Individualizing Prostate Cancer Management: Employing Evidence-Based Strategies to Impact Community Care Across the Disease Continuum

Chair, Alicia K. Morgans, MD, MPH, FASCO, Matthew R. Smith, MD, PhD, and Sandy Srinivas, MD, discuss prostate cancer in this CME/MOC/AAPA/IPCE activity titled “Individualizing Prostate Cancer Management: Employing Evidence-Based Strategies to Impact Community Care Across the Disease Continuum.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/AAPA/IPCE information, and to apply for credit, please visit us at https://bit.ly/3C26ESp. CME/MOC/AAPA/IPCE credit will be available until March 14, 2026.

1. Individualizing Prostate Cancer Management

Employing Evidence-Based Strategies to Impact Community Care
Across the Disease Continuum

Alicia K. Morgans, MD, MPH, FASCO
Associate Professor, Harvard Medical School
Director, Survivorship Program

Dana-Farber Cancer Institute

Boston, Massachusetts

Matthew R. Smith, MD, PhD ‘Sandy Srinivas, MD

Claire and John Bertucci Endowed Chair in Professor, Medical Oncology
Genitourinary Cancers Stanford University Medical Center
Professor of Medicine, Harvard Medical School Stanford, California

Director, Genitourinary Malignancies Program

Massachusetts General Hospital Cancer Center

Boston, Massachusetts

Go online to access full CME/MOC/AAPA/IPCE information, including faculty disclosures.

Copyright © 2000-2025, Peerview

2. Our Goals for Today

Augment your knowledge of the rationale and efficacy data
supporting approved and emerging prostate cancer treatments

Equip you with strategies to create individualized treatment plans
incorporating modern treatments for patients across prostate cancer
disease stages

Provide guidance on team-based strategies to proactively mitigate
and manage adverse events associated with contemporary
therapeutic regimens for patients with prostate cancer

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3. Unmet Needs

Numerous therapeutic advances, including
in high-risk localized prostate cancer, mHSPC, and mCRPC

Yet...

There is still a lack of implementation in practice

How can we improve effective decision-making
and optimize patient care?

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4. Factors Contributing to Treatment Decisions‘

Shared decision-making must take into account the...
Cancer | Extent of disease, de novo vs recurrent, prior treatments, molecular features

Patient Life expectancy, comorbidities, concomitant medications, performance status,
aan symptoms, social supports, preferences and beliefs
Clinici Experience with treatment options, comfort with AE management,
zo interpretation of clinical trial data, preferences and beliefs
| Therapy availability, schedule of treatment and monitoring, cost, expected
Treatment | oficacy and toxicities

1.Morgans AK ot J Cn Oncol 202240318824 PeerView

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5. Importance of Shared Decision-Makin

ask the

+ Although SDM is supported by
evidence, it can be difficult to implement
in clinical settings

+ Trust and continuity in physician-patient
relationships can support SDM

Common barriers include limited
appointment times and poor health
literacy

Educational materials, which can help
physicians to convey health information
within a limited time frame and provide
patients increased autonomy over
decisions, can support SDM

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1.Pokala KR etal. Not Rev Uo. 2024.21-320:336

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6. Leveraging Therapies for High-Risk
Locally Advanced Prostate Cancer

7. Defining High-Risk Localized
and Locally Advanced Prostate Cancer!

Patterns of Presentation

+ Patients with high-risk disease have an
increased risk of biochemical
recurrence (BCR), metastases, and
death from prostate cancer

20%-40% of patients with high-risk
localized disease who undergo RP
and/or RT develop BCR

Regional

Increased Mortality in High-Risk Prostate Cancer

Hig! k 15-Year PCSM
PSA >20 ng/mL 22
Gleason 8-10 34
cT3 38
High-risk disease 19
1. Coopebarg MF et lJ On Oncol 201028. 1171123.2 Mekay RR tl Am Soe Gin Oncol Book 2020 401-12. api ME ASCO GU 2022. PeerView

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8. Unmet Needs

Within 10 years following definitive therapy, 20% to 50% of patients

experience disease recurrence characterized by rising PSA levels

Limited level 1 clinical data exist for the treatment of patients with BCR

Patients with high-risk BCR are at increased risk of prostate cancer—
specific mortality3-5

1. Kupoian PA et al. Cancor 2002 95: 2302-2307. 2. Kupokan PA et al. Uralogy: 2006:68:593-598. 3. Froodland SJ otal. JAMA. 2005.294:433-43. PeerVi
4. Froedland SJ et al. J Clin Oncol. 200725:1765-1771. 5. Markowski MC et al. Clin Genitourin Cancer. 2019,17:470-471. eerview

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9. Impact of Physicians’ Awareness of PSADT on Treatment
Decisions in High-Risk BCR Prostate Cancer!

+ PSADT is one of the strongest predictors of outcomes in patients with BCR prostate cancer
+ Given new recommendations around treatment specific to patients with high-risk BCR nmHSPC (ie, enzalutamide, based on the
EMBARK study) per NCCN and EAU guidelines, determination of PSADT is even more crucial now than in the past

+ However, itis unclear whether physicians routinely calculate and document PSADT in electronic medical records (EMRs) and how this

influences Tx in routine practice
Conclusions From Retrospective Analysis

+ PSADT was unknown by the treating physician for nearly two-thirds of patients at the time of a high-risk BCR nmHSPC diagnosis
+ A greater proportion of patients received Tx within a shorter timeframe when PSADT was known than when it was unknown

patients with BCR nmHSPC

‘poe a mw 390149,
i son wo ow 8 6716394)
> HR = 3.4 (95% 01.2644)

ES
Rs, urssor
os a & & » + 2 @ à ©

De Time to First Treatment, mo

CC

*UPSADT i he reference grau
‘Morgans AK tat ASCO GU 2026, Absvact 64,

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Many patients with high-risk BCR nmHSPC may remain unidentified in clinical practice; greater use of formal PSADT calculators and
documentation of PSADT by physicians could improve rates of Tx intensification and time to treatment, contributing to better outcomes for

inthe KPSADT Group

Rotrospoctvely Calculated PSADT

Prynclan-Raporund KPSADT

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10. Select Phase 3 Cl

ical Trials i

calized Disease

al Treatment
High-risk Apalutamide + ADT vs
FROUEUEN 2530 localized placebo + ADT
High-risk EBRT + ADT + enzalutamide vs
ENZARAD? 802 localized EBRT + ADT + NSAA
High-risk EBRT + ADT + bicalutamide vs
US > localized EBRT + ADT + apalutamide
. High-risk EBRT + ADT + darolutamide vs
DASEHICAP. vs localized EBRT + ADT + placebo
+ Ms nai ove NCTOTE724. 2 ps ici po NCTOZAAGA. penis nu CTS PeerView

4. tps Iclicaltralsgovistucy INCTOS 196363,

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11. Select Phase 3 Cl

calized Disease

al Treatment

— TN
CE 0
me ee Ga emt
manon a
ewan E
ARASTEPS 750 BCR nel ve

1. ps elnicatias gout NCTOS767244. 2. ps rial goustudy/NGTO2446444. 3. tp nicolas govstudyNCTO2ES1516. Pesficw

4. tips Ielicaltialsgov/stadyINCTOS 196363, 5. htpscnicatals ovstudyINCTOZ319837. 6, ps chnicarials govistudyINCTOS794906,

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12. Phase 3 PROTEUS: APA Plus ADT in the Neoadjuvant Setting for

Localized, Locally Advanced, and High-Risk Prostate Cancer’?

