Emerging Targeted Combinations for Prostate Cancer

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
Emerging Investigational Targets and Combinations
Supported by educational grants from Exelixis, Inc.; Lilly; and Pfizer, Inc.

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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, Bayer,
Bristol-Myers Squibb, Calithera, Caris, Dendreon, Exelixis, Johnson & Johnson,
Lilly, Merck, Myovant, Novartis, Pfizer, Sanofi, SeaGen, Sorrento Therapeutics,
Telix, Tempus; researcher: AstraZeneca, Bayer, Tempus.

pRB
Cyclin D1 and CDK4/6 Drive Cellular Proliferation
Downstream of Signaling Pathways
Lange. Endocr Relat Cancer. 2011;18:C19. Kundsen. Trends Cancer. 2017;3:39. Otto. Nat Rev Cancer.
2017;17:93. Corona. Drug Des Devel Ther. 2018.12:321. Tripathy. Clin Cancer Res. 2017;23:3251.
Gene
transcription
G2 S
M G1
Inactive
Active tumor
suppressor
E2F
E2F
Restriction point
p16
p21
p53
CDK4/6
Cyclin D
CDK2
Cyclin E
pRB
P P P
G0
Pl3K/Akt
STATs MAPKs
ER/PR/AR Wnt/β-catenin
NF-κB
FGFR
■ The CDK4/6-Rb-axis is a critical modulator of cell cycle
progression and is commonly altered in cancers
■ CDK4/6 associated with D-type cyclins to drive
progression through the G1/S restriction point by
phosphorylating and inactivating the tumor
suppressor Rb

Comparison of Available CDK4/6 Inhibitors
Abemaciclib1 Ribociclib2 Palbociclib3
Route PO PO PO
Dosing schedule Continuous 3 wk on/1 wk off 3 wk on/1 wk off
Disease state(s) with
FDA approval
HR+/HER2- EBC
HR+/HER2- MBC
HR+/HER2- MBC HR+/HER2- MBC
Preliminary/published
activity in prostate cancer
TBD Yes4 No5
Selected ongoing
clinical trials
NCT04408924 (CYCLONE 1)
NCT05113537 (UPLIFT)
NCT04751929
NCT02555189 NCT02905318
Notable toxicities Neutropenia, diarrhea, ILD
Neutropenia, QTc prolongation,
hepatotoxicity, ILD
Neutropenia, ILD
1. Abemaciclib PI. 2. Ribociclib PI. 3. Palbociclib PI. 4. de Kouchkovsky.
Clin Cancer Res. 2022;28:1531. 5. Palmbos. Clin Cancer Res. 2021;27:3017

CYCLONE 2: Abiraterone/Prednisone ± Abemaciclib in
mCRPC
 Multicenter, randomized, double-blind, placebo-controlled phase II/III study
 Primary endpoint: rPFS
 Key secondary endpoints: safety, ORR, time to symptomatic progression, time to PSA progression, OS, PK
Patients with
mCRPC by
radiographic and/or
PSA progression
during continuous
ADT/post
orchiectomy;
ECOG PS 0/1
(estimated N = 350)
Abiraterone* 1000 mg QD
+ Abemaciclib RP2D BID
+ Placebo BID
2:2:1:1
Part 1 Lead-in (N = 30)
Abiraterone* 1000 mg QD +
Abemaciclib 150 mg BID
(n = 10)
Abemaciclib 200 mg BID
(n = 10)
RP2D
designation
and second
randomization Abiraterone* 1000 mg QD
+ Abemaciclib RP2D BID
Patients will receive study treatment until radiographic or symptomatic PD or
unacceptable toxicity
*All patients received abiraterone plus prednisone/prednisolone 5 mg BID.
†If prespecified adaptive expansion criteria met at an Adaptive Interim
analysis, Part 3 will open
Placebo BID
(n = 5)
Placebo BID
(n = 5)
Part 2 RP2D (planned N = 150) Part 3 (planned N = 170)
Adaptive
interim
analysis† and
third
randomization
+ Placebo BID
Residual disease,
radiographic progression,
docetaxel for mHSPC
Smith. ASCO 2022. Abstr TPS198.

