endpoints including time to PSA progression, PFS2
Patients with metastatic castration-
sensitive prostate cancer; ECOG PS 0/1;
prior ADT ≤6 mo for mCSPC or ≤3 yr for
local disease
(N = 1052)
Apalutamide 240 mg QD + ADT
(n = 525)
Placebo + ADT
(n = 527)
Slide credit: clinicaloptions.com
Gleason score (≤7 vs >7), region (NA/EU vs other),
prior docetaxel (yes vs no)
PD

12. TITAN: rPFS and OS
Slide credit: clinicaloptions.com
Chi. NEJM. 2019;381:13.
PFS
(%)
Mos
HR: 0.48 (95% CI: 0.39-0.60, P < .001)
100
75
50
20
0
36
0 6 12 18 24 30
Apalutamide + ADT
(n = 525)
Placebo + ADT
(n = 527)
Mos
OS
(%)
HR: 0.67 (95% CI: 0.51-0.89, P = .005)
36
0 6 12 18 24 30
100
75
50
20
0
Apalutamide + ADT
(n = 525)
Placebo + ADT
(n = 527)

13. ARCHES: Enzalutamide + ADT vs Placebo + ADT in
mHSPC
 International, double-blind, randomized phase III trial
Armstrong. JCO. 2019;37:2974.
 Primary endpoint: centrally assessed radiographic PFS
 Secondary endpoints: OS, ORR, time to first SSE, PSA progression, time to new
antineoplastic therapy, time to castration resistance, PSA undetectable rate
Patients with mHSPC,
ECOG PS 0/1, on ADT for
≤3 mo or ≤6 mo if
received prior docetaxel
(N = 1150)
Until radiographic PD,
unacceptable toxicity, or
initiation of new or
investigational agent for PC
Enzalutamide 160 mg/day + ADT
(n = 574)
Placebo + ADT
(n = 576)
Stratified by disease volume (low
vs high*), previous docetaxel for
mHSPC (none vs 1-5 vs 6 cycles)
*High disease volume defined as either visceral metastases or ≥4 bone lesions with ≥1 lesion in bony structure beyond vertebral column and pelvic
bone.

14. ARCHES: rPFS (Primary Outcome)
Armstrong. JCO. 2019;37:2974.
*Included only patients with no documented progression event and censoring at the date of the last radiologic assessment prior to the cutoff date.
Enzalutamide + ADT
(n = 574)
Placebo + ADT
(n = 576)
Median rPFS,
mo (95% CI)
NR (NR-NR) 19.0 (16.6-22.2)
HR 0.39 (95% CI: 0.30-0.50, P <.001)
Slide credit: clinicaloptions.com
Mo
rPFS*
(%)
100
90
80
70
60
50
40
30
20
10
0
33
0 3 6 9 12 15 18 21 24 27 30
Enzalutamide + ADT (574)
Placebo + ADT (576)
+ ++
+
+
+
+
+
+
+
+
+
+ +
+
+
++
+
+
+
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+ ++
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+ +
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+
+
+
+
+
+ +
+
+
+ ++
+
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+
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+
+
 Overall survival: HR 0.81 (95% CI: 0.53-1.25); P = .3361; however, survival data were immature with
only 14.4 mo median follow-up and 84 deaths

15. ARCHES: rPFS Subgroup Analysis
Armstrong. JCO. 2019;37:2974. Slide credit: clinicaloptions.com

16. ENZAMET: Enzalutamide + ADT vs NSAA + ADT in
mHSPC
 Randomized, open-label, multicenter phase III clinical trial
 Primary endpoint: OS
 Secondary endpoints: PSA PFS (including clinical progression if occurring first), clinical PFS,
AEs, HRQoL
Davis. NEJM. 2019;381:121. Slide credit: clinicaloptions.com
Patients with metastatic prostate
cancer, starting first-line ADT
(max 12 wk prior to
randomization); ECOG PS 0-2;
2 cycles prior docetaxel allowed
(N = 1125)
Enzalutamide 160 mg/day +
testosterone suppression
(n = 563)
Standard NSAA*+
testosterone suppression
(n = 562)
Stratified by volume of metastases (high vs low), antiresorptive
therapy (yes vs no), ECOG PS (0/1 vs 2), comorbidities (ACE-27:
0/1 vs 2/3), study site, planned use of early docetaxel (yes vs no)
Evaluate
every 12 wk
CRPC tx at PD
(investigator
discretion)
Follow for time
to progression
and OS
Evaluate
every 12 wk
*Bicalutamide, nilutamide, or flutamide.