Apalutamide + ADT Versus Placebo + ADT in the Neoadjuvant Setting for Patients With Localized or
Locally Advanced and High-Risk Prostate Cancer

Screenin: 6-mo Treatment RP 6-mo Treatment Post
9 (Cycles 1-6) (Cycles 7-12) Treatment
FT PAZO + PSA levels monitored
Patients 240 mg RP with PLND PA 240 mg every 3 mo for BCF
+ Localized or locally QD + ADT be QD + ADT + Conventional imaging
at BCF and then every

advanced, high-risk!
very high-risk PC
+ Candidates for RP
with PLND

6 mo until distant
metastasis on
conventional imaging

PBO + ADT RP with PLND PBO + ADT

(N= 2517) or death

+ Conventional imaging + PSAtestingand + Conventional imaging + Adjuvant or + PSMA-PET imaging at
(CT or MRI and radiological within 4 wk after RP salvage radiation 3-mo post-adjuvant
bone scan) assessment for + Cardiovascular and therapy post RP lreatment, at BCF,

+ Cardiovascular and progression thrombotic risk at investigator's and every 6 mo until
thrombotic risk assessment prior to. discretion distant metastasis on
assessment and after RP PSMA-PET or

conventional imaging
+ Primary endpoints: pCR rate and MFS or death
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1. Kibol AS et al. ASCO GU 2022. Abstract TPS285. 2. tps cinicarial govlstudyINCTOS767244,

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13. PeerView.com/WQG827

Phase 3 ATLAS: Apalutamide Plus ADT

in High-Risk Localized or Locally Advanced Prostate Cancer‘?

Apalutamide + ADT + RT Treatment Phase: 28-Day Cycles + 2 Days
Screening (635 di Neoadjuvant to RT Concurrent With RT Adjuvant to RT
screening (536 days) (Cycles 1-2) (Cycles 3-4) (Cycles 5-30)

Koy Eligibility Criteria
High-risk localized prostate

RT with APA
240 mg QD +

APA 240 mg QD + APA 240 mg

bicalutaı le + a QD + GnRH
cancer Pe bicalutamide + e
+ ECOG PS 0-1 PBO + GnRH agonist Ill ono + GnRH agonist agonist
+ Charison index <3
+ Candidates for primary RT PBO+ RT with PBO + PBO+
+ No distant metastasis, history

GnRH
agonist

bicalutamide +
GnRH agonist

bicalutamide +
GnRH agonist

of bilateral orchiectomy, pelvic
radiation, or seizure
PSA and testosterone testing for BCF

Conventional and PET imaging initiated at BCF

Conventional imaging

+ Long-term follow-up

= PSA and testosterone levels monitored every 3 months until distant metastasis by BICR

= Conventional imaging every 6 months until distant metastasis by BICR or death

— PET imaging every 6 months until distant metastasis on PET or conventional imaging by BICR or death
+ Primary endpoint: MFS

1. paint govistudyINCTO2SS1516, 2. Sander HM etal. ASCO 2022. Abstract 084. PeerView

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14. Phase 3 DASL-HiCaP
Darolutamide Plus ADT in the Adjuvant Settin

Darolutamide + ADT + RT
Key Eligibility Criteria =

+ Very (da a prostate Stratification Darolutamide 600 mg
cancer to be treated with definitive + Previous RP <a
radiation or very high-risk features + {yes or no) EN
PSA persistence/rise within 12 mo + Planned docetaxel
following RP to be treated with use (yes or no)
post-RP radiation + Clinical or

+ Suitable for EBRT + brachytherapy pathological pelvic

+ CT/MRI and bone scan negative for LN involvement
distant metastases (allow pelvic LN) (yes or no)

N= 1,100

+ Primary endpoint: MFS

+ Secondary endpoints: OS, prostate cancer-specific survival, PSA-progression free survival, time to
subsequent hormonal therapy, time to castration resistance, frequency and severity of AEs, HRQOL,
fear of cancer recurrence

+ Pus RT stating at wook 8-24 post randomization, n
“ntpsieneatils gowstudyNCTOS196959. 2. Nai Y etal. ASCO GU 2023, TPS396, PeerView

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15. Phase 3 EMBARK: Enzalutamide Plus Leuprolide Acetate’

N n
ia Enzalutamide 160 mg oral QD +
Key Eligibilit iteri:
Sales PS en leuprolide acetate 22.5 mg IM Q12W

Suspend

e
8
and 22 ng/mL above the nadir for ie) < traaiment at
primary EBRT Blinded E week 37;
SEI) Placebo + ® monitor PSA
* No metastases on bone scan or CT/MRI leuprolide acetate 22.5 mg IM Q12w MY 2 (reinitiate if
per central read E PSA rises)e
+ Testosterone 2150 ng/dL ES rises)
+ Prior hormonal therapy 29 mo prior to S
RT (neoadjuvant/adjuvant for s36 mo Y a
OR <6 mo for rising PSA) ES emain on
E treatment

N= 1,068

+ Stratification: screening PSA (<10 ngimL vs >10 ng/ml), PSADT (<3 mo vs >3 to $9 mo), prior hormonal therapy (yes vs no)

+ Primary endpoint: MFS by BICR (enzalutamide + leuprolide acetate vs leuprolide acetate)

+ Key secondary endpoints”: MFS by BICR (enzalutamide vs leuprolide acetate), time to PSA progression, time to first use of
new antineoplastic therapy, OS*

+ Other secondary endpoints: safety, *PRO

+ Study reatment was suspended onc a week 37 PSA was <0.2 ng and restated when PSA vas 250 gi (wiheu prot RP) and 2 ni (noe RP). TT popa. «Primary

‘endpoint and key secondary endroit or enzalamise Combinalon and enaltamde manaterapy aro slpheprekeces. P value ele sgrfcanc or OS of combination and

‘Ponoterapy reamed comparons was dependen on otcomes of nar endpeint and ey secondary andpors * Salty population

Y ios. fc caia govetasyINCTO23 0697, 2, Shore ND et a. AUA 2023, Abstract LBAD2-09. 3. Preedand Sd et al. N Engl Med. 2023:309:1450-1465, PeerView
4. Froodland SJ e al. NEJM Evid, 2023;2.EVID0a2300251. 5, Shore ND etal. ASCO GU 2024. Absiact 15.6. Shore ND ot al ASCO GU 2024. Abstract 156. eerview

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16. EMBARK: Met Primary Endpoint of MFS'?

‘Median follow-up, mo X 60.6
Events, n (%) 92 (28)
MMS per BICR, mo NR
(95% CI) (NR) (85.1-NR)

so Enzalutamide
combination
& 60
g :
Es H Leuprolide Key Secondary Endpoint:
H acetate Interim OS
791 WR = 0.42 (95% Cl, 0.31-0.61) H HR = 0.59
P<.0001 H H
or Y + He Y + $ Y Y
0 6 12 18 2% 30 % 42 45 54 60 06 72 78 84 90 9
Time, mo (pre-specified effic
A ee om me om me ne moe 0 boundary, P < .0001)
eu mm we

Data cuofl January 31.2023. Symbole indicate censored data,

"HR was based on a Cox regression model with teaiment as the only covariate stratified by screening PSA, PSADT, and prior hormonal therapy as reportes inthe IWR:

relative to leuprolide acetate <1 favoring enzalutamido combination; the two-sided P value was based on a safe log rank
41 Shore ND at al AUA 2023. Abstract LBA02-09. 2, Frowdiand SJ eta. N Engl J Med, 2023;380:1453-1485,

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17. EMBARK: Enzalutamide Combination Significantly

Extended Time to PSA Progression!

Key Secondary Endpoint
100
8 Enzalutamide combination
$ 30
E Leuprolide acetate
S 60
g ss:
El
poe
z $ Events, n (%) Er] 93 (28)
= Median time to PSA,
2 lH (95% Cl, 0.03-0.14) Medanime Pen, cn NR (NR) NR (NR)
ot T T T
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90
No. at Risk Time, mo
A 0
mm m mn Emm 4 2 7 3

Leuproide acetate 358 341 314 203
Data cuofl January 31. 2023. Symbols indicate censored data,
* The HR was based on a Cox regression model with treatment as the ony covariate stratified by screening PSA, PSADT, and prior hormonal therapy as reported inthe
IWS; relative to leuproice acetato <' favoring enzahsamice combination; the two-sided P vales based ona stratified log-rank tos! PeerView
41. Shore ND etal. AUA 2023. Abstract LBA02-09. 2, Freedland SJ eta. N Engl J Med, 2025;380:1453-1485,

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18. EMBARK: Enzalutamide Monotherapy Demonstrated

Significantly Improved MFS Versus Leuprolide Acetate’?