CYCLONE 3: Abiraterone/Prednisone ± Abemaciclib in
High-Risk mHSPC
 Multicenter, randomized, double-blind, placebo-controlled phase III study
 Primary endpoint: rPFS (investigator assessed)
 Key secondary endpoints: rPFS (BICR), OS, PK
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
de novo mHSPC, visceral
metastasis, prior docetaxel
McKay. ESMO 2022. Abstr 1423TIP. NCT05288166.
Radiographic PD or

UPLIFT: Abemaciclib Before 177Lu-PSMA-617 in mCRPC
 Nonrandomized, open-label phase I/II study
 Primary endpoints: RP2D (Part A), safety (Part A), change in maximum SUV at
3 lesions (Part B)
Abemaciclib Days 1-14 +
177Lu-PSMA-617 IV Day 15
Q6W for up to 4 cycles
Patients with mCRPC
and PSMA PET
positive disease
(≥3 lesions); prior
ARTA; prior taxane
therapy;
ECOG PS 0-2
(planned N = 30)
RP2D Abemaciclib Days 1-14 +
177Lu-PSMA-617 IV Day 15
Q6W for up to 4 cycles
NCT05113537.
Part A: Escalation Part B: Expansion
Absence of
disease, PD, or
unacceptable
toxicity

Multicenter, Open-Label Phase II Study of Abemaciclib ±
Atezolizumab for mCRPC
 Preclinical synergy noted in studies of CDK4/6i and PD-1/PD-L1 therapy; loss of function alterations of
CDK12 (found in 5%-7% of mCRPC) may confer vulnerability to anti–PD-L1 agents
Rao. GU ASCO 2022. Abstr TPS213.
Adult patients
with unselected
mCRPC; prior
ARTA; taxane
ineligible; ECOG
PS 0/1
(N = 54)
Abemaciclib
(n = 15)
Atezolizumab + Abemaciclib
(n = 15)
Stage 1 Arm A*
Abemaciclib
(planned n = 12)
(planned n = 12)
Interim efficacy
analysis
Stage 2 Arm A*
Exploratory, single stage; Arm C*
Adult patients with
mCRPC with CDK12
loss; prior ARTA;
taxane ineligible;
ECOG PS 0/1
(N = 21)
*All cycles are 21 days.
Stage 1 Arm B* Stage 2 Arm B*
Abemaciclib
(n = 5)
(n = 16)
PD or
intolerance
PD or
intolerance
 Primary endpoints: 6-mo PFS, ORR
 Secondary endpoints: clinical benefit rate,
DoR, OS, safety

Ribociclib + Docetaxel/Prednisone in mCRPC
 Multicenter, open-label phase Ib/II study of
ribociclib in combination with docetaxel/
prednisone
‒ Docetaxel 60 mg/m2 every 21 days
‒ Ribociclib 400 mg/day (Days 1-4, 8-15)
‒ Filgrastim (Days 5-7)
 43 patients total enrolled (N = 30 in phase II)
 Phase II primary endpoint: 6-mo rPFS
‒ 6-mo rPFS rate: 65.8% (95% CI: 50.6-85.5;
P = .005)
‒ Median rPFS: 8.1 mo (95% CI: 6-10.mo)
 32% of evaluable patients achieved PSA50
response
Patients
Mo
0 2 4 6 8 10 12 14 16 18 20 22 24
Ribociclib + docetaxel
Maintenance ribociclib
Partial response
PSA50
Adverse event
Subject withdrawal/physician decision
Progression
de Kouchkovsky. Clin Cancer Res. 2022;28:1531.

PI3K/AKT/MTOR Pathway and Crosstalk With AR Signaling
Growth factors
RTK
PI3K
P-AKT
mTOR
AKT
Inhibition
PTEN
PHLPP
PHLPP
degradation
Proliferation & progression
through PI3K/AKT dependent
signaling
Growth factors
RTK
(HER2/3)
T
T
Abiraterone
AR AR
AR Targeted genes
FKBP5
Differentiation
& survival
RAS/RAF/ERK
signaling
AR transcription
factor activity
 Aberrant activation of
the PI3K/AKT pathway
predominately due to
PTEN loss is common in
prostate cancer
especially in later stages
 AR signaling and AKT
pathway are reciprocally
cross-regulated so that
inhibition of one leads
to upregulation of the
other
Fizazi. ASCO GU 2021. Abstr TPS 178.

