Prostate TT TM_Downloadable Slides.pptx

Expert Think Tank on Applying the Latest Data to
Individualize Treatment in Prostate Cancer
Provided by Clinical Care Options, LLC in partnership with ZERO Cancer
Supported by educational grants from AstraZeneca; Bayer HealthCare Pharmaceuticals Inc.;
Janssen Biotech, Inc. administered by Janssen Scientific Affairs, LLC; Lilly; Merck Sharp &
Dohme Corp.; and Novartis Pharmaceuticals Corporation.

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Program Chair
Alicia K. Morgans, MD, MPH
Associate Professor
Dana-Farber Cancer Institute
Boston, Massachusetts
Alicia K. Morgans, MD, MPH: consultant/advisor/speaker: AAA, Astellas, AstraZeneca,
Bayer, Dendreon, Foundation Medicine, Exelixis, Janssen, Lantheus, Myovant, Myriad,
Novartis, Pfizer, Sanofi, SeaGen, Telix.

Faculty
Tanya B. Dorff, MD
Professor, Section Chief
Genitourinary Cancers
Department of Medical Oncology and Therapeutics Research
City of Hope
Duarte, California
Tanya B. Dorff, MD: consultant/advisor/speaker: Astellas, AstraZeneca, Bayer,
Exelixis, Janssen, Sanofi, SeaGen.

Faculty
Rana R. McKay, MD
Associate Professor of Medicine
Division of Hematology/Oncology
Department of Medicine
University of California, San Diego
Genitourinary Oncology Team Lead
Moores Cancer Center
La Jolla, California
Rana R. McKay, MD: consultant/advisor/speaker: AstraZeneca, Aveo, Bristol Myers
Squibb, Bayer, Calithera, Caris, Dendreon, Eisaix, Exelixis, Johnson & Johnson, Lilly,
Myovant, Merck, Novartis, Pfizer, Sanofi, Seagen, Sorrento, Telix, Tempus.
Institutional Research Funding: Artera, AstraZeneca, Bayer, Bristol Myers Squibb,
Exelixis, Oncternal, Tempus.

Faculty
Michael T. Schweizer, MD
Associate Professor
Clinical Research Division
Department of Medical Oncology
University of Washington
Fred Hutchinson Cancer Research Center
Seattle, Washington
Michael T. Schweizer, MD: consultant/advisor/speaker: AstraZeneca, PharmaIN,
Sanofi; researcher (paid to institution): AstraZeneca, Ambrx, Bristol Myers Squibb,
Epigenetix, Hoffman-La Roche, Immunomedics, Incyte, Janssen, Merck, Novartis,
Pfizer, SignalOne Bio, Tmunity, Xencor, Zenith Epigenetics.

Faculty
David VanderWeele, MD, PhD
Associate Professor
Hematology/Oncology
Northwestern University
Attending Physician
Jesse Brown VA Medical Center
Chicago, Illinois
David VanderWeele, MD, PhD: consultant/advisor/speaker: Astellas, AstraZeneca,
Bayer, Exelixis, Janssen, Myovant; researcher (paid to institution): AstraZeneca, Bayer,
Genentech.

ZERO Prostate Cancer Patient Survey
Disparities in Prostate Cancer Care
 455 patients with metastatic prostate cancer
87%
6%
7%
White
Black
Other
9%
36%
44%
10%
49 and younger
50-59
60-69
70-79
80 and older
5%
47%
46%
7%
Prolonging life
QoL
Other
<5% with difficulty accessing
care or transportation
Prolonging life
Maintaining QoL
Respondent Demographics
Race
Age (Yr)
Transportation
to Therapy
Patient Goals
for Therapy

How Can My Patient Access Genetic Testing?
 Shortage of genetic counselors
‒ Order test, refer only patients
with positive results to genetic
counselors
‒ GENTleMEN study: Internet-based
approach feasible1
 Insurance coverage can be
problematic
‒ PROMISE Registry offers free
testing2
‒ FORCE website has resources
 Any person with
prostate cancer
diagnosis
 Patient-directed
self-registration
 Free germline
genetic testing,
web/mail based
 Long-term
follow-up for
men with
germline variants
of interest (eg,
BRCA2, PALB2,
ATM, CHEK2)
1. Cheng. JCO Precis Oncol. 2023:7. 2. NCT04995198.
Participant
outreach
Participant
self-consent
Saliva
collection kit
Positive for
PV or LPV
(n = 400)
Presence of
VUS
(n = 100)
Negative
for PV, LPV,
or VUS
Required genetic
counseling
Ongoing clinical
data collection
PROs collected
Educational
newsletters
Optional genetic
counseling
Educational
newsletters
www.prostatecancerpromise.org
Promise. A Prostate Cancer Registry of Outcomes and Germline
Mutations for Improved Survival and Treatment Effectiveness2

ZERO Prostate Cancer Patient Survey
Disparities in Prostate Cancer Care
prostatecancerpromise.org
Free testing for patients
59%
41% 37%
63%
Discussed biomarker
testing with their HCP
Discussed clinical trial
enrollment with
their HCP
Yes
No

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.

Patient Case: mHSPC
 72-yr-old man
 Presents with worsening fatigue, lower back pain, weight loss
 PSA 655 ng/mL
 Gleason 5 + 5
 CT scan reveals metastatic disease

SoC in mHSPC: Doublet and Triplet Therapy
mOS, Mo HR (95% CI)
LATITUDE1 mHSPC
(N = 1199)
Abi/pred + ADT 53.3
36.5
0.66 (0.56-0.78;
P <.0001)
Placebo + ADT
STAMPEDE2
Advanced/
recurrent HSPC
(N = 1917)
Abi/pred + ADT 79
46
0.60 (0.50-0.71;
P <.0001)*
ADT alone
ARCHES3 mHSPC
(N = 1150)
Enza + ADT NR
NR
0.66 (0.53-0.81;
P <.001)
Placebo + ADT
TITAN4 mHSPC
(N = 1052)
Apa + ADT NR
52.2
0.65 (0.53-0.79;
P <.0001)
Placebo + ADT
PEACE-15 mHSPC
(N = 1173)
Abi/pred + ADT +
doc NR
53
0.75 (0.59-0.95;
P = .017)
ADT +
doc
ARASENS6 mHSPC
(N = 1306)
Daro + ADT +
doc NE
48.9
0.68 (0.57-0.80;
P <.001)
Placebo + ADT +
doc
1. Fizazi. Lancet Oncol. 2019;20:686. 2. James. Int J Cancer. 2022;151:422. 3. Armstrong. JCO. 2022;40:1616.
4. Chi. JCO. 2021;39:2294. 5. Fizazi. Lancet. 2022;399:1695. 6. Smith. NEJM. 2022;386:1132.
Doublet therapy
decreases risk of
death by 34%-40%
vs ADT alone
Triplet therapy
decreases risk of
death by 25%-32%
vs ADT + docetaxel
alone
*In subgroup with metastatic disease.