Key Secondary Endpoint

‘Median follow-up, mo
Events, n (%) 63 (18)
MMES per BICR, mo (95% Cl NR (NR)

100

Enzalutamide signe

Lo re FDA approved for patients
os ae a lao with high-risk BCR
Lo Leuprolide acetate prostata cancer!
20
Key Secondary
o Endpoint: Interim OS
6 12 18 24 30 36 42 48 54 60 68 72 78 84 90 9% HR = 0.77
Mo. at Risk Time, mo (95% CI, 0.51-1.15)
EAN us agp me m am an thm Nominal P = 1963
AA

Data cutof January 31,2023, Symbols indicate censored data,

("The HR was basod on a Cox regression mod wih treatment as the oly covaiata stratified by screening PSA, PSADT, and prior hormonal therapy as reported inthe IWRS; lative to
leuprolide acetate <1 favoring enzalutamide monotherapy; the two-sided Poralue was based on a srt logrark st.

4. Shore ND ot al. AUA 2023. Abstract LBA02-09. 2. Frogdland SJ tal. N Engi Mod. 2023:389: 1453-1485. 3. XTANDI (enzalutaride) Prescribing Information, PeerView
tps: accesedata fda govirugeatidadoeslabeV 2025/213674501 3203415602300 po.

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19. EMBARK: Neither Enzalutamide Combination nor Monotherapy

Negatively Affected Overall HRQOL*4

Enzalutamide Combination | Leuprolide Acetate | Enzalutamide Monotherapy
Event, n (%)° (n= 353) (n= 354) {n = 354)
All Grades All Grades All Grades
Any AE 343(972) 164(46.5) 345(97.5) 151(427) 347(980) 177 (50.0)

Treatment-related AE 305(864) 62(17.6) 283799) 31(88) 312(881) 57(16.1)
Serious AE 123 (34.8) 110(31.2) 112(31.6) 100(28.2) 131(370) 116(32.8)
Treatment-related serious AE 26 (7.4) 22 (6.2) 8 (23) 7 (2.0) 17 (4.8) 17 (4.8)

AE leading to dose reduction 25 (7.1) 14 (3.1) 16 (4.5) 5(1.4) 56 (15.8) 14 (4.0)
AE leading to permanent

discontinuation 73 (20.7) 31 (8.8) 36 (10.2) 19 (5.4) 63 (17.8) 34 (9.6)
AE leading to death sm? = 30.8 = 8 (237 =

+ Median treatment duration excluding treatment suspension was 32.4 mo (range, 0.1-83.4 mo) for enzalutamide combination,
35.4 mo (range, 0.7-85.7 mo) for leuprolide acetate, and 45.9 mo (0.4-88.9 mo) for enzalutamide monotherapy

+ The most common AE leading to study drug discontinuation was fatigue (enzalutamide combination, 3.4% [n = 12]; leuprolide
acetate, 1.1% [n = 4]; enzalutamide monotherapy, 2.3% [n = 8))

Data euof January 31,2023. + Percentages may not otal 100 because of rounding. Shown are AEs that occured from the timo of Fst dose of study treatment through 30 d ater permanent
<iscontinuaton. AES were graded according o te NCI CTCAE v4.03. Grade 5 AE. none were considered treatent-elate,

1. Shore ND et al. AUA 2023. Abstract LBA02-09, 2, Freediand SJ etal N Engl J Med, 2023,388:1453-1465, 3, Frooland SJ e a, NEJM Evid, 20292. View
4, Froodiand SJ et a. SUO 2023, Abstract 41

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20. Impact of Enzaluta

EMBARK study treatment was
suspended at week 37 if PSA was
undetectable (<0.2 ng/mL)

Enzalutamide -
monotherapy

304 patients (86%)

suspended treatment

Leuprolide acetate
240 patients (67%) ( n= 358

suspended treatment

Among those with treatment suspension,
patients receiving enzalutamide
combination vs leuprolide acetate alone
were also more likely to have undetectable
PSA (16.8% vs 9.6%; P = .009) and remain
treatment-free 2 years after treatment
suspension (34.6% vs 27.1%; P = .044)

Offers greater opportunity for
treatment de-intensification
in patients with a favorable

biochemical response

1. Stee NO aa, ASCO GU 2024 Abstract 15.2 Fresco Sl. ASCO GU 202, Asta 16.3. Freednd SJ eta ASCO GU 2024, Poster 06 PeerView

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21. Phase 3 ARASTEP: Darolutamide Plus ADT

in High-Risk BCR Prostate Cancer‘?
E à

Key Eligibility Criteria

+ High-risk BCR defined as 24-mo treatment period
- No metastasis on conventional De Eee
mag 600 mg PO twice daily ER
= PSADT <12 mo

— PSA 20.2 ng/mL after RP followed by
ART or SRT (or RP alone in patients
unfit for ART or SRT) OR

-PSA 22 ng/mL after primary RT only

—21 PSMA PETICT positive lesions

21 PSMA PET/CT positive lesions À
o 2 PSMA PETICT at any time

11
(N = 750)

+ Stratification factors: PSADT <6 mo vs 26 to <12 mo, ITT baseline PSMA PET/CT lesions with
IGRT/surgery (yes vs no), distant metastasis (+ locoregional lesions) vs locoregional lesions only

+ Primary endpoint: PFS by PSMA PETICT assessed by BICR

+ Secondary endpoints: MFS by conventional imaging by BICR, time to CRPC, time to initiation of
first subsequent systemic antineoplastic therapy, time to locoregional progression by PSMA PETICT,
time to first SSE, OS, PSA <0.2 ng/mL at 12 mo, time to deterioration in FACT-P total score, safety

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1. Mis lcinicalals gow'study/NCTOS794006. 2. Chotvazi-Ratfle A etal, ASCO 2024. Abstract TPSS122.

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22. Phase 2 ARAMON: Darolutamide Monotherapy in

Patients With HSPC After BCR‘?

Lead-in phase (52 wk)

Darolutamide monotherapy
increased baseline testosterone
levels to a lesser degree than

Key Inclusion Criteria

+ HSPC with BCR after local
treatment

+ PSA 20.2 ngimL after

Endpoints at weok 12

Darolutamide
600 mg twice daily

adjuvant or salvage RT previously reported for other
ee Un ARI agents administered as
se monotherapy and provided

(OR PSA 22 ngimL after RT deep PSA responses at week 12

on
PSA doubling time 20 mo
+ asymptomatic

Primary Endpoint: Change in Serum Testosterone

Proportion of Patients Achieving

metastatic lesions an PSA <0.2 ng/mL and PSA90
+ ECOG PS 0-1 noto. e es
m we
y go] mn
rE g | mvvook 12 Deep PSA responses
i CR E ES en
as" Mestostorone trom E atenta 12 a
58 1 bool vas oia © = Sons saves
£8 al GA EA nen
¿> > 703% ostenta
i « in Sera PSAID
EA E PAZ PSAMD
No.otpatents D ease P.
eerView

1. Nils /einiaial gowstudyNCTO5526248, 2. Goo X ot al. ASCO GU 2025. Abstract 150.

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23. Thoughts from real-world use?
+ Impact for community practices/providers?

+ Experiences from your own clinic?

+ RT vs RP, specifically neoadjuvant and adjuvant strategies?

+ How effective are your shared decision-making
communications?

What tips do you have for a busy practice?

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24. Navigating Therapeutic Choices
in mHSPC

Copyright © 2000-2025,

25. Liver disease and <3bone lesions

4 bone spots, 1 in ib spine and lymph nodes. e COTE

%) (95% Cl)
Metachronous/low volume — 125 (50) 7.7 (6.7-10.6)
Metachronous/high volume 67(75) 4.6(3.7-6.7)
De novollow volume 96 (70) 4.3 (4.0-6.5)
De novo/high volume 148 (84) 36(3:147

Overall Survival

S)

Sos
2
Zoo
E
ga Metach/LV
El De novo/LV
EM Metach/HV
E, De novo/HV

TRH HOD wh w www

1. Borata PC ot al. Concer, 2019:125:1777-1788. 2. FranciniE ot a. Prosole. 2018:78:889-895 Time From ADT Start, mo PeerView

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26. Unmet Needs in mHSPC15

Despite progress in many areas...

Patients with mHSPC have poor clinical outcomes

Despite level 1 evidence for improved OS with combination regimens,
adoption has been insufficient

Many patients still receive ADT monotherapy or first-generation
anti-androgen therapies

There has been discordance between centers of excellence vs
community settings

— Why (eg, education, access, AE management, communication)?

