prjijjhgyyhijnhgujkmnjhguiokmkjhko5.pptx

Epidemiology of Prostate Cancer
High incidence but most detected at curable stage (PSA screening)
Higher incidence and death rate in African American men
2x risk if first-degree relative, 4x risk if >2 relatives diagnosed at age
<70 years
Association with occupations/exposures (military, firefighters)
Dietary: cruciferous vegetables good, animal fat bad?
HG-PIN

Slide credit: clinicaloptions.com
Prostate Cancer Diagnosis May Occur at Various
Stages and Progress Through Different Pathways
Biochemical
recurrence*
Definitive
therapy
mCRPC
mHSPC
nmCRPC
Localized/locally
advanced prostate
cancer
Rising
PSA
Start
ADT
Criterion 2: Rising
PSA despite
castrate levels of
testosterone
Criterion 1:
Identification of
metastases
Rising PSA despite
castrate levels of
testosterone
Identification of
metastases
Both criteria
met
Anantharaman. Expert Rev Anticancer Ther. 2017;17:625.
NCCN. Clinical practice guidelines in oncology: prostate cancer. v.1.2023. nccn.org.
*Slow PSA doubling time (eg, >12 mo) suggests indolent disease.

Clinical Risk Stratification:
D’Amico
NCCN = National Comprehensive Cancer Network.
NCCN, 2022; D’Amico et al, 1998.
Risk group Clinical/pathologic features Additional evaluation
Very low
Has all of the following:
• cT1c
• Grade group 1
• PSA <10 ng/mL
• <3 prostate biopsy fragments/cores positive, ≤50% cancer in each fragment/core
• PSA density <0.15 ng/mL/g
Confirmatory testing can be used to assess
the the appropriateness of active
surveillance
Low
Has all the following but does not qualify for very low-risk:
• cT1-cT2a
• Grade group 1
• PSA <10 ng/mL
surveillance
Intermediate
Has all the following:
• No high-risk or very high-risk
risk group features
• Has ≥1 intermediate risk factor
factor (IRF):
o cT2b-cT2c
o Grade group 2 or 3
o PSA 10-20 ng/mL
Favorable
intermediate
Has all the following:
• 1 IRF
• Grade group 1 or 2
• <50% biopsy cores positive (eg, <6 of 12 cores)
surveillance
Unfavorable
intermediate
Has one or more of the following:
• 2 or 3 IRFs
• Grade group 3
• ≥50% biopsy cores (eg, ≥6 of 12 cores)
Bone and soft tissue imaging
• If regional or distant metastases are found,
found, additional stratification per NCCN
High
Has no very-high-risk features and has exactly 1 high-risk feature:
• cT3a OR
• Grade group 4 or 5 OR
• PSA >20 ng/mL
• If regional or distant metastases are
found, found, additional
stratification per NCCN
Very high
Has ≥1 of the following:
• cT3b-cT4
• Primary Gleason pattern 5
• 2 or 3 high-risk features
• >4 cores with Grade group 4 or 5
• If regional or distant metastases are
found, found, additional
stratification per NCCN

Biomarkers to Guide Treatment Selection
Localized Prostate Cancer
NCCN, 2022.
aMolecular testing NOT recommended for VERY–low-risk patients age >65.
bCurrently ongoing clinical trials: ERADICATE (EA8183), PREDICT-RT (NRG GU-009), and GUIDANCE (NRG GU-010).
RNA = ribonucleic acid ; BCR = biochemical recurrence; RT = radiation therapy; mets= metastases.
Test name Methodology Clinical role(s) Publication(s)
Prolaris®
Tumor RNA:
31 cell cycle genes
BCR after surgery
Cuzick et al
Lancet Oncology, 2011
Oncotype DX® Tumor RNA:
12 cancer-related genes
Low-/intermediate-risk: active
surveillancea. Risk of upstaging at
at surgery, BCR
Klein et al
Eur Urol, 2014
Decipher®
Tumor RNA:
22 coding and
non-coding
High-risk: need for adjuvant RT, risk
risk of mets, intensification/de-
intensificationb
Intermediate-risk: intensification/de-
intensification/de-intensificationb of
Den et al
JCO, 2015
Ross et al
PCAN, 2014

Decipher Score Changes Treatment Decisions
ADT = androgen deprivation therapy.
Gore et al, 2017.
Post-Prostatectomy Management
Decipher Low-risk Decipher High-risk
Decipher Intermediate-risk