17. ENZAMET: OS (Primary Endpoint)
 Varied inclusion: high and low volume, de novo vs metach mets, concurrent
docetaxel, many permutations
Davis. NEJM. 2019;381:121. Slide credit: clinicaloptions.com
Patients Alive at Mo 36, %
Enzalutamide NSAA
80
(95% CI: 75-83)
72
(95% CI: 68-76)
HR: 0.67 (95% CI: 052-0.86; P = .002)
Mo
Enzalutamide (n = 563)
NSAA (n = 562)
48
0 6 12 18 24 30 36 42
OS
(%)
100
60
40
20
0
80

18. 0.00
ENZAMET: PFS and OS With Concurrent Docetaxel
Davis. NEJM. 2019;381:121.
Testosterone
Suppression
+
Docetaxel
(n = 503;
71% high volume)
Testosterone
Suppression
+
No Docetaxel
(n = 622;
37% high volume)
Slide credit: clinicaloptions.com
PFS OS
Months
Proportion
Event-Free
1.00
0.75
0.50
0.25
0.00
48
0 6 12 18 24 30 36 42
Enzalutamide
NSAA
HR = 0.48 (95% CI: 0.37 to 0.62)
Months
Proportion
Alive
1.00
0.75
0.50
0.25
48
0 6 12 18 24 30 36 42
Enzalutamide
NSAA
HR = 0.90 (95% CI: 0.62 to 1.31)
0.00
Months
Proportion
Event-Free
1.00
0.75
0.50
0.25
0.00
48
0 6 12 18 24 30 36 42
Enzalutamide
NSAA
HR = 0.34 (95% CI: 0.26 to 0.44)
Months
Proportion
Alive
1.00
0.75
0.50
0.25
48
0 6 12 18 24 30 36 42
Enzalutamide
NSAA
HR = 0.53 (95% CI: 0.37 to 0.75)

19. ENZAMET: Select Docetaxel-Relevant AEs
Sweeney. ASCO 2019. Abstr LBA2. Davis. NEJM. 2019;381:121. Slide credit: clinicaloptions.com
AE in First 6 Mo, n (%)
Enzalutamide +
Docetaxel
(n = 254)
NSAA + Docetaxel
(n = 246)
Enzalutamide
No Docetaxel
(n = 309)
NSAA
No Docetaxel
(n = 312)
Neutropenic fever 35 (14) 32 (13) 1 (<1) 0
Sensory neuropathy
 Grade 2 24 (9) 7 (3) 0 2 (<1)
 Grade 3 3 (1) 1 (<1) 0 0
Motor neuropathy
 Grade 2 4 (2) 1 (<1) 0 0
 Grade 3 0 0 1 (<1) 0
Nail discoloration 25 (10) 13 (5) 0 0
Grade 1/2 watery eyes 52 (20) 15 (6) 0 0
Grade 2 fatigue 52 (20) 35 (14) 32 (10) 9 (3)

20. STAMPEDE: SOC + Abiraterone Acetate/P
vs SoC + DocP
 Recruitment: 11/2011 to 3/2013
 Patients: SoC + DocP, n = 189; SoC + AAP, n = 377 (n = 566 randomized)
Sydes. Ann Oncol. 2018;29:1235. Slide credit: clinicaloptions.com

21. STAMPEDE: Docetaxel vs Abiraterone Comparison
Sydes. Ann Oncol. 2018;29:1235.
OS
Outcomes
OS
(%) Mo
SoC + AAP (n = 189)
SoC + DocP (n = 377)
Slide credit: clinicaloptions.com
48
0 12 24 36
100
80
60
40
20
0
HR
2.0
0.5 1.0
Favors
SoC + AAP
Favors
SoC + DocP
Failure-free survival
PFS
Metastatic PFS
Symptomatic
skeletal events
Cause-specific
survival
OS
HR = 1.16 (95% CI 0.82-1.65), P = .40
Strong
evidence
favoring
SoC + AAP
No
evidence
of
difference

22. Guideline Recommendations: 2021 Treatment Options
for mHSPC
ADT
Slide credit: clinicaloptions.com
ADT plus:
Abiraterone
Apalutamide
Enzalutamide
Docetaxel
ADT plus EBRT to primary tumor (for low-volume disease)
NCCN. Clinical practice guidelines in oncology: prostate cancer. v2.2021.
How to choose? Quality of life and patient preferences must also be considered!