4. Mat, Forsyth M. J Gin Oncol, 2021:29(supp 8}21. 2. Goebel P. ESMO 2021. Abstract 623P. 3. Swami ot al. J Chin Oncol. 2021:39(5uppl 15) 5072 PeerVi
4. George DJ et al. J Clin Oncol. 2021;39(suppl 15/5074. 5. Swami U et al. Cancers. 2021,13:4951. eerview

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27. Unmet Needs:

Many Patients Still Only Receive ADT Monotherapy!

United States

ADT Monotherapy
Abiraterone + ADT
FGARI + ADT

M 2020

Other 2019

Ml 2018
SGARI + ADT

Docetaxel + ADT
0 10 20 30 40 50 60 70 80

Patients, %
E Docetaxel SGARI Other, % FGARI Abiraterone ADT
+ADT,% + ADT, % +ADT,% +ADT, Monotherapy, %
2020 801 2.5 8.6 9.9 9.5 166 52.9
2019 1,566 42 6.1 9.9 12.5 13.3 54
2018 1,526 29 3.5 9.6 17.1 12.6 54.3
1. Goebel PJ et al Futuro Oncol. 2024-20:903-918. PeerView

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28. Level 1 Evidence for Improved Outcomes in mHSPC

With Treatment Intensification’

Clinical Trial(s) Intervention Control Comments
Prostate radiation + ADT ADT r

STAMPEDE-H a zn Benefit in low-volume subgroup

GETUG-15

CHAARTED Docetaxel + ADT ADT Benefit in high-volume subgroup

STAMPEDE-C

es Abiraterone + ADT ADT Similar benefits by risk group

oes Enzalutamide + ADT ADT Similar benefits by risk group

TITAN Apalutamide + ADT ADT Similar benefits by risk group

ARANOTE Darolutamide + ADT ADT Similar benefits by risk group
Similar OS benefit for recurrent

ARASENS Darolutamide + ADT + docetaxel ADT docile ee

PERCE Abiraterone + ADT + docetaxel ADT + docetaxel TPFS benefit forall;

(+ prostate radiation) (+ prostate radiation) OS benefit in high-volume subgroup

1. Parkor CG et al. Lane. 2018:3922353-2368, 2. Armstrong AJ ot al J Cin Oncol 2022.40: 1616-1622. 3. Davis IO et al N Engl J Med. 2019:381:121-131
4. James N eta. Lance. 2016:387 1169-1177. 5. Sweeney CJ et al. N Eng! J Med. 2015;373:737-T46. 6. ChiKN et al N Engl J Mad, 2019381 13-24

7. FizaziK tal. N Eng! J Med. 2017:377:352:360. 8. James NO et al N Engl J Mod. 2017.377:336-351, 9, Smith MR ot al. N Engl J Mod. 2022:386:1132-1142, PeerView
10.FizaziK tal Loncot. 2022.309:1895-1707, 11, Saad Fetal. Cin Oncol 2024:42:4271-4281.

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29. Level 1 Evidence for Improved OS in mHSPC

With Treatment Intensification’?

CHAARTED! STAMPEDE?

All Patients

3

SOC + docetaxel Median OS docetaxel = 81 mo
Median OS SOC = 71 mo

ADT + docetaxel
(megan OS, 57.8 mo)

„a HR = 0.2 (95% Ci, 069-097)
Ê
zo ADT alone ® soc
á (mesa 08, 449 m0) Foo
do H u
i 2 401 — soc by Kaplan Meier
ai : SOC by fable parametric model
Ror deat wit ADT + docto! À 204 — SOC + DOC by Kaplan Meier
Oss (oem CL OA 20) Pe 008 +++ SOC + DOC by flexible parametric model
ot
A -- _— —_————
o iS a 5 e u a # o 12 24 36 48 so 72 84
Tin) Time, mo
Long-term analysis: HR = 0.72 Long-term analysis‘: HR = 0.81
1. Snceno Cot Engl Mod 2015373797748 2 James NO et ab. Lancat 2016387:116-117 n
3 Kyokopouoe CE.) Can Oncol 2018 9510801087. 4 Gare Weta An Oncol 208830 702-2069, PeerView

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30. vel 1 Evidence for Improved Ge n mHSPC
With Treatment Intensification’

TITAN 465 ARCHES?

(apalutamide) a. + aor 2 (enzalutamide) enzalutamido + ADT
2 Median OS: NR 5 °° IR
&
E nn <°
g 2
Ó 4 Placebo + ADT Eso Placebo + ADT
Median OS: 52.2 mo 2 Median OS; NR
2
3 HR = 0.65 e HR = 0.66
DER AD DS a 8 4 © ss à à à à à
om LATITUDE? Tine. mo
(abiraterone)
eo
eT AAP + ADT
o
8 s
3 Placebo + ADT

HR = 0.66

0 6 12 18 2 30 36 42 4% 54 60 66

Time, mo E
1 CIN al. On Oncl.221:992062303.2. Amstong Jet al. ln Oncol 2022411616622 3. FzaziK el Lancet Ono 201920666700. PeerView

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31. + Addition of either docetaxel or an ARPI improves
PFS and OS

+ In addition to efficacy, QOL is also maintained—
or even improved—with ADT-ARPI doublet

What if an ARPI + ADT + docetaxel were used
together in a triplet combination?

PeerView

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32. SOC + Abiraterone soc

(n= 355) (n= 355)
q Median, y (GR) 4:45(19-NR) 203 (1.09-NR)
Events, No. 139 zu
eo HR (99.9% CI): P 0:50 (0.34-0.71); <.0001
* 60
ys
go SOC + abiraterone
soc
20
0
5
No. at Risk my
soc 355 274 137 61 16 0
SOC + abiraterone 355 303 200 105 35 0

Adding abiraterone to ADT + docetaxel significantly improved rPFS

1. Fzazi la. Lancet. 2022399:1895-1707.

PeerView

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33. ARASENS: Improved OS

With Darolutamide Plus ADT Plus Docetaxel’

August 2023: FDA approved for
patients with mHSPC?

Darolutamide + ADT + docetaxel

Placebo + ADT + docetaxel

Patients Alive, %

Median survival, mo (95% Cl)
Darolutamide, NE vs placebo, 48.9 (44.4-NE)
HR = 0.68 (95% Cl, 0.57-0.80)

P<.001

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60
No. at Risk Time, mo

Dardutamide 651 G4S 697 627 609 503 570 54 525 509 496 408 452 496 402 267 139 55 9 0 0
Placebo 054 646 690 607 580 555 595 S10 498 470 dat 424 402 983 040 218 107 97 6 1 0
4. Sma MR et a Engl al 2022.26 1132-12 n
2 npr mda govougsrosoucos normaton prod dugatds approvos rolando metatabchomane sense prostate-cancer PeerView

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34. ARASENS: Volume and Risk Subgroups’

High-Volume mHSPC Low-Volume mHSPC
Daran + ADT + dotnet!” Pme ADT + doce! | « Risk of death reduced by
* dan. mow pS E ~30% across volume and
I 0 H 70 risk groups
3 > 3 > Medan, mos NR SOL ARA) + mOS not reached in
E En the darolutamide group,
2» Medan ca orcas) 30 regardless of volume
E HN oy oat.) oe
E 1 [HR = 0.69 (95% Ct, 0.57-0.82) E [HR = 0.68 (05% Cl 041-419) + Favorable safety profile
STTTRERANERESTERTEEEn VSTTTRRTANTERBERRENE tree ail
ia; High-Risk mHSPC al Low-Risk mHSPC volume and risk subgroup
“ “ Deroltamide + ADT + docetaxel . E
# Darolutamide + ADT + docetaxel ze co Nedan, mo: NR (@s%CL NRA) | populations, consistent
jo E iiniihe overall
2 x 4
en eo ARASENS population
E a Placebo + ADT + docetaxel
so Placebo + ADT + docetaxel 50 Median, mo: NR (95% CI, NR-NR) + Post-hoc analyses
Ë Fr re E o ui and
HE] ¿o durable PSA responses?
À 0] ur=o71 05001 088-026) À 10] ur = 0.82 99% c1,0.42090)
ERRE TETERA ATTE RE? IPC RE RRE SEED
Timo, mo ime, mo A
+ Hussain ota ASCO GU202 Aa 1.2. Saud tl Jo 225209300 PeerView