ARASENS: Overall Survival by Disease Volume
Hussain. JCO. 2023;41:3595.
High-Volume Metastatic Disease Low-Volume Metastatic Disease
Patients
Who
Survived
(%)
Mo
Patients
Who
Survived
(%)
Mo
60
57
54
51
48
45
42
39
36
33
30
27
24
21
18
15
12
9
6
3
0
0
20
40
60
80
100
Placebo + ADT + docetaxel
Median, 42.4 mo (95% CI: 39.7-46.0)
Darolutamide + ADT + docetaxel
Median, NE (95% CI: 50.3 mo to NE)
HR: 0.69 (95% CI: 0.57-0.82)
57
54
51
48
45
42
39
36
33
30
27
21 24
18
15
12
9
6
3
0
0
20
40
60
80
100
Median, NE (95% CI: NE-NE)
Median, NE (95% CI: NE-NE)
HR: 0.68 (95% CI: 0.41-1.13)

ARASENS: Overall Survival by Risk Group
High-Risk Group Low-Risk Group
High-Risk Group Low-Risk Group
Overall
Survival
(%)
Overall
Survival
(%)
Mo Mo
0
20
40
60
80
100
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57
HR: 0.71 (95% CI: 0.58-0.86)
Median OS: 43.2 mo (95% CI: 40.0-48.9)
Median OS: NE (95% CI: NE-NE)
57 60
54
51
48
45
42
39
36
33
30
27
24
21
18
15
12
9
6
3
0
0
20
40
60
80
100
HR: 0.62 (95% CI: 0.42-0.90)
Hussain. JCO. 2023;41:3595.

CHAARTED Trial 8-Yr Follow-up: OS by Disease Volume
 Median follow-up of 9.7 yr in patients with metastatic hormone-sensitive prostate cancer randomized to
receive ADT + docetaxel vs ADT alone (N = 790)
Tripathi. ASCO 2022. Abstr 5081.
De Novo High-Volume Disease De Novo Low-Volume Disease
Survival
Probability
Survival
Probability
Mo Mo
OS Rate, %
ADT + docetaxel 28.5
ADT alone 15.4
HR: 0.67 (95% CI: 0.53-0.84; P = .0005)
OS Rate, %
ADT alone 40.9
HR: 0.77 (95% CI: 0.51-1.18; P = .23)
Survival
Probability
Survival
Probability
Mo
Mo
Metachronous High-Volume Disease Metachronous Low-Volume Disease
OS Rate, %
ADT alone 19.8
HR: 0.84 (95% CI: 0. 49-1.46; P = .54)
OS Rate, %
ADT alone 64.2
HR: 1.65 (95% CI: 0.95-2.87; P = .07)
ADT + docetaxel
ADT alone
ADT + docetaxel
ADT alone
ADT + docetaxel
ADT alone
ADT + docetaxel
ADT alone
1.0
0.8
0.6
0.4
0.2
0
0 25 50 75 100 125
1.0
0.8
0.6
0.4
0.2
0
0 25 50 75 100 125
1.0
0.8
0.6
0.4
0.2
0
0 25 50 75 100 125
1.0
0.8
0.6
0.4
0.2
0
0 25 50 75 100 125 150

ARASENS: OS by Metastatic Stage at Diagnosis
OS
(%)
HR for death:
0.71 (95% CI: 0.59-0.85)
HR for death:
0.61 (95% CI: 0.35-1.05)
Smith. NEJM. 2022;386:1132.
Recurrent Metastatic Disease
De Novo Metastatic Disease
Mo Since Randomization Mo Since Randomization
100
80
60
40
20
0
0 60
57
54
51
48
45
42
39
36
33
30
27
24
21
18
15
12
9
6
3
Darolutamide
Placebo
57
54
51
48
45
42
39
36
33
30
27
24
21
18
15
12
9
6
3
0
0
20
40
60
80
100
Darolutamide
Placebo

PEACE-1: Triplet Therapy With Abiraterone +
Docetaxel + ADT vs Docetaxel + ADT in de Novo mCSPC
Fizazi. Lancet. 2022;399:1695.
AAP + Doc +
ADT*
(n = 355)
Doc +
ADT*
(n = 355)
Median OS, yr NR 4.4
HR (95.1% CI) 0.75 (0.59-0.95; P = .017)
Patients at Risk, n
AAP + Doc + ADT* 355 328 287 183 98 25
Doc + ADT* 355 329 281 172 78 18
PEACE-1
Median f/u: 4.4 yr
OS
(%)
Yr Since Randomization
0
20
40
60
80
100
0 1 2 3 4 5
*With or without RT.
 Coprimary endpoints: rPFS and OS with 2x2
factorial design and hierarchical testing
PEACE-1*
Men with de novo mCSPC
with mets detected by CT,
MRI, or bone scan; ECOG PS
0/1 (2 if due to bone pain);
ADT for ≤3 mo before
randomization permitted
(N = 1173)
AAP + Doc +
ADT†
(n = 355)
Doc + ADT†
(n = 355)
Stratified by study site, ECOG PS (0 vs 1/2), disease burden
(LN only vs bone vs visceral mets), ADT type (GnRH agonist
vs antagonist vs surgery), planned docetaxel (yes vs no)
Dosing: Abi 1000 mg/day + pred 5 mg BID + doc 75 mg/m2 Q3W x 6 +
continuous ADT. RT given at 74 Gy in 37 fractions after doc.
*2 other arms not shown: ADT + RT (n = 116), ADT alone (n = 118).
†With or without RT.

