What’s new - AFPHB in prostate.pdf · What’s new in prostate cancer therapy ? Page 7 ......

What’s new in prostate cancer therapy ?

Anne Sacré – CHR Verviers

10 mars 2017

BOPP Days 2017

Participation to advisory boards/honorarium for:

- Astellas,

- Novartis,

- Pfizer,

- Sanofi.


Disclosure


Prostate cancer therapy in 2017

Targeting the androgen axis

- Sequence of new generation hormonotherapy

- Biomarkers

- Next generation anti androgen

- Earlier use of novel anti androgen therapies

Chemotherapy : when ?

PARP inhibitor

Immunotherapy

Metabolic radiotherapy




Prostate cancer therapy in 2017

Novel androgen-directed strategies


Androgen Deprivation Therapy (ADT)

Birth of prostate systemic therapy

Huggins et al, Cancer Res 1941 – Arch Surg 1941

Charles Huggins recognized prostate

cancer as androgen-sensitive disease in

1941

ADT = testosterone lowering therapy =

hormonal therapy

21 patients with metastatic prostate cancer

- Orchiectomy or administration of phenolic

estrogens (stibestrol)

- Resulted in regression in prostate cancer,

extended life span and decreased pain

Despite initial response to androgen deprivation therapy,

invariable progression to castration-resistant state.

Better understanding of disease biology showed the traditional

androgen deprivation therapy doesn’t completely deplete :

- intratumoral androgens;

- expression of androgen receptor (AR) target genes.


Limits of traditional endocrine therapy


Androgen synthesis inhibitor

Abiraterone

Extragonadal and intratumor inhibition.

By selective and irreversible inhibition of the enzyme CYP 17.


Prevention of side effects by low dose prednisone (10mg/day)


COU-AA-302 (post-ADT and pre-chemotherapy)

Abiraterone in chemonaïve patients

Ryan et al. NEJM 2013; 368: 138-148




Ryan et al. NEJM 2013; 368: 138-148

Co-primary endpoint : statistical significant improvement in rPFS




Rathkopf et al. Eur Urol 2014 Nov; 66 (5): 815-825

Co-primary endpoint : statistical significant improvement in OS


COU-AA-301

Abiraterone post-docetaxel

De Bono et al. NEJM 2011; 346 (21): 1995-2005

Fizazi et al. Lancet Oncol. 2012; 13 (10): 983-992


COU-AA-301

Abiraterone post-docetaxel

Fizazi et al. Lancet Oncol. 2012; 13 (10): 983-992

Primary endpoint : OS

What’s new in prostate cancer therapy ? Page 16

Second-generation androgen receptor antagonist

Enzalutamide (=MDV3100)

Tran et al, Science 2009; 324 (5928): 787-790

5- to 8-fold greater affinity to AR

compared with bicalutamide


PREVAIL (post-ADT and pre-chemotherapy)

Enzalutamide (MDV3100) in chemonaïve patients




Beer et al. NEJM 2014; 371: 424-433

Co-primary endopoint : rPFS

- rPFS at 12 months : 65% among patients treated with enzalutamide, 14%

among patients receiving placebo




Beer et al. NEJM 2014; 371: 424-433

Co-primary endopoint : OS

- mOS: 32,4 months in enzalutamide group and 30,2 months in placebo group


AFFIRM (post-chemotherapy)

Enzalutamide (MDV3100) after chemotherapy

Scher HI et al. N Engl J Med 2012; 367(13): 1187–1197.


AFFIRM (post-chemotherapy)

Enzalutamide (MDV3100) after chemotherapy

Scher HI et al. N Engl J Med 2012; 367(13): 1187–1197.