IPATential150: Ipatasertib ± Abiraterone in mCRPC
 Randomized, double-blind, placebo-controlled phase III study
 Primary endpoint: investigator-assessed rPFS in ITT and PTEN-loss (IHC)
 Secondary endpoints: OS, time to pain progression, time to chemotherapy initiation, ORR,
investigator-assessed rPFS in PTEN-loss (NGS)
Asymptomatic or mildly
symptomatic mCRPC
(N = 1101)
Ipatasertib 400 mg PO QD +
Abiraterone 1000 mg PO QD*
Placebo+
Abiraterone 1000 mg PO QD*
Tumor PTEN loss, prior
docetaxel, liver/lung mets,
geographic region
*Prednisone/prednisolone 5 mg BID was administered with
abiraterone.
Sweeney. Lancet. 2021;398:131.
Radiographic progression of
disease

IPATential150: Ipatasertib + Abiraterone Improves rPFS
PFS in the ITT Population
PFS in the PTEN Loss by IHC Population
Mo
Events,
n
124
154
Median PFS,
Mo (95% CI)
18.5 (16.3-22.1)
16.5 (13.9-17.0)
1-Yr PFS,
% (95% CI)
64.4 (58.3-70.5)
63.3 (57.3-69.3)
Ipat/abi (n = 260)
Pbo/abi (n = 261)
PFS
(%)
Stratified HR: 0.77 (95% CI: 0.61-0.98;
P = .034)
Mo
0 3 6 9 12 15 18 21 24 27 30 33
0
20
80
100
40
60
Events,
n
252
306
Median PFS,
Mo (95% CI)
19.2 (16.5-22.3)
16.6 (15.6-19.1)
1-Yr PFS,
% (95% CI)
65.3 (61.1-69.5)
63.0 (58.9-67.1)
Ipat/abi (n = 547)
Pbo/abi (n = 554)
PFS
(%)
0 3 6 9 12 15 18 21 24 27 30 33
0
20
80
100
40
60
Stratified HR: 0.84 (95% CI: 0.71-0.99;
P = .043)

IPATential150: Biomarker Assessments by NGS
PFS in the PTEN Loss by NGS
Events, n
47
70
Median PFS,
Mo (95% CI)
19.1 (13.9-NE)
14.2 (10.9-18.7)
Ipat/abi (n = 105)
Pbo/abi (n = 103)
Mo
PFS
(%)
Stratified HR: 0.65 (95% CI: 0.45-0.95)
0 3 6 9 12 15 18 21 24 27 30 33
0
20
80
100
40
60
PFS in PIK3CA/AKT1/PTEN Altered by NGS
Events, n
56
83
Median PFS,
Mo (95% CI)
19.3 (16.4-NE)
14.1 (11.1-18.4)
Ipat/abi (n = 105)
Pbo/abi (n = 103)
Mo
PFS
(%)
Stratified HR: 0.63 (95% CI: 0.44-0.88)
0
20
80
100
40
60
0 3 6 9 12 15 18 21 24 27 30 33