ARASENS: Safety
Selected Grade 3/4
AE, n (%)
Darolutamide +
ADT + Docetaxel
(n = 652)
Placebo + ADT +
Docetaxel
(n = 650)
Neutropenia 220 (33.7) 222 (34.2)
Febrile neutropenia 51 (7.8) 48 (7.4)
Hypertension 42 (6.4) 21 (3.2)
Anemia 31 (4.8) 33 (5.1)
Pneumonia 21 (3.2) 20 (3.1)
Hyperglycemia 18 (2.8) 24 (3.7)
Increased ALT 18 (2.8) 11 (1.7)
Increased AST 17 (2.6) 7 (1.1)
Increased weight 14 (2.1) 8 (1.2)
UTI 13 (2.0) 12 (1.8)
Safety Outcome,
n (%)
Darolutamide +
ADT + Docetaxel
(n = 652)
Placebo + ADT +
Docetaxel
(n = 650)
Any AE 649 (99.5) 643 (98.9)
Worst grade
 1 28 (4.3) 35 (5.4)
 2 162 (24.8) 169 (26.0)
 3 248 (38.0) 232 (35.7)
 4 183 (28.1) 181 (27.8)
 5 27 (4.1) 26 (4.0)
Serious AE 292 (44.8) 275 (42.3)
AE leading to permanent
d/c of trial agent
 Darolutamide or
placebo
 Docetaxel
88 (13.5)
52 (8.0)
69 (10.6)
67 (10.3)
Smith. NEJM. 2022;386:1132.

Selected Randomized Phase II, III Trials in
Oligometastatic Prostate Cancer
NCT Number Acronym Interventions Outcome Phase
Planned
Enrollment
NCT03940235 RADIOSA SBRT ± ADT PFS II 150
NCT04443062 Bullseye 177Lu-PSMA-617 vs SoC
Disease progression
(PSA or clinical)
II 58
NCT04641078 DART SBRT ± darolutamide MFS II 124
NCT05053152
NRG
PROMETHEAN
Relugolix + SBRT vs SABR rPFS II 260
NCT05223803 TERPS Best systemic therapy + primary prostate radiation ± SABR MDT 2-yr FFS II 122
NCT04115007 PRESTO SoC + SBRT vs SoC CRPC-free survival III 350
NCT04983095 METRO SBRT + ADT + local RT vs ADT + local RT FFS III 114
NCT05352178 SPARKLE MDT + 1 mo ADT or MDT + 6 mo ADT + enzalutamide vs MDT alone Poly-MFS III 873
NCT05404139 Enzalutamide + SoC SBRT + ADT vs SoC SBRT + ADT PFS II 66
NCT03143322 STEREO-OS Systemic therapy + SBRT vs systemic therapy PFS III 196
NCT04423211 INDICATE
EBRT/goserelin/leuprolide/apalutamide ± RT vs
EBRT/goserelin/leuprolide
PFS III 804

PSMA-PET Imaging in Patients With Early BCR
After Prostatectomy in Advanced Prostate Cancer
1. Gallium Ga 68 gozetotide PI. 2. Hofman. Lancet. 2020;395:1208.
3. Hennrich. Pharmaceuticals (Basel). 2021;14:713. 4. Piflufolastat F 18 PI.
5. Pienta. J Urol. 2021;206:52. 6. Pouliot. ASCO GU 2023. Abstr 61. 7. Flotufolastat F 18 PI.
Gallium Ga 68 Gozetotide (Illuccix)
 FDA approved for PET of PSMA+
lesions in men with PCa*†1
 Trials: PSMA-PreRP, PSMA-BCR,
VISION1
 Improved sensitivity, specificity
vs conventional imaging2
 Half-life: 68 min3
 Needs special generator, must
do batch production3
 UCLA and UCSF hold marketing
authorizations3
Flutufolastat F 18 (Posluma)7
lesions in men with PCa*
 Trials: LIGHTHOUSE and
SPOTLIGHT
 Half-life: 110 min
 Uses cyclotron
Piflufolastat F 18 (Pylarify)
lesions in men with PCa*4
 Trials: CONDOR, OSPREY4
 Improved specificity vs
conventional imaging5
 Offers actionable clinical utility
at lower PSA values6
 Half-life: 110 min4
 Uses cyclotron4
*With suspected metastasis who are candidate for initial definitive treatment or with suspected recurrence per elevated serum PSA levels.
†For selecting patients with metastatic prostate cancer for whom 177Lu-PSMA-617 is indicated.

Mo
100
80
60
40
20
0
0 6 12 18 24 30 36 42 48 54 60
Final OS Results for Phase III Trials of
AR Inhibition + ADT in mHSPC
1. Fizazi. Lancet. 2019;20:686. 2. Armstrong. JCO. 2022;40:1616. 3. Chi. JCO. 2021;39:2294.
AAP + ADT Pbo + ADT
Median OS, mo 53.3 36.5
HR (95% CI) 0.66 (0.56-0.78; P <.0001)
OS
(%)
Enza + ADT Pbo + ADT
Median OS, mo NR NR
HR (95% CI) 0.66 (0.53-0.81; P <.0001)
Apa + ADT Pbo + ADT
Median OS, mo NR 52.2
HR (95% CI) 0.65 (0.53-0.79; P <.0001)
Cross-trial comparisons have significant limitations. This information is presented to
generate discussion, not to make direct comparisons among study results.
LATITUDE: ADT + Abiraterone
vs ADT (N = 1199)1
Median f/u: 51.8 mo
TITAN: ADT + Apalutamide
vs ADT (N = 1052)3
Median f/u: 44.0 mo
ARCHES: ADT + Enzalutamide
vs ADT (N = 1150)2
Median f/u: 44.6 mo
Mo
100
80
60
40
20
0
0 6 12 18 24 30 36 42 48 54 60 66
Mo
100
80
60
40
20
0
0 6 12 18 24 30 36 42 48 54 60

