New Hormonal Therapies Roberto The New era of CRPC: few targets for a pletora of agents! ADT Docetaxe l Abiratero ne Cabazita xel Alpharad in MDV3100 Sipuleuce l-T PD PD TAK700 Hormonal therapy Chemotherapy Radiometabolic therapy Immunotherapy Legend:
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New Hormonal Therapies Roberto Iacovelli The New era of CRPC: few targets for a pletora of agents! ADT Docetaxel Abiraterone Cabazitaxel Alpharadin MDV3100.
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New Hormonal Therapies Roberto Iacovelli
The New era of CRPC: few targets for a pletora of agents!
ADT Docetaxel
Abiraterone
Cabazitaxel
Alpharadin
MDV3100
Sipuleucel-T
PDPD
TAK700
Hormonal therapy
Chemotherapy
Radiometabolic therapy
Immunotherapy
Legend:
New Hormonal Therapies Roberto Iacovelli
Current strategies for androgen inibition in CRPC
AR
Abiraterone TAK700
BicalutamideMDV3100
LH-RHa
New Hormonal Therapies Roberto Iacovelli
Molecular basis for Androgen inibition in CRPC
Dillard et al. Mol Cell Endocrinol. 2008
Negative control
CRPC cells
Hormon sensitive
PCa
Il recettore per l’androgeno (AR) è espresso (RNA) sia nei tumori sensibili che resistenti alla castrazione
de Bono JS, et al. N Eng J Med. 2011;364:1995-2005. Scher HI, et al. ASCO GU 2011. Abstract 4.
*Most frequent cardiac disorders were tachycardia and atrial fibrillation.
New Hormonal Therapies Roberto Iacovelli
Abiraterone acetate
• Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites in 12 countries; USA, Europe, Australia, Canada
• Stratification by ECOG performance status 0 vs. 1
AA 1000 mg dailyPrednisone 5 mg BID
(Actual n = 546)
Co-Primary:
• rPFS by central review
• OS
Secondary:• Time to opiate use (cancer-
related pain)• Time to initiation of
chemotherapy• Time to ECOG-PS
deterioration• TTPP
Efficacy end points
Placebo dailyPrednisone 5 mg BID
(Actual n = 542)
RANDOMIZED
1:1
• Progressive chemo-naïve mCRPC patients(Planned N = 1088)
• Asymptomatic or mildly symptomatic
Patients
Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)
CRPC
chemo- naïve
New Hormonal Therapies Roberto Iacovelli
Abiraterone acetate
AA + P(n = 546)
Placebo + P(n = 542)
Median age, years (range) 71 (44-95) 70 (44-90)
Median time from initial diagnosis to first dose (years) 5.5 5.1
Median PSA (ng/mL) 42.0 37.7
Median testosterone (ng/dL) 4.0 4.0
Median alkaline phosphatase (IU/L) 93.0 90.0
Median hemoglobin (g/dL) 13.0 13.1
Median lactate dehydrogenase (IU/L) 187.0 184.0
Gleason score (≥8) at initial diagnosis 54% 50%
Extent of disease
Bone metastases
>10 bone lesions
Soft tissue or node
83%
48%
49%
80%
47%
50%
Pain (BPI Short Form)
0-1
2-3
66%
32%
64%
33%
Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)
CRPC
chemo- naïve Treatment Arms Evenly Matched
New Hormonal Therapies Roberto Iacovelli
Abiraterone acetate: PFS
100
80
60
40
20
00
Prog
ress
ion-
Free
(%)
3 6 9 15 1812
546542
489400
340204
16490
123
00
AAPL
4630
Time to Progression or Death (Months)
AA + PPL + P
AA + P (median, mos): NRPL + P (median, mos): 8.3
HR (95% CI): 0.43 (0.35-0.52)
P value: < 0.0001
CRPC
chemo- naïve
Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)
New Hormonal Therapies Roberto Iacovelli
Abiraterone acetate: OSCRPC
chemo- naïve
546542
538534
482465
452437
2725
00
524509
503493
02
120106
258237
412387
100
80
60
40
20
00
Surv
ival
(%)
3 12 15 27Time to Death (Months)
33
AA + PPL + P
6 9 30242118
AAPL
AA + P (median, mos): NRPL + P (median, mos): 27.2
HR (95% CI): 0.75 (0.61-0.93)
P value: 0.0097
Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)
New Hormonal Therapies Roberto Iacovelli
Abiraterone acetate: secondary end-points
AA + P Placebo + P
Median (months)
Median (months) HR (95% CI) P Value
Time to opiate use
(cancer related pain)NR 23.7
0.69
(0.57, 0.83)0.0001
Time to chemotherapy initiation
25.2 16.80.58
(0.49, 0.69)<0.0001
Time to ECOG PS deterioration
12.3 10.90.82
(0.71, 0.94)0.0053
Time to PSA progression
11.1 5.60.49
(0.42, 0.57)<0.0001
Patient Reported Outcomes favored AA +P vs. Placebo +P Full data to be reported
Note: All secondary end points remain significant after adjusting for multiplicity testing
CRPC
chemo- naïve
Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)
AA + P(n = 546)
n (%)
Placebo + P(n = 542)
n (%) No. with selected subsequent therapy for mCRPC
242 (44.3) 327 (60.3)
Docetaxel 207 (37.9) 287 (53.0)
Cabazitaxel 45 (8.2) 52 (9.6)
Ketoconazole 39 (7.1) 63 (11.6)
Sipuleucel-T 27 (4.9) 24 (4.4)
Abiraterone acetate* 26 (4.8) 54 (10.0)
*Prior to unblinding (e.g. not per protocol)
New Hormonal Therapies Roberto Iacovelli
Abiraterone acetate: Subsequent Therapy Was CommonCRPC
chemo- naïve
Despite 16% of patients did not receive subsequent therapy compared to placebo, AA increase OS!
New Hormonal Therapies Roberto Iacovelli
Abiraterone acetateAdverse Events
Treatment-Related AEs, % COU-AA-301(n = 791)
COU-AA-302(n = 542)
All Grades Grade 3/4 All Grades Grade 3/4
All treatment-related AEs 99 55 NA NA
Fluid retention 31 2 28 0.7
Hypokalemia 17 3 17 2
Cardiac disorders* 13 3 19 6
Hypertension 10 1 22 4
LFT abnormalities 10 3
ALT increase10 4
12 5.4
AST increase 11 3
de Bono JS, et al. N Eng J Med. 2011;364:1995-2005. Scher HI, et al. ASCO GU 2011. Abstract 4.
*Most frequent cardiac disorders were tachycardia and atrial fibrillation.
New Hormonal Therapies Roberto Iacovelli
Totalmente dipendente da T circolante >20-50 ng/dl
DIPENDENTE da T circolante 20-50 ng/dl IPERSENSIBILE
INDIPENDENTE da T circolante - autoproduzione T
• AR normale• No enzimi produzione T
• AR ipersensibile o iperespresso• sintesi di alcuni enzimi produzione T
• AR ipersensibile o iperespresso• sintesi di TUTTI gli enzimi produzione T
• AR stimolato anche aspecificamente
• sintesi enzimi produzione T
Abiraterone acetate: Correct timing
Cytoreduction and androgen signaling modulation by abiraterone acetate (AA) plus leuprolide acetate (LHRHa) versus LHRHa in localized high-risk prostate cancer (PCa): Preliminary results of a randomized preoperative study.
AA 1000 mg dailyPrednisone 5 mg BID +
LHRHa for 12 wks
Co-Primary:
• difference in down staging (≤ ypT2)
• safety
Secondary:• difference in androgen
biosynthesis, androgen signaling, proliferation apoptosis and candidate treatment resistance pathways.
Efficacy end points
LHRHaFor 12 wks
RANDOMIZED
2:1
• high risk PCa (clinical stage ≥T1c and biopsy Gleason score ≥8, or ≥T2b, Gleason ≥ 7 and PSA > 10ng/ml).
Patients
SURGERY
AA+LHRHa LHRHa
ypT2N0 60% 33%
Near pCR 24% 8%
N+ 28% 50%
R1 8% 33%
Results:
New Hormonal Therapies Roberto Iacovelli
Abiraterone acetate
35% of patients had PD as best response a 3 mos with Abiraterone.
What is the mechanism of resistance?
New Hormonal Therapies Roberto Iacovelli
Enzalutamide (MDV3100)
New Hormonal Therapies Roberto Iacovelli
Enzalutamide (MDV3100)
New Hormonal Therapies Roberto Iacovelli
Enzalutamide (MDV3100)
Antitumor activity of Enzalutamide in Phase I/II study
Scher HI, et al. Lancet 2010;375:1437
Activity seems to be independent of previous chemotherapy