Primary endpoint : OS


Approved novel hormonal therapies for mCRPC

ABIRATERONE

ENZALUTAMIDE

Sequence of new androgen-directed therapies


Abiraterone after Enzalutamide

• 38 patients

• PSA decrease ≥ 50% in 8%

• mPFS = 2,7 months

• Only 1 PR (8%)

• 30 patients

• PSA decrease ≥ 50%

in 3%

• mPFS = 3,5 months

• No objective response


Enzalutamide after Abiraterone

Bianchini D

Eur J Cancer 2014

Schrader AJ

Eur Urol 2014

Badrising,

Cancer 2014

n = 39 patients n = 35 patients n = 61 patients

PSA response = 13% PSA response = 29% PSA response = 21%

PFS = 2,8 months PFS < 4 months PFS = 4 months

1 partial response (3%)

Predictive biomarker

for androgen-directed therapies


Androgen receptor and splice variants

Dehm SM et al. Endocr Relat Cancer 2011.

Actualités Page 29

Androgen receptor variant 7 (AR-V7)

AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer.

Antonarakis – NEJM 2014.

Prospective study

- 31 patients with abiraterone

- 31 patients with enzalutamide

Detection of circulating tumour cells

RT-PCR analysis to detect ≥ 1 copy AR-V7 complementary DNA

Actualités Page 30

AR-V7 and novel hormonotherapy



Actualités Page 31

AR-V7 and novel hormonotherapy



Lower PSA response and shorter clinical

or radiographic PFS in AR-V7 positive

patients

Prospective study

- 37 mCRPC patients initiating treatment with taxane chemotherapy

(docetaxel ou cabazitaxel)

Detection of circulating tumour cells

RT-PCR analysis to detect ≥ 1 copy AR-V7 complementary DNA

Association bewteen AR-V7 status and

- PSA response rate

- PSA PFS

- Clinical/radiographic PFS

Actualités Page 32

AR-V7 and taxanes

AR-V7 and efficacy in taxane chemotherapy in patients with mCRPC.

Antonarakis – JAMA Oncol 2015.

No significant difference in terms of PSA response (P = .19) :

- 41% for AR-V7 positive patients

- 65% for AR-V7 negative patients

No significant difference in terms of PFS (P = .11) :

- 5.1 mois pour patients AR-V7 positif

- 6.9 months pour patients AR-V7 négatif

Actualités Page 33

AR-V7 and taxanes



AR-V7 positive patient has a higher risk of clinical or radiological

progression with enzalutamide or abiraterone than with taxane.

Inversely, for AR-V7 negative patients, PFS results are similar

independently of treatment.

Actualités Page 34

AR-V7 and taxanes



Future new antiandrogens ?


Orteronel, galeterone, ARN509, ODM201, EPI506…

Future new antiandrogens ?

Cancer 2014, Volume 121 issue 3, 361-371

EPI506


partially selective inhibitor of CYP 17,20-lyase

Orteronel (TAK-700)

Dreicer et al, Clinical Cancer Research 2014; 20 (5): 1335-1344.

Phase I/II showed declines in PSA and testosterone, with

evidence of radiographic responses.


partially selective inhibitor of CYP 17,20-lyase

Orteronel (TAK-700)

Fizazi K, JCO 2015 – Saad F, Lancet Oncol 2015.

Negative phase III trials with docetaxel-naïve (ELM04) and

docetaxel-pretreated (ELM05) patients.


ARN509 and ODM201 (darolutamide)

Next-generation androgen receptor antagonists

Fizazi K, et al. Lancet Oncol 2014; 15: 975-85.

Promising results in term of PSA response (Phase I and II).


Constitutively active, independent of ligands.

Androgen receptor splice variants (V7)


Galeterone

Bastos et al. Drug Des Devel Ther 2016; 10: 2289-2297.

3 mechanisms of action

- CYP lyase inhibition

- AR antagonism to both

full-length and mutant AR

- Degradation of AR,

including AR splice

variants.


Response in AR C-Terminal loss patients

Galeterone

ARMOR2, Taplin ME, presented at ASCO 2016.

Seven ARMOR2 patients

retrospectively identified

as C-term loss positive.

6/7 patients had PSA50

response.

Median time to PSA

progression in responders

was 7,3 months.


ARMOR3-SV : first precision medicine prostate cancer pivotal trial

Galeterone

ARMOR2, Taplin ME, presented at ASCO 2016.


Toward N-term targeting drugs of AR Splice variants ?

Should we keep using “old” hormonal manipulations

before using next-generation AR-targeting drugs?