Systemic Therapy for Metastatic
Hormone-Sensitive Prostate Cancer 2023
Patients
with
mCSPC
Abiraterone or apalutamide or enzalutamide
If chemotherapy is
not preferred*
If chemotherapy is
preferred*
+ local therapy to primary (SWOG-S1802)1
+ RT to oligomets (STAMPEDE,2 PLATON3)
Docetaxel + abiraterone or docetaxel + darolutamide4
Denosumab 60 mg SC every 6 mo
Zoledronic acid 5 mg IV/yr
Alendronate 70 mg PO/wk
*Considerations
for
chemotherapy
preference
1. NCT03678025. 2. Clarke. Ann Oncol. 2019;30:1992. 3. NCT03784755. 4. Smith. ASCO 2022. Abstr 13.
5. Gravis. Eur Urol. 2018;73:847. 6. Velez. Prostate Cancer Prostatic Dis. 2021;[Epub]. 7. Hamid. Ann Oncol. 2021;32:1157.
ADT plus:
For men with a 10-yr risk of hip fracture of ≥3% based on the FRAX algorithm
 Chemotherapy fitness, symptom burden, cost/insurance coverage, patient preference
 Low- vs high-volume disease, prior local therapy vs no5
 Histologic/molecular features
‒ Poorly differentiated, low PSA producing
‒ Genetic features6
‒ Gene expression profiling7

Cardiovascular Assessments Needed in
Patients With Prostate Cancer Receiving ADT
 In patients receiving ADT:
‒ In 2010, AHA, ACS, AUA recommend regular assessment
of CV risk factors (eg, BP, lipids, blood glucose)2
‒ In 2021, NCCN guidelines recommended screening and
intervention to prevent/treat diabetes and CVD3
 In a study of US veterans with prostate cancer,
including those initiating ADT, >30% did not get
comprehensive CV assessment1
1. Sun. JAMA Netw Open 2021;4:e210070. 2. Levine. Circulation. 2010;121:833.
3. NCCN. Clinical practice guidelines in oncology: prostate cancer. v.1.2023. nccn.org.

Phase III EA8191 INDICATE: Defining Actionability of
PSMA PET in Biochemical Recurrence
Objectives
 For patients without PET evidence of extrapelvic metastases: to evaluate whether addition of enhanced
systemic therapy to SoC salvage RT can prolong PFS
 For patients with PET evidence of extrapelvic metastases: to evaluate whether addition of metastasis-directed
RT to enhanced systemic therapy and SoC salvage RT can prolong PFS
Current trial status: 116 patients enrolled (recently accruing ~6 per mo)
(N = 804)
Patients with PC and
biochemical recurrence
after radical prostatectomy;
negative or equivocal for
extrapelvic mets by
conventional imaging;
candidate for SoC RT + ADT;
ECOG PS 0-2
Step 0
SoC PET/CT
at baseline
PET negative for
extrapelvic mets
PET positive for
extrapelvic mets
Arm B: SoC Salvage Therapy +
Enhanced Systemic Therapy
Arm A: SoC Salvage Therapy
Arm C: SoC Salvage Therapy +
Enhanced Systemic Therapy
Arm D: SoC Salvage Therapy +
Enhanced Systemic Therapy +
Metastasis-Directed Therapy
PFS
Repeat PET/CT at
PSA recurrence or
12 mo after
completion of
systemic therapy
Step 1
Stratified by PET+ vs PET-
for intrapelvic LNs
Stratified by 1-5 vs >5
extrapelvic lesions
NCT04423211.

 Randomized phase III trial
 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
Shore. AUA 2023. Abstr LBA02-09.
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
Stratified by PSA (≤10 ng/mL vs >10 ng/mL), PSADT
(≤3 mo vs >3 to ≤9 mo), prior hormonal therapy (Y/N)
Yes
No

EMBARK Enzalutamide/Leuprolide vs
Leuprolide/Placebo: MFS
Enzalutamide
Combination
(n = 355)
Leuprolide
Acetate
(n = 358)
60.7
45 (13)
NR
(NR)
60.6
92 (26)
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
Leuprolide acetate
Mo
MFS
(%)
100
80
60
40
20
0
0 6 12 24
18 30 36 42 48 60
54 66 72 78 90
84 96
366
368
331
336
324
321
304
280
318
303
292
259
281
238
265
221
251
203
180
138
234
183
116
88
60
32
24
15
0
1
6
6
0
0
Enzalutamide combination
Leuprolide acetate

 Randomized, open-label phase III trial
 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
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.

 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
 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
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
Patients at Risk, n
LHRH
LHRH + APA
166 121 31 8 0
168 137 52 17 3
0 6 12 18 24 30 36 42 48
%
Without
Event
Mo
100
80
60
40
20
0
ARM
LHRH
LHRH +
APA + AAP
Events/Total
75/165
67/169
+ censor
Patients at Risk, n
LHRH
LHRH + APA + AAP
166 121 31 8 0
169 133 60 20 2
0 6 12 18 24 30 36 42 48
%
Without
Event
Mo
100
80
60
40
20
0

EMBARK: Selected AEs
AEs, %
Enzalutamide Combination
(n = 353)
Enzalutamide Monotherapy
(n = 354)
Leuprolide
(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

Metastasis-Directed Radiotherapy for
Oligometastatic Prostate Cancer
Ost. JCO. 2017;36:446. Phillips. JAMA Oncol. 2020;6:650. Siva. Eur Urol. 2018;74:455.
STOMP ORIOLE POPSTAR
Trial design
Multicenter, randomized
phase II
Multicenter, randomized
phase II
Single-center, single-arm
phase I
Patients
Recurrent PC; M1a-c;
1-3 extracranial metastases
(PET-CT)
Recurrent HSPC; M1a-b;
1-3 metastases (CT, MRI, or
radionucleotide bone scan)
Recurrent HSPC or CRPC;
M1a-b; 1-3 metastases
(PET-CT)
SABR number
treated
25 36 33
Dose 30 Gy/3 Fr 19.5-48.0 Gy/3-5 Fr 20 Gy/1 Fr
Efficacy ADT-FS: median 21 mo
PFS (by PSA, imaging,
symptomatic, or ADT):
81% at 6 mo
LPFS: 97% at 1 yr; 93% at 2 yr
DPFS: 58% at 1 yr; 39% at 2 yr