After prostatectomy According to AUA guidelines, a biochemical recurrence is defined as a
serum PSA ≥0.2 ng/mL, which is confirmed by a second determination
with a PSA ≥0.2 ng/mL.
After radiotherapy A PSA rise of 2 ng/mL or more above the nadir PSA is considered the
standard definition for biochemical failure after external beam RT,
regardless of whether or not a patient receives androgen deprivation
therapy.
High Risk relapse Various clinical, pathologic, and molecular factors can be used to
predict an increased likelihood of metastatic disease and death from
prostate cancer. The most important of these are:
a short PSA doubling time after radical prostatectomy,
A short interval to biochemical recurrence after radiotherapy,
a higher Gleason score and a local recurrence following local therapy
Hormone-sensitive
Castration-resistant
relapse
Most of these individuals have testosterone levels that are >50 ng/mL,
and their prostate cancer is described as castration-sensitive. However,
some will have rising PSA despite suppressed testosterone levels, and
such patients are said to have a castration-resistant biochemical
Definitions of biochemical recurrence

Treatment Options in M0 CRPC
Non-metastatic defined by conventional imaging
LN = lymph node; bPSA = benign prostate-specific antigen; MI = myocardial infarction.
Smith et al, 2018; Fizazi et al, 2019; Hussain et al, 2018.
Agent
Apalutamide
240 mg daily
Darolutamide
600 mg BID
Enzalutamide
160 mg daily
Study name SPARTAN ARAMIS PROSPER
Design 2:1 apa/placebo 2:1 daro/placebo 2:1 enza/placebo
Number of
patients
1,207 1,509 1,401
Inclusion:
PSA DT <10 months
Pelvic LN <2 cm OK
PSA DT ≥10
months Pelvic LN
<2 cm OK bPSA ≥2
PSA DT ≤10 months
bPSA ≥2
Metastasis-free
survival
40.5 vs 16.2 months placebo
placebo (HR 0.29)
(HR 0.41)
(HR 0.29)
Discontinuation 10.6% apa, 7.0% placebo 8.9% daro, 8.7% placebo 10% enza, 6% placebo
Adverse events
Higher rate of rash,
hypothyroidism, and fracture
fracture
Incidence similar to placebo,
except higher rate of fatigue
Higher rate of grade ≥3; higher
higher rate of hypertension, MI,
MI, fatigue, falls, and fractures

Treatment Options in M0 CSPC
ADT for M0 Castration-Sensitive Disease After Maximal Pelvic Therapy
• Monitoring until diagnosis of metastatic disease is preferred for patients with
non-metastatic castration-sensitive disease who are not candidates for pelvic
therapy.
• PSADT and Grade Group should be considered when deciding whether to begin
ADT for patients with M0 disease.
• ADT monotherapy is an option or these patients, and intermittent ADT can be
considered.
• Enaluztamide with or without leuprolide is an option for patients who have the
following high-risk criteria (EMBARK trial):
1. M0 by conventional imaging;
2. PSADT ≤9 months;
3. PSA≥2 ng/mL above nadir after RT or ≥1 ng/mL after RP with or without
postoperative RT;
4. and not considered a candidate for pelvic-directed therapy.

 Randomized phase III trial
Stratified by PSA (≤10 ng/mL vs >10 ng/mL), PSADT
(≤3 mo vs >3 to ≤9 mo), prior hormonal therapy (Y/N)
 Primary endpoint: MFS by BICR for enzalutamide + leuprolide vs leuprolide
 Secondary endpoint: MFS by BICR for enzalutamide vs leuprolide, time to PSA progression,
time to first use of new therapy, OS, safety
EMBARK: Enzalutamide or Placebo + Leuprolide or
Enzalutamide Alone in Biochemically Recurrent PC
Patients with PC post RP with
screening PSA ≥1 ng/mL and
≥2 ng/mL above nadir for
primary EBRT; PSADT ≤9 mo;
no bone mets by bone scan
or CT/MRI and central
review; testosterone ≥150
ng/dL; prior hormonal
therapy
≥9 mo before randomization
(N = 1068)
Enzalutamide 160 mg oral QD +
Leuprolide Acetate 22.5 mg IM/q12w
(n = 355)
Placebo + Leuprolide Acetate
22.5 mg IM/q12w
(n = 358)
Enzalutamide Monotherapy
160 mg oral QD
(n = 355)
PSA
<0.2 ng/mL
at Wk 36
Suspend
treatment at
Wk 37;
monitor PSA
Continue
therapy
Yes
No
Shore. AUA 2023. Abstr LBA02-09.