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35. ARASENS Subgroup Analysis: Age-Related Efficacy and Safety

of Darolutamide Plus ADT and Docetaxel in mHSPC*

Patients with mHSPC
benefited from darolutamide +
ADT + docetaxel irrespective
of age (<75 y and 275 y)
Darolutamide was well
tolerated in both age

subgroups, with most patients
(280%) able to receive the full
6 cycles of docetaxel and with
similar incidences of TEAES
compared with placebo,
including TEAEs commonly
associated with ARIs

oes aUReuse

1. Gares Jot al. ASCO GU 2025. Abstract 143.

PeerView.com/WQG827

Tine From andante, mo

AY ani OF some

PeerView

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36. Concomitant G-CSF Use When Delivering Docetaxel in
Combination With Darolutamide in Patients With mHSPC'

ication occurred mostly after the
docetaxel, as secondary prophylax

RDI in Patients Receiving Darolutamide or Placebo G-CSF Use and Docetaxel Dose Modification

In both darolutamide and placebo treatment groups, >97% of. Overall, 800/1,279 (63%) patients required docetaxel

dose modification, and 556/1,279 (43%) patients required
G-CSF, mainly for secondary prophylaxis (>98%)
- 376/800 (47%) of patients with docetaxel dose

patients received an efficacious dose of docetaxel (RD! >80%)
and over 88% received RDI >85%, indicating that darolutamide
does not have an impact on received docetaxel dose intensity

argent Patents Reg modification received G-CSF
POR SR RD m0 RO + The addition of darolutamide did not increase G-CSF use
Pe or docetaxel dose modification
100 si bil
0 924 a Proportion of Patients Treated With Docetaxel Who Received G-CSF
2
DOC Dose Modif
7 = Overall Population
*o Subgroup
in
de IRC OT) (US APM 244
» Primary G-CSF propias 205) 20) 305) 2(03)
‘0 Secondary G-CSF prophyianis — 104 (471) 188,46) 260(41.8) 282433)
o
PTE capes Without concomitant G-CSF 2051524) 2190635) © S7O(TS) 331884)
PeerView

1. Ong M et al ASCO 2025. Abstract 182.

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37. Phase 3 ARANOTE: Is Docetaxel Needed?" Under FDA review

for expanded indication

ARANOTE was designed to evaluate darolutamide + ADT vs ADT, without docetaxel

10
Key Eligibility Criteria
+ mHSPC = Eley os Darolutamide + ADT
lx 08 l70.30 Median rPFS: NR
ECOG PS 0-2 2. RAS

Stratification Factors
+ Visceral metastases (yes/no)
+ Prior local therapy (yes/no)

Placebo + ADT
‘Median rPFS: 25 mo
(95% Cl, 19-NR)

FPFS Probabilit
eo
25

HR for (PFS = 0.54
(95% Cl, 0.410.717
P< 0001 ;
4
0 3 6 9 12 15 18 21 24 27 30 33 36 39
No, at Risk Time, mo
Darolutamide 446 422 388 358 330 309 285 262 186 113 54 9 1 0
Placebo 223 197 178 158 137 109 96 83 58 32 12 2 0 0

Primary endpoint: rPFS by central blinded review Median follow-up: darolutamide, 25.3 mo; placebo, 25 mo

Data cutott: June 7, 2028
Primary analysis Oocured air 222 events (derolutamide, 128; placebo, 4) * HR and 95% CI were calculated using the Cox model stratified on visceral metastases (yes/no) and prior

therapy peso)
‘Saad Fa a Cin Oncol, 2024:42:4271-4201. 2. ip cialis govlstudyNCTOA7Q6100, PeerView

Darolutamide
mg BID + ADT
146)

Placebo
+ADT

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38. ARANOTE Subgroup Analysis: Darolutamide Plus ADT in

Patients With mHSPC by Disease Volume!

rPFS in Patients With HV Disease

Radiological PFS Probability

0

Darolutamide + ADT
Median: 30.2 mo
(28.8-NR)

Placebo + ADT
Median: 19.2 mo
(16.1-26)

1
HR = 0.6 (95% Cl, 0.44-0.8)

darolutamide + ADT was improved vs placebo + AD

Radiological PFS Probability

regardless of disease volume

‘PFS in Patients With LV Disease

09
Darolutamide + ADT

Median: NR (NR-NR)
06 Es bus

Placebo + ADT
05 Median: NR (25.0-NR)
04
03
02
0.1

HR = 0.3 (95% Cl, 0.15-0.6)

0 3 6 9 1215 18 21 24 27 30 33 36 39

1. Saad F etal. ASCO GU 2025. Abstract 151.

PeerView.com/WQG827

Time, mo

0 3 6 9 12 15 18 21 24 27 30 33 36

sl PeerView

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39. ARANOTE Subgroup Analysis: Darolutamide Plus ADT in
Patients With mHSPC by Disease Volume’
Efficacy outcomes with darolutamide + ADT were improved vs placebo + ADT,
regardless of disease volume

Time o MORPO In Patents WAN HV and LV Disease ‘Other Secondary Efficacy Endpoints Overall and by Volume of Disease

m HV Disease soy LV Disease

men 9 TETAS ae

à o a gem RE

ee E am nn me MIE men + ES

a En an

= Lo Seer aes ea

a pm a Go oc M A

5 un „Am Die ne men mem + mney

Lies, EEE rere a A | ean
LEE 2 PET sn

Er Ye
a a À

+ The combination was well tolerated in both high-volume and low-volume subgroups, with low treatment
discontinuation rates

+ Patients with low-volume mHSPC had marked treatment efficacy with minimal treatment burden
1. Sand Fell. ASCO GU 2025. tract 151 PeerView

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40. TITAN Post-Hoc Analysis: Apalutamide in Patients With mHSPC

With a History of Cardiovascular or Metabolic Risk Factors!

Treatment Effect of APA on rPFS Was Similar in Those With and Without
Baseline CV or Metabolic Risk Factors + Concomitant Medications

+ Alarge majority of

With History of CvMetabote Rsk and Con Mads No Hstory of CViMetaboic Risk 5 A
we. so patients enrolled in
Fa apalutaniée TITAN reflected an
EN elderly population
E with a considerable CV
FU isk profile
Br $. ise of APA resulted
MELZEIITEIZIZ) MZLILTIIIEZTZ) in a significant
Time From Randomization, mo Time From Randomization, mo Time From Randomization, mo INTA
Treatment Effect of APA on OS Was Similar in Those With and Without tPFS and OS anda
Baseline CV or Metabolic Risk Factors + Con Meds aoe a oe
n o A es s nen regardless of prior
Vin ty Van Ra ison l Cebo Rik and Con Mes Nosy of Cut sk a
I» Apalutamice io Apalutamido is Apotutanids risk or with con meds
de és EN at baseline for these
cm o 570 a
si. EE ide conditions
a La a Placebo 3»
ES 3? 3»
„les E .
Timo From Randomization, mo Time From Randomization, mo Time From Randomization, mo .
1.AcasA ol. ASCO GU 2025.Abstrac 165 PeerView

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41. LIBERTAS: Deep PSA Decline in Early Participants With

Apalutamide + Continuous Versus Intermittent ADT in mHSPC*?

Initial findings from LIBERTAS
showed that 70% of
=== participants had a rapid and
f Ps TE) deep PSA decline at 6 months
Seas} Som
ran

with APA + ADT, consistent
with results from the phase 3
TITAN trial and real-world
study observations

romo ten
AAA

armen an #60
pa

PSA Change at 6 Months From Baseline Among Enrolled Participants With PSA Date at 6 Months (n = 179)

12 n = 120 participants achieved
PSA <0.2 ngimL at 6 months.

Enrolled Participants With a PSA Result at Cycle 6 Day 14

“Participants win a percentage change rom baseline exceeding 100% (1 instance noted) are capped at 100%. PeerView
1. nos ri clara gow/stdyNCTOSEBA398.2:Azad A et a ASCO 2024, Abstract TPSZIO, 9. Azad A et a. ASCO GU 2025. Abstract 147.