 Randomized phase II trial to assess whether SABR improves outcomes in men with
oligometastatic prostate cancer (1-3 asymptomatic mets ≤5.0 cm in largest axis)
ORIOLE: Metastasis-Directed Therapy
With PSMA PET Improves Outcomes
Phillips. JAMA Oncol. 2020;6:650.
Composite PFS Stratified by Study Arm PFS Stratified by Presence of Untreated Lesions
PFS
(%)
0 6 12 18 24
100
80
60
40
20
0
Patients at Risk, n
SABR
Observation
Mo
36
18
26
8
13
1
7
1
2
0
Observation
SABR
HR: 0.30 (95% CI: 0.11-0.81;
P = .002)
PFS
(%)
0 6 12 18 24
100
80
60
40
20
0
Mo
Patients at Risk, n
No untreated
Any untreated
19
16
14
7
10
1
6
1
2
0
Any untreated lesions
No untreated lesions
HR: 0.26 (95% CI: 0.09-0.76;
P = .006)

nmCRPC: Patient Case
 74-yr-old man
 2 yr post prostatectomy
 Nonmetastatic disease by conventional imaging
 PSA now 2.1 ng/mL with doubling time of 4 mo
 Patient has been receiving ADT

60
SPARTAN, PROSPER, and ARAMIS: OS
(Secondary Endpoint)*
1. Smith. Eur Urol. 2021;79:150. 2. Sternberg. NEJM. 2020;382:2197. 3. Fizazi. NEJM. 2020;383:1040.
*Caveat: comparing across trials is problematic; not a head-to-head comparison.
PROSPER2
SPARTAN1 ARAMIS3
HR: 0.73 (95% CI: 0.61-0.89; P = .001)
Median follow-up: 48 mo
Mo
100
80
60
40
20
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56
Darolutamide
Placebo
HR: 0.69 (95% CI: 0.53-0.88; P = .003)
Median follow-up: 29.1 mo
HR: 0.78 (95% CI: 0.64-0.96; P = .016)
Median follow-up: 52 mo
Enzalutamide
Placebo
Apalutamide
Placebo
OS
(%)
Mo
Mo
100
80
60
40
20
0
0 4 8 12162024283236404448 76
525660646872
100
80
60
40
20
0
0 4 8 12162024283236404448525660646872

SPARTAN, PROSPER, and ARAMIS: MFS
(Primary Endpoint)*
1. Smith. NEJM. 2018;378:1408. 2. Hussain. NEJM. 2018;378:2465. 3. Fizazi. NEJM. 2019;380:1235.
 Median MFS, mo: Apa 40.5 vs Pbo 16.2
 72% reduction of distant progression or
death
 24-mo additional MFS benefit
 Median MFS, mo: Enza 36.6 vs Pbo 14.7
death
HR: 0.29
(95% CI: 0.24-0.35;
P <.001)
PROSPER2
Mo
*Caveat: comparing across trials is problematic; not a head-to-head comparison.
HR: 0.28
(95% CI: 0.23-0.35;
P <.001)
SPARTAN1
Metastases-Free
Survival
(%)
Mo
100
80
60
40
20
0
44
40
36
32
28
24
20
16
4
0 12
8
100
80
60
40
20
0
44
40
36
32
28
24
20
16
4
0 12
8 48
ARAMIS3
Mo
HR: 0.41
(95% CI: 0.34-0.50;
P <.001)
Apa
Pbo
Enza
Pbo
Daro
Pbo
 Median MFS, mo: Daro 40.4 vs Pbo 18.4
death
100
80
60
40
20
0
42
39
36
30 33
27
24
21
18
3
0 12 15
9
6

PSMA PET: SNMMI “Appropriate Use” Criteria
Jadvar. J Nucl Med. 2022;63:59.
Scenario Description Rank Score
9 nmCRPC (M0) on conventional imaging Appropriate 7
3
Newly diagnosed unfavorable
intermediate‒risk, high-risk, or
very high‒risk PC
Appropriate 8
4
Newly diagnosed unfavorable
intermediate‒risk, high-risk, or very
high‒risk PC with negative/equivocal
or oligometastatic disease on
conventional imaging
Appropriate 8
6
PSA persistence or PSA rise from
undetectable level after radical
prostatectomy
Appropriate 9
7
PSA rise above nadir after definitive
radiotherapy
Appropriate 9
Scenario Description Rank Score
2
Very low‒, low-, and favorable
intermediate‒risk PC
Rarely
appropriate
2
1
Suspected PC (high/rising PSA levels,
abnormal digital rectal examination
results) evaluated for targeted biopsy
and detection of intraprostatic tumor
Rarely
appropriate
3
5
Newly diagnosed PC with widespread
metastatic disease on conventional
imaging
May be
appropriate
4
8
PSA rise after focal therapy of primary
tumor
May be
appropriate
5
11 Evaluation of response to therapy
May be
appropriate
5
10
Posttreatment PSA rise in mCRPC
setting
May be
appropriate
6

Current PSMA PET/CT Imaging Molecules
 PSMA PET/CT uses a radiolabeled PSMA-specific ligand to visualize the distribution
of PSMA
‒ Radioligands currently FDA approved for patients with suspected metastasis who are
candidates for initial definitive therapy or those with suspected recurrence based on
elevated serum PSA level
68Ga-PSMA-11 18F-DCFPyl 18F-rhPSMA-7.3
 Approved in Dec 2020 on
limited basis with follow-
up approval in Dec 2021
 Shorter half-life than 18F
 Included in FDA approval
for selection of patients
for 177Lu-PSMA-617
 Approved in May 2021
 Alternative to
68Ga-PSMA-11
 Longer half-life than 68GA
 Approved in May 2023
 New approval
 Longer half-life than 68GA
Gallium Ga 68 gozetotide PI. Piflufolastat F 18 PI. Flotufolastat F 18 PI.

mCRPC Patient Case
 65-yr-old man
 PSA: 380 ng/mL; Gleason 5 + 3
 Bone mets
 Prior therapy for mHSPC with docetaxel + ADT
 BRCA wild-type by germline and tumor testing

Overview of Advanced CRPC Options
Local
Disease
Biochemically
Recurrent
Radiographic Metastatic Disease
Castration Sensitive Castration Resistant
ADT ADT
Surgery/
Radiation Apalutamide
Enzalutamide
Darolutamide
Abiraterone
Enzalutamide
Docetaxel
Cabazitaxel
Radium-223
Sipuleucel-T
Olaparib
Rucaparib
Pembrolizumab
Yamada. Cancer Lett. 2021;519:20. Abou. Front Oncol. 2020;10:884.