23. CHAARTED (Docetaxel): Comparison of Mean FACT-P
Morgans. JCO. 2018.36:1088. Slide credit: clinicaloptions.com
Time (months)
FACT-P
Total
122
120
118
116
114
12
0 3 6 9
ADT + Doc ADT alone 95% CI

24. LATITUDE (Abiraterone): Mean Change from Baseline
FACT-P
Chi. Lancet Oncol. 2018. 19:194. Slide credit: clinicaloptions.com
Treatment Cycle
FACT-P
total
score,
mean
change
from
baseline
6
4
2
0
-2
-4
0 33
1 2 3 4 5 6 7 8 9 10 11 12 13 15 17 19 21 23 25 27 29 31
ADT plus abiraterone acetate and predisone
ADT plus placebos
Better
Worse

25. TITAN (Apalutamide): Mean Change from Baseline
FACT-P
Agarwal. Lancet Oncol. 2019;20:1518. Slide credit: clinicaloptions.com
Treatment Cycle
FACT-P
total
(score)
6
4
2
0
-2
-4
0 25
1 2 3 4 5 7 9 11 13 15 17 19 21 23
Placebo
Apalutamide
Better
HRQOL
Worse
HRQOL

26. ARCHES (Enzalutamide): Comparison of Mean FACT-P
Armstrong. ASCO GU 2019. Abstr 687. Slide credit: clinicaloptions.com
Analysis visit week
Baseline 13 25 37 49 61 73 85 97
FACT-P
total
score,
mean
(95%
CI)
156
144
132
120
108
96
84
72
60
48
36
24
12
0
ENZA + ADT
PBO + ADT
Mean FACT-P Total Score

27. ENZAMET (Enzalutamide): Differences in Least Square
Means (EORTC QLQ-C30)
Stockler. ESMO 2019. Abstr 5387. Slide credit: clinicaloptions.com
HRQL scores over time
least squares mean difference, 95% CI, P value
Deterioration-free survival
percent deterioration-free at 3 years, P value
Physical Function
2.5, 1.2 to 3.8, P = .0002
Cognitive Function
3.9, 2.4 to 5.4, P <.0001
Fatigue
5.0, 3.3 to 6.7, P <.0001
Global Health and QOL
1.1, -0.4 to 2.6, P = .16
Physical Function
31% vs 22%, P = .001
Cognitive Function
33% vs 21%, P = .0003
Fatigue
26% vs 18%, P = .1
Global Health and QOL
32% vs 18%, P <.0001
Weeks
156
100
80
70
60
50
40
30
20
10
0
90
0 12 36 60 84 108 132
Weeks
156
100
80
70
60
50
40
30
20
10
0
90
0 12 36 60 84 108 132
Weeks
156
100
80
70
60
50
40
30
20
10
0
90
0 12 36 60 84 108 132
Weeks
156
100
80
70
60
50
40
30
20
10
0
90
0 12 36 60 84 108 132
Months
36
1.00
0.75
0.50
0.25
0.00
0 6 12 18 24 30
Proportion
Event-Free
Months
36
0 6 12 18 24 30
Months
36
0 6 12 18 24 30
Months
36
0 6 12 18 24 30
NSAA
Enzalutamide

28. STAMPEDE (Docetaxel vs Abiraterone): Global QoL
Rush. ASCO GU 2020. Abstr 14. Morgans. JCO. 2018.36:1088. Slide credit: clinicaloptions.com
Global QOL
Weeks from randomization
80
75
70
65
60
104
96
0 6 12 18 24 36 48 60 72 84
+ Docetaxel
95% CI
SOC
+ Abiraterone
95% CI
Better
Worse
Abiraterone
Docetaxel

29. Slide credit: clinicaloptions.com
Patients Also Consider Other Things!
 How many clinic visits? How often?
 How long will I need this treatment?
 Pills or IV?
 How does this affect my ability to work or care for my family?
 How much will this cost?

30. Select Ongoing Randomized Phase III Trials in mHSPC
Slide credit: clinicaloptions.com
Trial Regimens Population
ARASENS
(NCT02799602)
ADT + docetaxel ± darolutamide
Newly diagnosed mHSPC
(planned N = 1300)
ARANOTE
(NCT04736199)
ADT ± darolutamide
mHSPC
(planned N = 555)
KEYNOTE-991
(NCT04191096)
ADT + enzalutamide ± pembrolizumab
mHSPC, no prior AR inhibitor
(planned N = 1232)
CAPItello-281
(NCT04493853)
ADT + abiraterone acetate ± capivasertib
De novo mHSPC, PTEN deficiency
(planned N = 1000)
TALAPRO-3
(NCT04821622)
Enzalutamide ± talazoparib
mHSPC, DDR mutation
(planned N = 550)
AMPLITUDE
(NCT04497844)
Abiraterone + prednisone ± niraparib
mHSPC, HRR gene alteration
(planned N = 788)

31. Overall Conclusions
 Treatment intensification with docetaxel or an AR-targeted therapy is
the new standard of care for mHSPC
‒ ADT alone is no longer the standard of care for the vast majority of men
 Treatment intensification is preferred regardless of how fast or far
PSA falls
 Quality of life and patient preferences should be considered when
choosing treatment
‒ Shared decision-making can help match a patient with the right treatment
for him
Slide credit: clinicaloptions.com

32. clinicaloptions.com/oncology
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