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42. Doublet Therapy
+ Monitoring with abiraterone
(HTN, edema, LFTs, hypokalemia)
+ Pill burden
+ Exacerbation of ADT AEs
+ CV, cognitive, bone health

Triplet Therapy

+ Infusional treatment

+ Chemotherapy toxicity (neutropenia,
neuropathy, fatigue)

+ Administration time

+ All considerations associated with

doublet therapy

PeerView

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43. Case Example and Panel Discussio

What are you doing in your practice for patients with
de novo low-volume mHSPC?

+ 56-year-old man with screening PSA 30 ng/mL Discussion
+ Prostate biopsies reported Gleason 5+4, 4+5, and 4+4
+ Prostate MRI reported: + Who needs/can tolerate
- Confluent PI-RADS 5 lesion throughout the left chemo vs when should
peripheral zone extending from apex to base chemo not be included?
- Probable metastasis in right iliac bone + What conversations do you
+ Bone scan reported a bone metastasis in the right iliac bone have with patients?

+ How do you manage AEs?
PSMA PET CT =

What are the considerations
for community practices?
+ Other key discussion points?

PeerView

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44. Integrating Modern Therapies
Into mCRPC Treatment Plans

Copyright © 2000-2025, Peerview

45. Classes of Approved Agents for C

Hormonal Axis
+ Enzalutamide
+ Abiraterone
+ Apalutamide
+ Darolutamide

Immunotherapeutic
+ Sipuleucel-T
+ Pembrolizumab for MSI-H/dMMR cancer (not prostate cancer-specific)
Cytotoxic
+ Docetaxel
+ Cabazitaxel
DNA Damage
+ Radium-223 (radiopharmaceutical)
+ Olaparib, rucaparib
+ Lu?” vipivotide tetraxetan

+ PARP/ARPI combinations (BRCA: niraparib + abiraterone, olaparib + abiraterone; Ti ou
HRR+: talazoparib + enzalutamide) PeerView

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46. Despite progress in many areas...

Selection is based on
+ Time between the agents

Symptomatic vs asymptomatic

Bone disease vs non—bone disease
Presence or absence of visceral metastases
Presence or absence of genomic aberrations
Oral vs IV

Distance from the center

Patient preference

PS/frailty

Prior ADT DOR

Sequencing drugs in CRPC

remains a challenge

+ Lack of level 1 evidence

+ Cross resistance between
NHAs

+ Cross resistance with
chemotherapeutics

+ Many of the existing
drugs/classes are used in
earlier lines of treatment

PeerView

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47. Treatment With Radium-223 Improved OS in mCRPC12

OS, Previous Docetaxel Use OS, No Previous Docetaxel Use

Radium-223 Placebo Radium-223 Placebo
100 (n= (n=174) IO (n=262) — (n=133)
Median, mo Median, mo. — 16 E
95% Cl 125-155 100-129 5 BC 139478 95-141
2 HR = 0.70 (95% Cl, 0.56-0.88)

HR = 0.69 (95% Cl, 0.52-0.92)
P= 002 © P=.01

OS, %

Radium-223 Radium-223

Placebo

o o
os 6 À 8D à B® eS à . à à À 6 à à à + à
Time, mo Time, mo
201

The FDA approved radium-223 for mCRPC
based on the phase 3 ALSYMPCA tri

4. Hoskin Pot al. Lancer Oncol 2014:15:1397-1406. 2. Xoigo (radium Ra 223 dichloride) Prescribing Information.
ipsum accessdata fda govicrugsatida_docslabeV2018/20387 150163 pa

PeerView

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48. PeerView.com/WQG827

Phase 3 ERA-223: Clear Excess of Fractures in the
ARPI Plus Radium-223 Combination Arm!2+

The ERA-223 Phase 3 Trial

Key Eligibility Criteria Abiraterone acetate 1,000 mg QD and
Patients with bone- prednisonelprednisolone 5 mg BID (AAP) +

predominant mCRPC radium-223 55 kBg/kg IV Q4W
(22 bone metastases) Stratification Factors
Asymptomatic or mildly + Geographical region
symptomatic. 1:1 + Use of Bone health agents

ECOG PS of 0 or 1 {N= 806) * Total ALP evel at baseline

No prior chemotherapy (ALP <90 vs 290 units/L)

for CRPC Abiraterone acetate 1,000 mg QD and
No known brain prednisonelprednisol

or visceral metastases, mg BID (AAP) + matching placebo oS CURE ENUT HHH DAS
Time Since Randomization, mo

Fracture Probabil

AAP + Placebo
(n= 394)

45 (11)

Time to fracture, median 317 NE
(95% Cl), mo (27.6-NE) (NE-NE)

Patients with 21 fracture, n (%) 112 (29)

1 Sie provides by Karim Faz MD. PR. i
mn tal ESO 2018. LBAJO 2. Sth Metal Lancet One 2019:20408419. PeerView

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49. Decreased Fracture Rate by Mandating
rotecting Agents With Radium Plus Enzalutamide!

+ Without BPA, fracture risk is increased

+ With BPA, the cumulative fracture incidence is
low for patients treated with either combination
therapy or enzalutamide alone

Enza + Rad without BPA
Enza without BPA
Enza + Rad with BPA
Enza with BPA.
ee a a 1 à oe aa
Time Since Randomization, mo
1. lesson So ASCO 2024. Abstract 502 PeerView

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50. Phase 3 PEACE

Combining Radium-223 With Enzalutamide*?

Key Eligibility Criteria?
+ Bone-predominant mCRPC

Abo cer) Stratification Enzalutamide w mg once daily
© ERE) + Coy _ radium-223 55 kBq/kg IV
symptomatic + Baseline pain nee

+ WHO PS 0-1 (BPI worst pain
+ No prior treatment with 0-1 vs 2-3)
enzalutamide, other radium-223 + Prior docetaxel
radionucleotides, or hemibody RT (yes vs no)
+ No prior or concomitant treatment + Use of bone Enzalutamide 160 mg
with CYP17 inhibitors health agents?
+ No known brain or visceral
metastases

+ Primary endpoint: PFS
+ Secondary endpoints: OS, DSS, SSE, time to initiation of next systemic antineoplastic therapy,
PFS2, BPI, EQ-5D-5L

+ Bone neath agents (denosurab or ischosphonaes) oy pen pains racing nem a basen. Ian during stucy pones to prevent
‘oeourdng ec 7
o tos.Isncatal govistudyINCTO21 94642, 2. lesson Set al. ASCO 2021. Abstract 5002 PeerView

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51. PEACE-3: Combining Radium-223 With Enzalutamide

Improved rPFS and OS!

Primary Endpoint: rPFS?

100 an
Am TN (5% CH, mo
Enzalutamide
es 199222 194(17.1-259)
Enzalutamide 160224 184 (138-192)
089 04087)

HR (85% CI)
dom 20008

rPFS, %

Enzalutamide
+ radium-223

Enzalutamide
0 6 12 18 2% 90 36 42 4 5 60 6 72
Time, mo

OS at Interim Analysis (80% of OS Events)?

Median

Arm m
100 Ereatrarico

reacio Ho? 42399840)
90 Enzalutamide 129/224 35(28.8-38.9)

HR (95% Cl) 0.69 (04
Log-rank P. 0051 fc

+ Assumption of proporional hazard achieve, Pres eve of sigaicance for interim analysis was 5.0034, Due to nonproportional hazards pus lack of unequivocal

significance for RMST (esticied mean survival time) senstivty analysis, study wil continue to final OS analysis

1. Giessen ot al, ESMO 2024. LBA!

PeerView.com/WQG827

70
= 60
yg 5
SÓ 40
30 Enzalutamide
à + radium-223
10 Enzalutamide
0
O 6 12 18 24 30 36 42 48 54 60 66 72
Time, mo
PeerView

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52. PSMA-Based Radioligand Therapy!"