IPATential150: Ipatasertib + Abiraterone Resulted in
Increased Toxicity
1. de Bono. ESMO 2020. Abstr LBA4. 2. Sternberg. ESMO 2021. Abstr 585P.
Safety Summary1
Ipatasertib +
Abiraterone
(n = 551)
Pbo +
Abiraterone
(n = 546)
Median tx duration,
mo (range)
 Ipatasertib or Pbo
 Abiraterone
11.1 (0-31)
14.2 (0-31)
14.0 (0-32)
14.0 (0-32)
Any grade AE, n (%)
 Grade 3/4
 Grade 5
548 (99.5)
386 (70.1)
24 (4.4)
519 (95.1)
213 (39.0)
20 (3.7)
Serious AEs, n (%) 218 (39.6) 124 (22.7)
AEs leading to dose
modifications, n (%)
 Ipat/Pbo discontinuation
 Ipat/Pbo dose reduction
 Ipat/Pbo dose interruption
 Abiraterone discontinuation
116 (21.1)
220 (39.9)
319 (57.9)
47 (8.5)
28 (5.1)
34 (6.2)
125 (22.9)
22 (4.0)
Diarrhea
Hyperglycemia
Rash
Transaminase
increase
Ipatasertib Placebo
Median Range
Duration
onset
Time
to
Duration
onset
Time
to
Duration
onset
Time
to
Duration
onset
Time
to
Patients With Recurrence After Pbo or Ipat Dose
Reduction Because of Selected AE, n/N (%)2
Patients
With AE, n
Patients
With AE
Resolution,
n (%)
123
440
117 (95)
362 (82)
100
264
68 (68)
198 (75)
62
228
51 (82)
207 (91)
68
131
56 (82)
123 (94)
0/1 (0)
11/34 (32)
3/14 (21)
18/47 (38)
0
8/36 (22)
0/3 (0)
0/6 (0)
400 mg to
300 mg
0
5/17 (29)
1/2 (50)
6/20 (30)
0
0/7 (0)
0
0/1 (0)
300 mg to
200 mg
0
2/5 (40)
0
0/1 (0)
0
0
0
0/1 (0)
400 mg to
200 mg
Days
0 200 400 600 800 1000
8 1-560
69 1-902
4 1-491
27 1-948
29 1-710
104 1-657
57 1-853
43 1-923
21 1-916
70 2-638
27 1-848
24 1-743
43 1-421
56 8-645
43 8-869
31 1-469

ProCAID: Docetaxel/Prednisone ± Capivasertib in
mCRPC
 Randomized, double-blind, placebo-controlled phase II trial
1. Crabb. JCO. 2021;39:190. 2. Crabb. European Urology. 2022;82:512.
PFS and OS With Respect to Primary Biomarker Status
Outcome
Capivasertib, Mo
(95% CI)
Placebo, Mo
(95% CI)
HR (95% CI)
P
Value
Median PFS 7.03 (6.28-8.25) 6.7 (5.52-7.36) 0.92 (0.65-1.31) .32
Median PFS,
biomarker
positive (n = 44)
7.75 (6.44-9.63) 7.98 (5.09-9.82) 1.17 (0.61-2.23)
Median PFS,
biomarker
negative (n = 92)
7.03 (4.21-8.25) 6.34 (4.76-7.13) 0.89 (0.57-1.37)
Median OS 31.15 (20.07-NR) 20.27 (17.51-24.18) 0.54 (0.34-0.88) .01
mOS, biomarker
positive
26.87 (14.59-NR) 20.27 (12.91-35.71) 0.62 (0.26-1.47)
mOS, biomarker
negative
32.43 (18.5-NR) 20.30 (16.82-24.18) 0.54 (0.30-0.99)
PFS1
PFS
Mo
Capivasertib
Placebo
HR: 0.92 (80% CI: 0.73-1.16)
0 3 6 9 12 15 18 21 24 27
0
0.25
0.75
1.00
0.50
ITT OS2
OS
Mo
0
0.25
0.75
1.00
0.50
HR: 0.70 (95% CI: 0.47-1.05)
0 6 12 18 24 30 36 42 48 54
Capivasertib
Placebo
*Composite biomarker subgroup for PI3K/AKT/PTEN pathway activation status.

CAPItello-281: Abiraterone/Prednisone ± Capivasertib
in mHSPC With PTEN Deficiency
 Multicenter, randomized, double-blind, placebo-controlled phase III study
 Primary endpoint: investigator-assessed rPFS
 Secondary endpoints: OS, TFST, SSE-FS, TTTP
de novo mHSPC (≥1 bone
lesion) without brain
mets or spinal cord
compression; PTEN
deficiency; ECOG PS 0/1
(N = 1000)
Capivasertib400 mg BID* QD +
Abiraterone 1000 mg PO QD†
Abiraterone 1000 mg PO QD † +
Placebo
*Capivasertib is administered 4 days on, 3 days off of a 28-day cycle.
†Abiraterone was given in combination with prednisone/prednisolone 5 mg QD.
Fizazi. ASCO GU 2021. Abstr TPS 178. NCT04493853.
PD or
intolerance