EMBARK Enzalutamide/Leuprolide vs
Leuprolide/Placebo: MFS
Enzalutamide
Combination
(n = 355)
Leuprolide
Acetate
(n = 358)
60.6
92 (26)
60.7
45 (13)
NR
(NR)
NR
(85.1-NR)
Median follow-up, mo
Events, n (%)
Per BICR, median MFS,
mo (95% CI)
HR: 0.42 (95% CI: 0.31-0.61;
P <.0001)
3-Yr Rate
92.9%
83.5%
5-Yr Rate
87.3%
71.4%
Patients at Risk, n
Enzalutamide combination 366 331 324 318 304 292 281 265 251 234 180 116 60 24 6 0 0
Leuprolide acetate 368 336 321 303 280 259 238 221 203 183 138 88 32 15 6 1 0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Mo
MFS
(%)
100
80
60
40
20
0
Enzalutamide combination
Leuprolide acetate

EMBARK: Selected AEs
AEs, %
Enzalutamide Combination Enzalutamide Monotherapy Leuprolide
(n = 353) (n = 354)
(n = 354)
Any Grade ≥3 Any Grade ≥3
Any Grade ≥3
Any TRAE 86.4 17.6 88.1 16.1 79.9 8.8
Serious TRAE 7.4 6.2 4.8 4.8 2.3 2.0
Hot flash 68.8 0.6 21.8 0.3 57.3 0.8
Fatigue 42.8 3.4 46.6 4.0 32.8 1.4
Falls 21.0 0.8 15.8 1.4 14.4 0.6
Cognitive and
memory impairment 15.0 0.6 14.1 0 6.5 0.6
Ischemic heart
disease 5.4 4.0 9.0 5.9 5.6 3.1
Gynecomastia 8.2 0 44.9 0.3 9.0 0

 Randomized, open-label phase III trial
PRESTO: Apalutamide ± Abiraterone + ADT vs
ADT in Biochemically Recurrent Prostate Cancer
Aggarwal. ESMO 2022. Abstr LBA63. Aggarwal. AUA 2023. Abstr LBA02-11.
Patients with PC post RP
and PSA ≥0.5 ng/mL;
PSADT ≤9 mo; no mets by
conventional imaging;
last ADT dose >9 mo before
entering study; prior
adjuvant/salvage RT unless
not a candidate for RT
(N = 504)
LHRH Analogue*
LHRH Analogue + Apalutamide
LHRH Analogue + Apalutamide +
Abiraterone Acetate + Prednisone
F/u for PSA
progression
Stratified by PSADT (<3 mo vs 3-9 mo)
52 wk
Investigator’s
choice of therapy
and long-term f/u
*Degarelix or leuprolide with bicalutamide.
 Primary endpoint: PSA PFS in ITT population
 Secondary endpoint: PSA PFS in testosterone-evaluable patients, PSA PFS comparison between ITT
and testosterone evaluable, time to castration resistance, serum testosterone, MFS, OS, safety, QoL

 Median f/u: 26.7 mo
 Median PSA PFS: 27.6 mo vs 21.0 mo (HR: 0.53; 95% CI:
0.38-0.74; P = .00006) for triple vs ADT alone
 Median f/u: 26.5 mo
 Median PSA PFS: 24.5 mo vs 21.0 mo (HR: 0.59;
95% CI: 0.42-0.81; P = .0006) for ADT/APA vs ADT
PRESTO: PSA Progression-Free Survival
Aggarwal. AUA 2023. Abstr LBA02-11.
ADT + Apalutamide vs ADT ADT + Apalutamide + Abiraterone/Prednisone vs ADT
ARM
LHRH
LHRH + APA
Events/Total
75/166
71/168
+ censor
%
Without
Event
100
80
60
40
20
LHRH +
APA + AAP
ARM Events/Total
LHRH 75/165
67/169
+ censor
%
Without
Event
Mo
Patients at Risk, n
12
18 Mo
36 42 48
Patients at Risk, n
12
18 24
30 36 42 48
LHRH 166 121 31 8 0 LHRH 166 121 31 8 0
LHRH + APA 168 137 52 17 3 LHRH + APA + AAP 169 133 60 20 2
100
80
60
40
20

CONCLUSIONS
 In patients with high-risk biochemical recurrence, compared with leuprolide
acetate, enzalutamide combination with leuprolide acetate demonstrated a
statistically significant and clinically meaningful improvement in MFS (HR:
0.42, 95% CI: 0.30 – 0.61, p<0.0001) according to EMBARK trial results
 A consistent treatment effect was observed across pre-specified subgroups
 Significant delays in time to PSA progression and time to first new
antineoplastic therapy were observed
 A trend towards improved survival in the interim analysis was noted; the
study is ongoing for final analysis
 Enzalutamide monotherapy also demonstrated statistically significant and
clinically meaningful improvements in MFS, time to PSA progression, and
time to first antineoplastic therapy
 A trend toward improved survival in interim analysis
 No new safety signals were observed
 As such, enzalutamide in combination with ADT, if approved in this setting,
has the potential to become a new standard of care for patients with high-
risk BCR with a PSADT <9 months and no evidence of metastasis on
conventional imaging
 Results of PRESTO trial are still considered immature