OS With AR Inhibitors in mCRPC
1. Ryan. Lancet Oncol. 2015;16:152. 2. Armstrong. Eur Urol. 2020;78:347.
3. Fizazi. Lancet Oncol. 2012;13:983. 4. Scher. NEJM. 2012;367:1187.
34.7
30.3
36
31
15.8
11.2
18.4
13.6
0
10
20
30
40
Median
OS
(Mo)
COU-AA-3021
(N = 1088)
PREVAIL2
(N = 1717)
COU-AA-3013
(N = 1195)
AFFIRM4
(N = 1199)
Pre-docetaxel AR inhibition
reduces risk of death by 17%-19%
Post-docetaxel AR inhibition
reduces risk of death by 26%-37%
Abi/Pred Pbo/Pred Enza Pbo Abi/Pred Pbo/Pred Enza Pbo

Genetic Testing in Prostate Cancer
4
Pritchard. NEJM. 2016;375:443. Robinson. Cell. 2015;161:1215. The Cancer Genome Atlas. Cell. 2015;163:1022.
NCCN. Clinical practice guidelines in oncology: prostate cancer. v.1.2023. nccn.org. Lowrence. J Urol. 2020;205:14.
Lowrence. J Urol. 2020;205:22.
Somatic mutations in DNA
repair pathways in 19% of
localized and 23% of
mCRPC tumors
11.8% of men with mPC
have germline DNA-repair
gene mutations regardless
of family history
BRCA1 or BRCA2 and other
DDR germline mutations
associated with increased
risk of prostate cancer
ALL men with mPC should
receive genetic testing after
genetic counseling, regardless of
family history

 Docetaxel (first-generation taxane)
‒ Until 2010, only approved drug to improve OS
for mCRPC
‒ Appropriate for castration-sensitive disease in
select patients1
 Cabazitaxel (next-generation taxane)
‒ Improves OS in docetaxel-pretreated mCRPC2
‒ Improves QoL; reduces pain through
10 treatment cycles3
‒ Approved at lower dosage (20 mg/m2) in 2017
for patients with mCRPC previously treated
with docetaxel
‒ Growth factor support is recommended
Cabazitaxel
2010
Docetaxel
2004
Cyclophosphamide
1993
5-FU
1991
Mitoxantrone
1996
Taxanes in mCPRC
1. Parimi. Int J Urol. 2016;23:726. 2. de Wit. NEJM. 2019;381:2506.
3. Bahl. BJU Int. 2015;116:880.

177Lu-PSMA-617–Targeted Radioligand Therapy
 177Lu-PSMA-617 binds with
high affinity to PSMA on cell
membranes
 177Lu is a radioactive atom that
emits β particles, resulting in
prostate cancer cell death
177Lu
PSMA-617
177Lu-PSMA-617
DNA damage
Endocytosis
PSMA
Prostate cancer cell
Morris. ASCO 2021. Abstr LBA4.

PSMAfore: 177Lu-PSMA-617 vs Change in ARSI in
Patients With mCRPC and No Previous Taxane Therapy
 Open-label, multicenter, randomized phase III study
 Primary endpoint: rPFS
 Secondary endpoints: OS, safety, PFS, rPFS2 for crossover patients, ORR, DCR, DoR, PSA50-RR,
time to first SSE, time to PSA progression, time to soft-tissue progression, time to pain progression, QoL
Patients with mCRPC and
disease progression on prior
ARSI; no previous taxane in
CRPC or HSPC settings;
PSMA positive on
68GA-PSMA-11 PET/CT
(N = 469)
177Lu PSMA-617 Q6W x 6 cycles
Change in ARSI Therapy
(Abiraterone or Enzalutamide)
Stratified by prior ARSI in CRPC vs HSPC;
asymptomatic vs symptomatic
Crossover
allowed upon
radiographic
progression
Sartor. ASCO GU 2022. Abstr TPS211.

TheraP: 177Lu-PSMA-617 vs Cabazitaxel in mCRPC
 Randomized, open-label phase II trial of 177Lu-PSMA-617 vs
cabazitaxel in mCRPC
‒ PSMA SUVmax ≥20 on 68Ga-PSMA-11 + FDG PET/CT
 Primary endpoint: PSA50-RR
 PSA50-RR 29% greater (95% CI: 16-42; P <.0001) for 177Lu-PSMA-617
100
80
60
40
20
0
-20
-40
-60
-80
-100
Change
From
Baseline
(%)
Cabazitaxel (n = 101)
37% (95% CI: 27-46)
PSA Reduction ≥50% From Baseline
No
Yes
No postbaseline
PSA assessment
177Lu-PSMA-617 (n = 99)
66% (95% CI: 56-75)
Hofman. Lancet. 2021;397:797. Hofman. ASCO 2022. Abstr 5000.
PFS (PSA and Radiographic)
Cabazitaxel
177Lu-PSMA-617
177Lu-PSMA-617 delayed progression
HR: 0.62 (95% CI: 0.45-0.85; P = .0028)
Proportion
Event
Free
Mo
1.0
0.75
0.50
0.25
0
0 3 6 9 12 15 18 21 24
Proportion
Alive
Mo
1.0
0.75
0.50
0.25
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Cabazitaxel
177Lu-PSMA-617
HR: 0.97 (95% CI: 0.70-1.4; P = .99)
OS

Ongoing Phase III Trials of
PSMA-Targeting Radionuclides
 Additional radiopharmaceutical in phase I development: JNJ-69086420 (225Ac-hk2)
PSMAddition PSMAfore SPLASH ProstACT ECLIPSE
Clinical trial
number
NCT04720175 NCT04689828 NCT04647526 NCT04876651 NCT05204927
Therapy 177Lu-PSMA-617 177Lu-PSMA-617 177Lu-PNT2002
177Lu-DOTA-
rosopatamb
177Lu-PSMA-I&T
Setting mHSPC
mCRPC taxane
naive
mCRPC taxane
naive
mCRPC post
taxane therapy
mCRPC taxane
naive (for CRPC)
Primary endpoint rPFS rPFS rPFS rPFS rPFS
Estimated
patient
enrollment
1126 469 415 387 400