Cabozantinib Promotes an Immune-Permissive TME
Macrophage
MHC-I
MDSC
Regulatory T-cell
CD8+ T-cell
Neutrophil
Agarwal. ASCO GU 2021. Abstr TPS190.
TAM Kinase (TYRO3, AXL, MER) Inhibition
 Circulating and tumor-infiltrating CD8+ T-cells
increased
 Promotes macrophage phenotype transition
from M2 to M1
AXL Inhibition
 Tumor MHC class I expression increased
MET Inhibition
 Blocks MET-induced tumor
expression of PD-L1
 Immunosuppressive neutrophil
mobilization blocked
VEGFR2 Inhibition
 Function/number of regulatory
T-cells and MDSCs decreased

COSMIC-021 Expanded mCRPC Cohort: Cabozantinib +
Atezolizumab
 Multicenter, multicohort phase Ib study
 Primary endpoint: investigator-
assessed ORR per RECIST v1.1
 Secondary endpoint: safety
(AEs and AEs of special interest)
Cabozantinib 40 mg QD PO +
Atezolizumab 1200 mg Q3W IV
(n = 30)
Patients with mCRPC and
radiographic progression in soft
tissue after enzalutamide
and/or abiraterone, measurable
disease (RECIST v1.1), ECOG
PS 0/1, no prior chemotherapy
(except docetaxel for mCSPC)
(N = 132)
 Exploratory endpoints: PFS, OS,
biomarker analyses
 ORR, PFS also analyzed by BIRC
Agarwal. ESMO 2021. Abstr LBA24. Agarwal. Lancet Oncol. 2022;23:899.
First extended
enrollment
(n = 50)
Second extended
enrollment
(n = 50)
‒ Tumor assessments per RECIST v1.1 Q6W for first year, then Q12W;
treatment until loss of clinical benefit or unacceptable toxicity
‒ Key subgroup: visceral metastases/extrapelvic lymphadenopathy

COSMIC-021 mCRPC Cohort: Baseline Characteristics
Characteristic
mCRPC
(N = 132)
Median age, yr (range) 70 (64-75)
ECOG PS 0/1, % 52 / 48
Gleason score ≥8 at diagnosis, % 53
Prior prostatectomy, % 41
Prior systemic anticancer therapy, %
 Prior docetaxel for mCSPC
 1 prior novel hormonal therapy
 2 prior novel hormonal therapies
25
55
45
Characteristic, %
mCRPC
(N = 132)
Measurable visc/EPLN
 Visc
 EPLN
77
32
60
Metastatic sites per CT/MRI
 Lymph node
 Bone
 Lung
 Liver
80
54
19
13
Bone metastases per bone scan 77
Agarwal. Lancet Oncol. 2022;23:899.

COSMIC-021 mCRPC Cohort: Response by RECIST v1.1
 PD-L1 status did not associate with response in 75 patients for whom status was known
 ORR patients with visceral mets: 18% (4/22); ORR patients with EPLN: 29% (17/59)
Response
Per Investigator Per BIRC
mCRPC
(N = 132)
Visc/EPLN
(n = 101)
mCRPC
(N = 132)
Visc/EPLN
(n = 101)
ORR, % (95% CI) 23 (17-32) 27 (18-37) 15 (10-22) 18 (11-27)
Best overall response, %
 CR
 PR
 SD
 PD
 Missing
2
21
61
14
2
2
25
61
11
1
0
15
66
17
2
0
18
66
15
1
Disease control rate, % 84 88 81 84
SD for ≥24 wk, % 17 21 27 32
Median DoR, mo (95% CI) 8.3 (4.6-11.0) 6.9 (4.2-9.8) 6.9 (4.1-8.4) 6.9 (4.1-9.5)
Median time to objective response, mo 1.7 1.7 2.8 2.8
Agarwal. Lancet Oncol. 2022;23:899.