Actualités Page 46

Asymptomatic/mildly symptomatic mCRPC

TERRAIN study

Shore ND, Lancet Oncol 2016; 17: 153-63.

Actualités Page 47

Asymptomatic/mildly symptomatic mCRPC

TERRAIN study

Shore ND, Lancet Oncol 2016; 17: 153-63.

Actualités Page 48

Nonmetastatic or metastatic CRPC

STRIVE study

Penson et al. JCO 2016; 34 (18): 2098-2106.

PSA response ≥ 50% =

31% 81%

mPFS in enzalutamide group = 19,4 months

mPFS in bicalutamide group = 5,7 months

Best timing for docetaxel ?


Usual sequence of therapies


Should we give chemotherapy earlier ?

3 randomised studies about early use of docetaxel :

- GETUG-AFU 15

- CHAARTED

- STAMPEDE

Actualités Page 52

Metastatic hormone-sensitive prostate cancer

mHSPC

Design :

- Open-label, randomised phase III study

- Metastatic prostate cancer, treated with ADT since ≤120 days

- Randomisation ADT alone versus ADT + docetaxel

Actualités Page 55

Chemohormonal Therapy in Metastatic Hormone-Sensitive PCa

CHAARTED

Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer

Sweeney – NEJM 2015

Actualités Page 56

CHAARTED



Actualités Page 59

Overall survival – Benefit = 13 months

CHAARTED



Actualités Page 60

Improvement of OS in « high volume »

CHAARTED



Actualités Page 61

Docetaxel and/or zoledronic acid for hormone-naïve PCa

STAMPEDE

James ND – ASCO 2015. Abstract 5001.

Actualités Page 62


STAMPEDE


Actualités Page 64


STAMPEDE


Metastases

None 39%

Metastases 61%

Bone 52%

Liver 1%

Lungs 3%

Nodes 20%

Other 5%

Type de maladie

New N0M0 20%

New N+M0 15%

New M1 59%

Relapse M0 3%

Relapse M1 3%

Primary : OS

Secondary :

- FFS = failure free survival

Local relapse

PSA rising

Nodes

Metastases

Death by prostate cancer

- Toxicity

- Quality of life

- SSE = symptomatic skeletal events

Actualités Page 65

Endpoints

STAMPEDE


Docetaxel showed significant OS advantage

Actualités Page 67

Results

STAMPEDE


OS advantage in patients newly diagnostic with metastatic PCa

Actualités Page 68

Subgroups analysis

STAMPEDE


OS advantage in patients newly diagnostic with metastatic PCa

Actualités Page 69

Subgroups analysis

STAMPEDE


Avantage significatif de docetaxel en FFS

Actualités Page 71

Results

STAMPEDE


FFS advantage – including M0

Actualités Page 72

Results

STAMPEDE


Confirmation of CHAARTED results, in favour of early

chemotherapy for newly diagnosed metastatic prostate cancer.

FFS advantage for non metastatic patients with high risk. Is it

sufficient to give early chemotherapy ? Waiting for long term OS

results…

Informations abour tumor load are missing…

Actualités Page 73

Discussion

STAMPEDE


Summary of 3 randomised studies

Actualités Page 74

Metastatic hormone-sensitive prostate cancer

mHSPC

Is Docetaxel Chemotherapy a New Standard of Care for mHSPC?

Liaw BC – Am Journal of Hematology/Oncology 2015.

= 17

months

= 22 months

Actualités Page 75

OS advantage with new drugs

Drug Study Line Control OS advantage

(months)

P-value

Docetaxel TAX 327 First line Mitoxantrone 2,9 0,004

Cabazitaxel TROPIC Post-docetaxel Mitoxantrone 2,4 <0,0001

Abiraterone COU-301 Post-docetaxel Placebo 4,6 <0,0001

Abiraterone

COU-302 Chemo-naïve Placebo

5,2

Enzalutamide AFFIRM Post-docetaxel Placebo 4,8 <0,0001

Enzalutamide PREVAIL Chemo-naïve Placebo 2,2 <0,0001

Radium 223 ALSYMPCA Bone metastases Placebo

3,6 <0,001

DNA repair defects and

PARP inhibitors

- BRCA2 mutations confer a 5-7 times higher risk of being diagnosed

with prostate cancer;

- BRCA2 mutations associated with a higher Gleason score and worse

prognosis;

- Mutation carriers of BRCA1/2 and ATM are associated with earlier age

at death and shorter survival time.