Phase III Trials of First-line PARP Inhibitor +
AR Inhibitor in mCRPC: PFS
MAGNITUDE1
1L mCRPC, HRR
prescreening
(N = 765)
HRRm+
Niraparib + AAP
Placebo + AAP
HRRm-
Closed following
prespecified futility
analysis
TALAPRO-23,4
1L mCRPC, prospective HRR
assessment required
(N = 1126)
Talazoparib +
Enzalutamide
Placebo +
Enzalutamide
Median rPFS per BICR in HRRm Cohort 24
NR
HR: 0.45 (95% CI: 0.33-0.61;
P <.0001)
13.8
Median rPFS per BICR in HRRm+ Cohort
16.5
HR: 0.73
(95% CI: 0.56-0.96; P = .022)
13.7
PROpel2
1L mCRPC,
no HRR screening required
(N = 796)
Olaparib + AAP
Placebo + AAP
Median ibPFS per Investigator in
HRRm+ Subgroup
NR
HR: 0.5 (95% CI: 0.34-0.73)
13.9
1. Chi. JCO. 2023;41:3339. 2. Clarke. NEJM Evid. 2022;1. 3. Agarwal. Lancet. 2023;[Epub]. 4. Fizazi. ASCO 2023. Abstr 5004.
May 31, 2023:
FDA approved for
deleterious/suspected
deleterious BRCAm
mCRPC
June 20, 2023:
FDA approved for HRR
gene–mutated mCRPC

Immunotherapy: Sipuleucel-T
 FDA approved for asymptomatic or
minimally symptomatic mCRPC
‒ Not recommended: visceral metastases,
small cell/NEPC, prior docetaxel and NHT
 Prolonged OS in clinical trial but cannot
determine benefit using routine testing
(PSA decline, scans)
‒ Most beneficial in less advanced disease
→ early use recommended
 AEs: chills, fatigue, pyrexia, nausea,
headache
Sipuleucel-T PI. NCCN. Clinical practice guidelines in oncology: prostate cancer. v.1.2023. nccn.org.
Kantoff. NEJM. 2010;363:411. Pieczonka. Rev Urol. 2015;17:203.
Phase III IMPACT:
OS in mCRPC (N = 512)
Placebo
Median OS:
21.7 mo
HR: 0.78 (95% CI: 0.61-0.98; P = .03)
Probability
of
OS
(%)
80
60
40
20
0
100
0 12 24 36 48 60 72
Sipuleucel-T (n = 341)
Placebo (n = 171)
Sipuleucel-T
Median OS: 25.8 mo
Mo Since Randomization

Radiopharmaceuticals: Radium-223
 FDA approved for CRPC with symptomatic bone mets and no known visceral mets
 Unlike β-emitting radioisotopes, radium-223, an α-emitting isotope, delivers less radiation to bone
marrow → fewer myelosuppressive AEs
 Most common AEs: bone pain, nausea, anemia (no between-group differences)
OS
HR: 0.70 (95% Cl: 0.58-0.83; P <.001)
Time to First Symptomatic Skeletal Event
HR: 0.66 (95% Cl: 0.52-0.83; P <.001)
0 3 6 9 12 15 18 21 24 27 30
Placebo
(median time to first SSE: 9.8 mo)
Radium-223
(median time to first SSE: 15.6 mo)
Patients
Without
SSE
(%)
Radium-223
(median OS: 14.9 mo)
Placebo
(median OS: 11.3 mo)
Survival
(%)
100
80
60
40
20
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39
ALSYMPCA: Symptomatic mCRPC With Bone Metastases1
100
80
60
40
20
0
Parker. NEJM. 2013;369:213. Radium-223 PI. Goyal. Cancer Lett. 2012;323:135.

TRITON3: rPFS in BRCA-Altered Subgroup
 Median rPFS in ITT population: 10.2 mo (95% CI: 8.3-11.2) with rucaparib vs 6.4 mo (95% CI: 5.6-8.2)
with physician’s choice (HR: 0.61; 95% CI: 0.47-0.80; P <.001)
Bryce. ASCO GU 2023. Abstr 18. Fizazi. NEJM. 2023;388:719.
Median rPFS,
Mo (95% CI)
Rucaparib (n = 201) 11.2 (9.2-13.8)
Physician’s Choice (n = 101) 6.4 (5.4-8.3)
rPFS
(%)
Mo
100
80
60
40
20
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Rucaparib
Physician’s Choice
Patients at Risk, n
Rucaparib
Physician’s Choice
201
(0)
101
(0)
169
(18)
69
(21)
124
(44)
42
(42)
83
(70)
19
(55)
55
(89)
9
(64)
41
(95)
4
(66)
27
(103)
3
(66)
16
(109)
0
(67)
13
(110)
10
(112)
7
(113)
6
(113)
3
(115)
2
(115)
2
(115)
0
(115)
HR: 0.50 (95% CI: 0.36-0.69; P <.0001)

CDK4/6 Inhibitor: Abemaciclib
Smith. ASCO GU 2023. Abstr TPS289. Smith. ASCO GU 2020. Abstr TPS5591.
CYCLONE 3: Randomized Phase III Study in High-Risk mHSPC
Patients with high-risk
mHSPC; ≥4 bone mets by
bone scan and/or
≥1 visceral met by
CT/MRI; ADT initiated;
ECOG PS 0/1
(planned N = 900)
Abiraterone +
Prednisone +
Abemaciclib
Abiraterone +
Prednisone +
Placebo
Stratified by de novo mHSPC, visceral metastasis, prior docetaxel
Primary
endpoint:
rPFS
CYCLONE 2: Randomized Phase II/III Study in mCRPC
Abiraterone +
Prednisone +
Abemaciclib
RP2D BID
Abiraterone +
Prednisone +
Placebo
BID
Randomized
2:2:1:1
Part 1: Lead-in (n = 30)
Abiraterone + Prednisone +
Abemaciclib 150 mg BID
Abemaciclib 200 mg BID
Placebo BID
Placebo BID
Part 2: RP2D
(planned n = 150)
Part 3: Adaptive
(planned n = 170)
Adaptive
interim
analysis
Stratified by residual disease, radiographic progression, docetaxel for mHSPC
Patients with
mCRPC by
radiographic and/or
PSA progression
during continuous
ADT/post
orchiectomy;
ECOG PS 0/1
(estimated N = 350)
Randomized
1:1
Abiraterone +
Prednisone +
Abemaciclib
RP2D BID
Abiraterone +
Prednisone +
Placebo
BID
Randomized
1:1
Abemaciclib: oral potent CDK4/6
inhibitor; approved for ER+/HER+ BC
Primary endpoint: rPFS