17Lu-PSMA-617 is now SOC for mCRPC post NHT and taxanes (phase 3 VISION)
17Lu-PSMA-617 and other beta-based RLTs are moving earlier in the disease paradigm

Localized
prostata cancer mHSPC mCRPC

Tumor
burden

Hormone sensitive

PSMA-Based Radioligand Therapy Phase 3 Trials

Jos latitud NTOSOSA14.2 hu att gowsusyINCTOA720157.& Tagawa Set a. ASCO 202 posa TPSS118
4. Sartor O etal, ESMO 2023, Abstract LBATS. 5, Fra K eta. ASCO. 6. nips icinicarals. govistudyINCTO4647526..
icincatategoveuyncTOS20W07- 0 gs Jana poda NCTSNICO, 7

7. Sator O et al. ESMO 2024 LBASS. 8. mps:
10. Noris MJ et al ASCO 2021. Abstract LBM. 11. FizaziK et al Lancet Oncol, 2023:24:597-610.

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53. 17 Radioliga

VISION Eligibility Criteria
+ mCRPC
— Prior treatments:
> 21 NAAD
> 1 or2 taxane
- PS of 0-2
- PSMA PET/CT+

"Lu. PSMA-517 binds to PSMA on

‘tho cell membrane with high affinity
particle emission

wi...

Prostate cancer cell
and neighboring cell

oun Best SOC

"ILu-PSMA-617
(7.4 GBq Q6W x
4-6 cycles)

Best SOC

Primary endpoint: PFS, OS

: Raducad bndginine kidnys, len fer, stay glands, arial lands uranio glands, and bone manon is expacte, n
Y Moris Meta ASCO 202, Abavact LM. 2 patinar god NETOS! TODS PeerView

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54. 177Lu-PSMA-617 Plus Best SOC
Improved OS and rPFS in mCRPC1*% March 2022:

FDA Approved
17Lu-PSMA-617 Improved OS 17Lu-PSMA-617 Improved rPFS

100

HR = 0.62 (95% CI, 0.52-0.74); P <.001 (one-sided)

HR = 0.40 (95% Cl, 0.29-0.57); P < .001 (one-sided)
Median OS: 15.3 vs 11.3 mo

Median rPFS: 8.7 vs 3.4 mo

3388

3

ViLu-PSMA-617 +
SOC (n= 551)

Patients Alive, %

Patients
Disease Progression, %
E

38

"Lu-PSMA-617 +
SOC (n = 385)

OFFER NNNKRARA BAND OTS 4S CTE SWNRIMI OT 192

Time From Randomization, mo

Time From Randomization, mo

+ Both primary endpoints met: improved OS and rPFS in patients receiving '77Lu-PSMA-617 + best SOC compared
with those receiving best SOC alonı

+ Delayed time to worsening in HRQOL and time to skeletal events

ips ass oa gorge ducs abeV2 022716855108 pl. Fiza Kel a Cancel Oncol 20232407 610 PeerView

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55. Phase 3 PSMAfore: 177Lu-PSMA-617 Prolonged rPFS Versus

ARPI Change in Taxane-Naïve PSMA+ mCRPC'2

Key Eligity Criteria

+ conlemed progressive
morc

+ 21 PSMA poste
‘metastatelesion on
(cajGa-Psua-t PETICT
and no exclusionary PSMA
Mega lions

+ Taxananaive (capt
{reolaguvant>12 mo 290)
— Not oigo tra PARP
+ ECOG PSO

»
ra

Event-Free Probability, %
8

+ Primary endpoint: PFS
+ Key secondary endpoint: OS

{PFS by BICR
Followup

"Lu-PSMA-617 — ARPI Change
(n= 234) (n= 234)
Events, n (%) 115 (49.1) 168 (71.8)
Median 1PFS, mo 1202 559
(85% Cl (930-1442) (417-585)

"Lu PSMA17

OS: HR <1 at third
interim analysis*

0
Primary HR = 041 aus

20 | (95% Cl, 0.29.0.58; P< 0001 Le:

[Updated HR = 043 (95% CL, 0:33-0.54) A

‘Time From Randomization, mo

With 73% information faction ITT analysis.
4. Sartor O et al ESMO 2023. Abstract LBAT3. 2. Fizazi K et al, ASCO 2024. Abstract 5009.

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56. PSMAfore: Association of Baseline and On-Treatment

ctDNA Fraction With Clinical Outcomes in mCRPC!

*7Lu-PSMA-617 Arm

Baseline
$ Cox agression
3 °°) 7] aDNAnotHR=eD 10
É (95% Gi, 1623)
zoe tected Pong o P< 0001
dz E indax (SE
gp 3e 0
E
Su u
3% | cona
ia “
detected
Fics „detected
ESS zur zur ur mr me EEE]

ctDNA not
detected

os

Proportion of Patients Ave

es [95% Ci, 3048.7)

(95% C1 164-417)
|? = 00052 <

[P<.0001
€ indox (Se) 077 003)

loratory analysis showed that higher
Post-treatment changes in ctDNA fraction may have cl

1.de Bono JS et al. ASCO GU 2025. Abstract 18.

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(05% C1, 10.1226)

C index (SEX 0.72 0.09)

CIDNA not
detected

| evamsrresuns, nin | Melon PES, mo (8% CH
Besse
OMA dec se 790810)
NA rot red 2030 maqazs
caos
SD detecto 200 24579)
cONA not dues 3246 12015182)

DNA detected aris 146 (133-19)
“DNA not detected 9180 NE

e201

‘IDNA detected 29196 13.1 (10716)

ical utility as a response biomarker
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57. -PSMA-617 AE Profile

y -PSMA-617 Safety Considerations

Gl effects, nausea, diarrhea

Myelosuppression: Check CBC before each administration
Fatigue, pain flare

Short-term radioactivity to others

Back pain, bone pain

Dry mouth (xerostomia): Typically mild, reversible with drinking extra water,
chewing gum, or sucking on sugar-free candy

Renal dysfunction: Check creatinine prior to each administration

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58. Other Targeted Radionuclide Therapy Approaches

+ Actinium-225 (225Ac)-labeled antibodies
+ PSMA-TAC (22Ac-pelgifatamab)!2

— Potentiates the antitumor efficacy of darolutamide in androgen-
dependent and -independent prostate cancer models

+ 225Ac-PSMA-Trillium?

1. nei govsyINCTO505200, 2. Shore ND etal, ASCO GU 202, Abe! 210.3. Nips: got NOTOGZ17822 PeerView

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59. Optimizing Germline and Somatic Testing for mCRP

Chart review of a Only 59.2% (n = 590)
de-identified of patients received HRRm testing
real-world cohort of

patients (N = 996)

from 500 US sites Calo

with newly a

diagnosed and wm

actively treated

mCRPC* from em

January 1, 2020, to En

December 31, 2021

Germline + somatic
41% (n= 24) —

Though 31.7% (n = 187) of patients
tested positive for an HRRm, only
66.8% (n = 125) received a PARPi

No PARPi/
unknown
33.2%
(n=62)

* Excluding hose wäh lymph node-only metastasis.
4. Shore ND otal ASCO GU 2024, Abstract 210.

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60. PARP Inhi
of mCRPC'

itor Combinati

Olaparib + abiraterone
+ PROpel
+ FDA approved for BRCA-mutated mCRPC

Niraparib + abiraterone?
+ MAGNITUDE
+ FDA approved for BRCA-mutated mCRPC

Talazoparib + enzalutamide
+ TALAPRO-2
+ FDA approved for HRR-mutated mCRPC.

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61. Biologic Rationale for Combination PARP and AR Inh

MRE11A
+» AR signaling promotes DNA NBN
damage repair ATR
DNAd
+ PARP1 regulates AR-mediated En Er
un a ANG
transcriptional activation XROC4 FANCC
XRCC5

+ AR inhibition upregulates
PARP-mediated repair pathways
with synthetic lethality between
ADT and PARP inhibition

1. Gooduin JF et a, Cancer Disco, 2013°3:12541271. 2. Pknghorn WR et a. Cancar Discov. 20193 245-1250 n
3 Alí Metal Not Commun 20178374. Schwer Mi et Cancer Decor 012211341148 PeerView

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62. Phase 3 MAGNITUDE: Niraparib Plus Abiraterone Improved rPFS
and Had a Positive Impact on OS‘?

