new hormonal therapies roberto iacovelli the new era of crpc: few targets for a pletora of agents!...

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:


Current strategies for androgen inibition in CRPC

AR

Abiraterone TAK700

BicalutamideMDV3100

LH-RHa


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



H&E

AR staining

PSA staining

Met

asta

sis

of C

RPC

BP=benign prostate tissue;CP=Prostate cancer;METS=castration-resistant metastatic tumor

Montgomery et al. Cancer Res 2008;68:4447-4454.



Normal epithelium CRPC cellsControl

CYP17 is not expressed in normal prostatic epithelium

CYP17 is expressed in CRPC cells.

CRPC cells

Hormon sensitive

PCa

CYP17 is not expressed in hormone sensitive cells.



Montgomery et al. Cancer Res 2008;68:4447-4454.

Expression of steroidogenic enzymetranscripts in primary and metastatic prostate tumors

BP=benign prostate tissue;CP=Prostate cancer;METS=castration-resistant metastatic tumor



CRPC cell acquires the ability to product itself testosterone from cholesterol by CYP17



Hormone sensitive PCa cell CRPC cell

AR

AR

CYP17

Testosterone

PARACRINE Pathway

AUTOCRINE Pathway

Increase of malignancy

ENDOCRINE Pathway



Efstathiou E. Clin Cancer Res 2010;16:1100-1107


Targeting CYP17

Iacovelli et al. Anti-Cancer Drugs 2011.

CYP17CYP17 inhibitor


Abiraterone acetate

Baseline PSA

ProgressionTumor/Bone Progression

Pain

Death

Chemotherapy

ECOG PS Decline

Increase OS

Increase the time to chemotherapy

24-48 months

Proved efficacy in post docetaxel patients

A new molecule who meet oncological need in prostate cancer:

Adapted from Halabi S. J Clin Oncol. 2009;27: 2766-2771Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)


Abiraterone acetate: proves of efficacy

Iacovelli et al. Anti-Cancer Drugs 2011.

Abiraterone acetate

CRPC chemo- naïve

CRPC TXT pretreated

1 phase III Trial 1 phase III Trial3 phase II Trials1 phase I Trial


Abiraterone acetateCRPC

TXT pretreated

Patients with mCRPC progressing after 1-2

chemotherapy regimens, 1 of which contained docetaxel

(N = 1195)

Abiraterone acetate 1000 mg/day +Prednisone 5 mg BID

(n = 797)

Placebo +Prednisone 5 mg BID

(n = 398)

Stratified by ECOG PS, worst pain over previous 24 hrs, previous chemotherapy, type of progression

de Bono JS et al. N Engl J Med. 2011;364:1995-2005.

Randomized 2:1

Study stopped at planned interim analysis at 534 events because OS improvement crossed predetermined stopping boundary

• Abiraterone acetate: selective inhibitor of androgen biosynthesis that blocks CYP17 activity

• Primary endpoint: OS


Abiraterone acetate

Pbo ABI

Median OS, mos 10.9 14.8

HR 0.65

95% CI 0.54-0.77

P value < .0001

Pbo ABI

Median PFS, mos 3.6 5.6

HR 0.58

95% CI 0.46-0.73

P value < .0001

OS PFS

CRPC

TXT pretreated


Abiraterone acetateAdverse Events

Treatment-Related AEs, % Abiraterone Acetate(n = 791)

Placebo(n = 394)

All Grades Grade 3/4 All Grades Grade 3/4

All treatment-related AEs 99 55 99 58

Fluid retention 31 2 22 1

Hypokalemia 17 3 8 1

Cardiac disorders* 13 3 11 2

Hypertension 10 1 8 < 1

LFT abnormalities 10 3 8 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.


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


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%


CRPC

chemo- naïve Treatment Arms Evenly Matched


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



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



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


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)


Abiraterone acetate: Subsequent Therapy Was CommonCRPC

chemo- naïve

Despite 16% of patients did not receive subsequent therapy compared to placebo, AA increase OS!


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.


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:


Abiraterone acetate

35% of patients had PD as best response a 3 mos with Abiraterone.

What is the mechanism of resistance?


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



The AFFIRM Trial Design

Primary End-Point: OSStratification variables: ECOG-PS, meand BPI (<4, ≥4)

Statistical design: power 90% to detect a 24% reduction in mortality (target HR= 0.76).



Baseline patient demographics:



RESULTS:The AFFIRM study was halted and unblinded after the interim analysis (520 events).

Target 0.76!



RESULTS:PSA response rate, PSA-PFS and Time To First Skeletal Event

HR denosumab vs placebo 0.84!*

*Sm

ith M

R et

al.

Lanc

et 2

012



RESULTS:Survival benefit across all subgroups



RESULTS:Safety

Conclusions

Androgen pathways is the driver of tumor progression of prostate cancer.

Resistance to LHRHa don’t mean resistance to all hormonal strategies.

CYP17 and AR are the main targets of new hormonal therapies

The sequential use of these agents may be feasible but not proven in large prospective trial.

Precocious use of new agents seems to be more active.

Hormonal strategies in CRPC: it’s only the beginning…


Q&A

Durante il trattamento l’analogo deve essere proseguito?

È Possibile rinunciare al trattamento con prednisone?

In controllo con placebo o Prednisone è idoneo?

AA + P(n = 546)

Placebo + P(n = 542) RR (95% CI) P Value

PSA decline ≥50% 62% 24% NA <0.0001

N=220 N=218

RECIST: Defined objective response

Complete responsePartial responseStable diseaseProgressive disease

36%

11%25%61%2%

16%

4%12%69%15%

2.273 (1.591, 3.247)

<0.0001

The AFFIRM study reported a PSA decline >50% in 2% of patients treated with placebo alone!


Is prednisone an active control for CRPC?

new hormonal therapies roberto iacovelli the new era of crpc: few targets for a pletora of agents!...

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