Agents Targeting the AR Pathway
 ARV-766: a bivalent chemical protein degrader
‒ Phase II enrolling patients with 1-3 prior NHTs and ≤2 prior CT
regimens (NCT05067140)
Gao. ASCO GU 2022. Abstr 17. Fizazi. ESMO 2022. Abstr 1364MO.
Bavdegalutamide (ARV-110): a bivalent chemical protein
degrader, degrades the androgen receptor
Phase I/II Trial in mCRPC After ≥2 Prior Tx
200
150
100
50
0
-50
-100
25
-25
-75
Best
%
PSA
Change
From
Baseline
Phase I
Phase II
AR R878X/H875 Positive
PSA50: 46%
PSA30: 57%
PSA30
PSA50
ODM-208: CYP11A1 inhibitor, suppresses
steroid hormone synthesis
CYPIDES Trial: Phase II Expansion in AR-LBDmut
mCRPC, Post ARSI and Post Taxane
Best PSA Change From Baseline
in Patients With AR-LBD Mutations
53% (24/45) of patients achieved serum PSA
reduction ≥50% from baseline
25
100
0
-25
-50
-75
Best
PSA
Change
(%)
75
50
-100
Previous Medication
Abiraterone
Enzalutamide
Both
Neither

CAR T-Cell Therapy for mCRPC
 Phase I trial of PSCA-targeted CAR  Phase I trial of P-PSMA-101 CAR T-cell (N = 17;
data presented for n = 14)
Dorff. ASCO 2023. Abstr 5019. Slovin. ASCO GU 2022. Abstr 98.
 DLT is cystitis
 Phase Ib ongoing: NCT05805371
Responses
Mo
0 3 6 12
9 15 18 21 24 30
27 33
Treatment Response Time Course Events
Death
Lost to follow-up
PI decision
Required disallowed therapy
Survival post progression
Stable disease
CAR T-cell infusion to eval
Lymphodepletion
Mo
Cohort 2
Cohort 1
Cohort -1
PSA response (≥30% decrease)
PSA response (≥50% decrease)
PSA progression
Deceased
Continuing PTFU
Patients
0 1 2 3 4 5 6 7 8 9
Responses
 Low doses of P-PSMA-101 induced durable
responses (PSA, radiographic)
 Any-grade CRS: 57%; 14% grade ≥3

Bispecific T-Cell‒Engaging Antibodies in mCRPC
1. Tran. ESMO 2020. Abstr 609O. 2. Zhang. ASCO GU 2021. Abstr TPS174.. 3. Danila. ASCO 2022. Abstr TPS5101.
4. Lim. Clin Genitourin Cancer. 2023;21:366. 5. de Bono. ASCO 2021. Abstr 5013.
T-cell
Tumor cell
Tumor cell antigen
CD3 or CD28
Agent Targets Ongoing Clinical Trials
Acapatamab1 PMSA x CD3 Phase I/II, NCT04631601,
active not recruiting
REGN56782 PMSA x CD28 Phase I/II with cemiplimab,
NCT03972657, enrolling
AMG 5093 STEAP-1 x CD3 Phase I, NCT04221542, enrolling
JNJ-0814 PMSA x CD3 Development deprioritized due to
toxicity and limited efficacy
HPN4245 PSMA x CD3 Development discontinued

LuPARP: Dose-Finding Study of
Olaparib + 177Lu-PSMA-617 in mCRPC
 Phase I trial in mCRPC post ARSI and docetaxel, PSMA SUVmax >15 at any site,
SUVmax >10 at other sites, no FDG discordance (N = 48)
 Primary endpoints: MTD, DLT, RP2D of olaparib
Sandhu. ASCO 2023. Abstr 5055.
 PSA-RR: 66%
 PSA ≥90% response: 44%
 ORR: 78%
 No DLT
 RP2D: 7.4 Gb 177Lu-PSMA-617
+ olaparib 300 mg BID Days -4 to
18; 6-wk cycle
Patients in cohorts 8 and 9 are early in treatment cycles.
Cohort 1: 50 mg Day 2-15
Cohort 7: 200 mg Day -4 to 14
PSA Response by Dosing Cohort
Maximum
PSA
Change
From
Cycle
1
Day
1
(%)
100
80
60
40
20
0
-100
-80
-60
-40
-20
Patients
5 10 15 20 25 30

CONTACT-02: Cabozantinib + Atezolizumab vs
Second NHT in mCRPC
 Multicenter, randomized, open-label phase III study
 Primary endpoints: PFS (BIRC), OS
 Key secondary endpoint: ORR (BIRC)
mCRPC treated with prior
NHT; measurable visceral
or extrapelvic
adenopathy; PSA
progression and/or
soft tissue disease
progression; ECOG PS 0/1
(N = 580)
Cabozantinib 40 mg PO QD +
Atezolizumab 1200 mg IV Q3W
Second NHT*
Enzalutamide 160 mg PO QD or
Abiraterone† 1000 mg PO QD
*Second NHT must differ from previous NHT.
†Abiraterone was given in combination with prednisone/prednisolone 5 mg QD.
Liver mets, prior docetaxel for mCSPC, disease stage for which
first NHT given (mCSPC, M0 CRPC, mCRPC)
Agarwal. ASCO GU 2021. Abstr TPS190.
Loss of clinical benefit or
unacceptable toxicity

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