CASE-1
3/2022-72 year old healthy male patient visited his
urologist because of an elevated level of prostate-
specific antigen (PSA-9.2 ng/ml), found on annual
screening examination by his GP
4/2022-MRI showed a prostatic carcinoma with
limited extracapsular extension, which was
confirmed on radical prostatectomy specimen
5/2019-Needle biopsies of the prostate were
performed and a diagnosis of adenocarcinoma of
the prostate was made, with a Gleason score of 8
6/2022-Radical Prostatectomy-Surgical specimen
confirmed a pT3a Gleason 4 + 5 PCa with infiltration
of the periprostatic fat of up to 4 mm
8/2022-Due to high risk features he received
adjuvant EBRT -64 Gy and 1 year of ADT

• Axial T2-weighted images of the prostate at the midgland at different levels show a PIRADS 5
lesion in the left peripheral zone. However, the zone of hypointensity can be seen extending
beyond the capsule toward the periprostatic fat with an interruption of the capsule (white
arrows) (ESUR Score 4, high risk of ECE).

• Surgical specimen confirmed a
pT3a Gleason 4 + 5 PCa with
infiltration of the periprostatic
fat of up to 4 mm (black
arrows)

CASE-1
06/2023-During follow-up visit a biochemical recurrence was
established-PSA:1.1 ng/ml
10/2023-PSA:1.7 ng/ml
01/2024-PSA: 2,2 ng/ml, normal testosterone levels, PSA
doubling time of 7 months and negative imaging-
thoracoabdominal CT-pelvic MRI and bone scan
As he was not candidate for any further local therapy and he
fulfilled criteria of EMBARK study, he began treatment with
enzalutamide and leuprolide acetate
No cardiovascular risk factor and normal bone density
BRIEF HISTORY OF RELAPSE

PSA
MONTHS
PSA KINETICS AFTER RELAPSE
6/23-1.1
10/23-1.8 1/24-2.2
4/24-1.3
7/24-0.4
TREATMENT INITIATION

We continue monitoring PSA and testosterone
levels every three months, bone scan and CT
imaging every six months and checking for
adverse events , especially cardiometabolic
and bone health.
Six months later he has a PSA response and
the only adverse event is Grade 1 fatigue.
A patient with biochemical recurrent prostate
cancer began treatment in January 2024,
according to Embark trial, with enzalutamide
and leuprolide acetate
Summary-Case 1

CASE-1
5/2020-75 year old male patient visited his urologist because of nocturia and
an elevated level of prostate-specific antigen
(PSA-15 ng/ml), found by his GP
5/2020-MRI showed a prostatic carcinoma with invasion or for right seminal
vesicle-T3b disease
6/2020-Needle biopsies of the prostate were performed and a diagnosis of
adenocarcinoma of the prostate was made, with a Gleason score of 8 (4+4)
and invasion of right seminal vesicle-T3b disease
7/2020-EBRT and 2 years of ADT due to T3b disease
Nadir PSA-0.5 ng/ml at 7/2021
CASE-2

Invasion of seminal vesicles (T3b disease)
(a) Axial, (b) coronal T2-weighted images
show tumoral invasion of the right seminal vesicle
extending from a PCa located in the right prostatic
base (partially seenas a hypointense lesion in B).
The right seminal vesicle presents an ill defined
abnormal hypointensity in its most caudal segment
Tumor is recognized within the smooth muscle
wall of seminal vesicle tissue

BRIEF HISTORY OF RELAPSE
08/2023-During follow-up visit a
biochemical recurrence was
established-PSA: 4 ng/ml
11/2023-PSA: 5.7 ng/ml
02/2024-PSA: 8 ng/ml, normal
testosterone levels, PSA
doubling time of 5 months and
negative imaging-
thoracoabdominal CT-pelvic MRI
and bone scan
As he was not candidate for any further local therapy and
he fulfilled criteria of EMBARK study, he began treatment
with enzalutamide monotherapy
Unstable angina after recent MI and normal bone density

PSA KINETICS AFTER RELAPSE
8/23-4
11/23-5.7
2/24-8
5/24-4
8/24-2

We continue monitoring PSA and testosterone
levels every three months, bone scan and CT
imaging every six months and checking for
adverse events , especially cardiometabolic
and bone health.
Six months later he has a PSA response
without any adverse event. His coronary
heart disease is improved
A patient with biochemical recurrent prostate
cancer began treatment in February 2024,
according to Embark trial, with enzalutamide
monotherapy
Summary-Case 2

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