0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12 15 18 21
COSMIC-021 mCRPC Cohort: PFS
Probability
of
PFS
Mo
Investigator Assessed
(All Patients)
Probability
of
PFS
Mo
BIRC Assessed
(All Patients)
0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12 15 18 21
mCRPC
Visc/EPLN
mCRPC
Visc/EPLN
Survival Outcome, Mo (95% CI)
mCRPC
(N = 132)
Visc/EPLN
(n = 101)
Median PFS
 By investigator
 By BIRC
5.5 (4.3-6.6)
5.7 (5.4-7.0)
5.6 (5.4-8.2)
6.8 (5.5-9.7)

COSMIC-021 mCRPC Cohort: OS
mCRPC
Visc/EPLN
Probability
of
OS
Mo
0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12 15 18 21 24 27 30 33
mCRPC
Visc/EPLN
Patients at Risk, n
132
101
124
95
105
83
78
64
48
42
35
31
27
23
13
10
9
8
5
4
2
2
0
0
Survival Outcome,
Mo (95% CI)
mCRPC
(N = 132)
Visc/EPLN
(n = 101)
Median OS 18.4 (14.3-24.7) 18.4 (13.6-24.7)

COSMIC-021 mCRPC Cohort: PSA Change From Baseline
Agarwal. ESMO 2021. Abstr LBA24.
 n = 118 with postbaseline
assessments
‒ PSA decrease: n = 55 (47%)
‒ PSA decrease ≥50%: n = 27
(23%)
 n = 92 with Visc/EPLN
‒ Decrease in PSA: n = 50
(54%)
‒ PSA decrease ≥50%: n = 24
(26%)
Best
Percent
Change
in
PSA
From
Baseline
PSA increase >100%
mCRPC without visc/EPLN
mCRPC with visc/EPLN
0
50
100
-50
-100

COSMIC-021 mCRPC Cohort:
Safety Overview and AEs of Special Interest
Agarwal. ESMO 2021. Abstr LBA24.
 High-dose steroids for AEs: n = 23 (17%)
Safety Outcome, %
mCRPC
(N = 132)
AEs leading to cabozantinib
dose reductions
43
AEs leading to atezolizumab
dose delays
43
Discontinuation of all study
treatment due to radiographic
progression
45
Discontinuation of study
treatment due to treatment-
related AEs
 Cabozantinib and/or
atezolizumab
 Cabozantinib
 Atezolizumab
 Both
21
18
14
10
AE of Special Interest, %
mCRPC (N = 132)
Any Grade Grade 3/4
Any AE of special interest 66.0 20.0
Rash 41.0 3.0
Hepatitis (diagnosis + lab abnormalities) 29.0 5.3
Hypothyroidism 15.0 0
Pancreatitis 14.0 6.1
Adrenal insufficiency 4.5 2.3
Colitis 3.8 3.0
Hyperthyroidism 3.8 0
Infusion-related reactions 2.3 0.8
Hepatitis (diagnosis) 1.5 0.8
Pneumonitis 1.5 0
Encephalitis 0.8 0.8
Myocarditis 0.8 0.8

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

CANOPY: Cabozantinib + Nivolumab in mCRPC
 Multicenter, single arm, 2-stage open label phase II trial
 Primary endpoint: rPFS per RECIST for soft tissue and PCWG3 for bone metastases
 Secondary endpoints: PSA per PCWG3, ORR per RECIST, OS
Cabozantinib 40 mg PO QD +
Nivolumab 480 mg IV Q4W
Patients with mCRPC; prior
treatment with docetaxel,
abiraterone and/or NHT;
no prior ICI therapy
(planned N = 50)
NCT05502315.
*Mandatory on-treatment biopsy during cycle 2.
Mandatory
baseline biopsy
rPD, toxicity, or
study withdrawal
28-Day Cycles*

Takeaway Messages
 CDK4/6 inhibition is a rational targeted therapy in prostate cancer
‒ Abemaciclib is being investigated in the Cyclone 1/2/3 trials
‒ Ribociclib 6-mo PFS rate of 65.8% vs docetaxel in mCRPC
 Ipatasertib has been tested in mCRPC in combination with abiraterone
and demonstrated improved rPFS particularly in patients with
PI3K/AKT/PTEN pathway alterations
 Other targeted therapies, particularly cabozantinib, are being
investigated in advanced prostate cancer

clinicaloptions.com/oncology
Go Online for More CCO
Coverage of Prostate Cancer!
CME-certified on-demand webcast of the live symposium presented prior to GU ASCO 2023
(coming soon!)
ClinicalThought commentary where experts answer key questions on emerging therapies in
prostate cancer (coming soon!)
Capsule slide summaries of key data from GU ASCO 2023 and expert analyses of the clinical
implications

Emerging Targeted Combinations for Prostate Cancer

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