August 2023: FDA approved for patients with BRCAm mCRPC*+
as a fixed-dose combination (once-daily dual-action tablet)"

OS at Final Analysis (Unadjusted)

142: rPFS by Central Review
in the BRCA Subgroup

& 0
5 =
E 5 go
a a
E E | Placebo + aap NIRA + AAP
3 60 NIRA + AAP 3
2 median rPFS: 19.5 mo À °° | OS: 285me > mOn me
Es E
= À 40 À HR=0708108%.c1,08841.120)
5 a = Nominal P = .1828
E 2] HR=0.55 (95% Cl, 0.39-0.78) Placebo + AAP $ 20 À va HR = 0663 95% ci, 04640947
E median rPFS: 10.9 mo & | Nominal P=.0257

ol d

o 3 e ‘(nen nee M 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Time, mo Time, mo

+ With 11.1 mo of additional follow-up from 1A2 and 19.2 mo from 1A1, OS favored NIRA + AAP in patients with BRCA+ mCRPC

+ PROs showed that patients in the NIRA + AAP arm had a longer time to pain progression; side-effect bother was minimal,
and remained stable or improved

* Fuxed-dove combination tablet: nrapanb 200 mg and abiraterone acetate 1,000 mg taken orly once daly in combination with prednisone 10 mg daly.

1. CMKN et al J Cin Oncol. 2023:41:3339-3351.2. Cn KN et al ESMO 2023, LBABS, 3 Akeega (nrapar and abraterone acetato)

Prescrting information, htps www janssenlabels,comipackage inser/product-monograph prescribing nformationAKEEGA- pip. PeerView
4.Rathkop DE et al. ASCO GU 2024, Abstract 105.

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63. Phase 3 PROpel: Abiraterone Plus Olaparib Improved rPFS and
Had a Positive Impact on OS in the BRCA-Mutated Population!

May 2023: FDA approved
for BRCAm mCRPC
os

rPFS

Abiraterone + olaparib

ity
E

Abiraterone + olaparib

FS, Probabili

oz Abiraterone + placebo
u Abiraterone + placebo
0 2 4 6 8 0 12 14 16 18 20 22 24 26 28 BERLEETTTITITEITTIETIITGZ
Time Since Randomization, mo Time Since Randomization, mo
Events/Patients, Median rPFS, mo EventsiPatients, _ Median OS, mo
n(%) (85% ch) n(%) (95% chy
Abiraterone + olaparib 14/47 (29.8) NR (NR-NR) Abiraterone + olaparib 13/47 (28) NR (NR-NR)
Abiraterone + placebo 28/38 (73.7) 8.4 (5.5-14.8) Abiraterone + placebo. 25/38 (66) 23.0 (17.7-34.2)
PeerView

1. Saad F ota. Ann Oncol. 2022;33(supp! 7):s616-9852.

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64. Phase 3 TALAPRO-2: Talazoparib Plus Enzalutamide

Significantly Improved PFS in HRR-Deficient mCRPC*3

June 2023: FDA approved for patients Talazoparb + Enzalutamide | Placebo + Enzalutamido
with HRR-mutated mCRPC* (05200) =)
Meet re, mo NR (21.9-NR) 13.8 (11.0-16.7)

(95% Cl)
Events, n 66 104

10

Talazoparib +
enzalutamide

Placebo +
enzalutamide

Stratified:
HR for disease progression or death = 0.45 (95% Cl, 0.33-0.61)
P<.0001

o+ -
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42
Time, mo
1. FiaaiK et al. ASCO 2023, Abstract 5008, 2. Agarwal N tal Lancet. 2023:402291-303, 3. Fzazh Kt al, Nat Mod. 2024:30-257-264, PeerView

4. nuda govldrugs'rug-approvale-and-dalabasesida-approvestalazoparb enzalutamice-wrgone-mutated metastate-castration resistant prostate

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65. TALAPRO-2: Final OS in Unselected Patients and Those With

HRR-Deficient mCRPC12

OS (Final Analysis)
20.4% reduction in risk of death, >8-mo improvement in median OS

vtaases Mason OS no

TALA + ENZA TEE Tapa 608
Peo-enza Zus farojan a0)

Bao improvement

Msn fon o.
sr OS wos 82.50

JALA + ENZA

Probability of OS

Any HRR Gene Alterations (HRR-Deficient ITT Population)

ds ‘Survival alo, % (95% Ci}
91 (67-95)

Even Patents Median 08,0

TALA + ENZA 5200 E
= 700) peor enza TU 31107234)
Dem Time, mo Suriväi rate “
57 (49464)
TRS” aon an our DN 0 385 250 26 242 mem nn 0 2° (95% Ch.
mu . HA h 4016050) — TALA + ENZA
aa a a ar mn aT TTS 4 1 0 Bn A sen)
al esos ° 4294-49)
(95% C1,0478:0.814) i 222136)
P= 0005 i

PRO + ENZA
RENE

o

a SERIE
pa aña Time, mo
A 20 mm m mem MS DE MH BS & Ho 8 + €

1 AgarwalN ot al ASCO GU 2025. LEA. 2. FzaziK etal, ASCO GU 2025. LBA.

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66. PARP Inhibitor Safety Considerations

+ Hematologic: anemia, thrombocytopenia, neutropenia
Nonhematologic: nausea/vomiting, diarrhea/constipation, asthenia/fatigue

+ Rare: AML, MDS, pneumonitis

1. Lymparza (olapart) Prescrbing Information. tps: accessdata da govidrugsaids_docs/abel2020208858=028
2 Ras (pars Prey momton, pea Taca) Sono Coen UCRANIA. 3 Akesg par and barons acetal) rer Norman,
ps: ur onsen iformation/AKEEGA pipa. 4. Talzenna (tlazopari) Prescribing Information. Peer View

nssenlabels.compackage”inseriproduet monograph prescribing:
ps. accessdata (da gowicrugsatida_docslabeV 2024/21 16510121 pa.

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67. MAGNITUDE

HHRm Cohort
(n = 212)!

Anemia

Fatigue 30
Nausea 24
Thrombocytopenia 23
Hypertension 33
Neutropenia 15
Pulmonary

embolism

Transfusion

AML/MDS

41. ChIKN ot a. Ann Oncol 2023:34:772:782. 2. Saad F et al. Lancet Oncol. 2023:24: 1094-1108, 3. FizaziK ot al. Nature Med. 2024.30.257.264.

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All Comers
(N = 398)?

TALAPRO-2
HHRm Cohort

33
21
25
18
32

(n= 198)?

n=2

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68. Patients Who Have Received PARP Combinations With Prior ARSI

PROPEL MAGNITUDE TALAPR'

ATM, BRCA, BARD1,
BRP1, CDK12, CHK1/2;

ATM, ATR, BRCA, CK2,

ATM, BRCA, BRP1, FANCL, MLH1,

eae FANCL, PALB2, ee MRE11A, NBN, PALB2,
RADS51B/C/D/54L ä RAD51C
Prior ARPI, % 0.15 3 8
Prior docetaxel, % 24 19 29
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69. Other Approaches he Horiz

+» Targeting the PISK/AKT/PTEN signaling through AKT inhibition
— AKT inhibitor capivasertib in monotherapy or combination strategies

> CAPltello-280: capivasertib + docetaxel in mCRPC

+ CAPItello-281 reported a statistically significant and clinically meaningful
improvement in the primary endpoint of rPFS in patients with PTEN-deficient
de novo mHSPC via press release!

+ Targeting androgen biosynthesis upstream of current treatments
— CYP11A1 inhibitor

> Phase 2 CYPIDES: administration of ODM-208 to heavily pre-treated patients with
mCRPC and AR-LBD mutation was highly effective in blocking the production of
steroid hormones?

> Phase 3 trial underway

e Comm One 2024 prop ana pre an in PeerView

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70. Panel Discussio

What are you doing in your practice for patients with mCRPC?

Radioligands PARPi Combos

Thoughts from real-world use?

+ How can community practices be best
implemented?
+ Pati iderati il ?
so Patient considerations (eg, pill burden)?
+ Other?

+ Thoughts from real-world use?
+ Experiences from your own clinic?

+ Logistics/workflow/access?

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71. Patient Advocacy Organizations Are Valuable Resources
for You, Your Staff, and Your Patients

ZERO’s Prostate Cancer Support Groups

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