Actualités Page 77

Some facts

ADN repair defects and prostate cancer

Rong et al. European Urology 2016.

Actualités Page 78

Some facts

ADN repair defects and metastatic CRPC

Robinson et al, Cell 2015.


TOPARP trial, Metao et al, NEJM 2015.

Actualités Page 80

Olaparib

Phase II single arm study

TOPARP trial, Metao et al, NEJM 2015.

PROfound trial opening Q12017

- Phase III olaparib

Multiple single-agent Phase II open/upcoming

- Medivation, Janssen, Clovus

Combination studies with PARP inhibitor and AR-targeted agents

Actualités Page 81

Targeting PARP in mCRPC : ongoing/upcoming trials

Immunotherapy


Prostate cancer is not very immunogenic

Alexandrov et al. Nature 2013


Preparation and mechanism of action

Sipuleucel-T = dendritic cell vaccination


IMPACT study

Sipuleucel-T

Kantoff et al. NEJM 2010; 363: 411-422.

Approved :

- By FDA in April 2010;

- By EMA in September 2013,

High cost.

Actualités Page 86

Sipuleucel-T (APC8015, trade name Provenge)

Actualités Page 87

2 negative phase III studies with ipilimumab

Targeting CTLA-4 in CRPC

Kwon et al, Lancet Oncol 2014.

Actualités Page 88

2 negative phase III studies with ipilimumab

Targeting CTLA-4 in CRPC

Beer et al, JCO 2017.

• No OS benefit.

• Improvement of PFS and PSA response rates

suggesting activity in a patient subset.

Actualités Page 89

Targeting PD-1 in CRPC

Suzanne et al. NEJM 2012.

Amongst 17 patients with mCRPC, no objective

response (0% RR).

Actualités Page 90

PD-L1 is highly expressed in enzalutamide resistant PCa

Bishop et al. Oncotarget 2014.

Actualités Page 91

Pembrolizumab in enzalutamide resistant PCa

Graff et al. Oncotarget 2016.

Early encouraging results – ongoing phase II trial

Actualités Page 92

Pembrolizumab in enzalutamide resistant PCa

Graff et al. Oncotarget 2016.

Early encouraging results – ongoing phase II trial

• 5 of 27 patients (19%) had confirmed PSA response.

• 4 of 19 patients (21%) had stable disease > 6 months

Actualités Page 93

Ongoing and upcoming trials, mostly with combination

Immunotherapy and mCRPC

Radium-223


Radium-223

Mechanism of action


Radium-223 (Alpharadin)

Phase III in mCRPC = ALSYMPCA

Parker et al. NEJM 2013.

Median time to first symptomatic skeletal event : 9.8m vs 15.6m.

PSMA-Targeted

radionuclide therapy

Transmembrane protein.

Nearly universally expressed by prostate epithelial cells.

Upregaluted in prostate cancer, with increase grade and

castration-resistance.


PSMA

Prostate Specific Membrane Antigene

Actualités Page 100

Diagnostic tool

68Ga-PSMA-11 PET/CT

Improves detection of lymph nodes metastases compared to

morphological imaging

→ better staging of primary prostate cancer

→ potentially more tailored therapeutic concept

Increases detection of metastatic sites even at low PSA-values, in

patients with biochemical recurrence after radical prostatectomy

Rauscher et al. Cancer Imaging 2016.


J591, anti-PSMA antibody

Liu et al. Cancer Res 1998.

Labeled with 177Lu or 225Ac for therapeutic use.


Few small studies

Lutetium-177 linked to PSMA

30 patients mCRPC, PSMA-positive tumor phenotypes.

1-3 cycles of 177Lu-PSMA-617

Results :

- 21/30 PSA response

- 13/30 PSA decrease >50%

- 11/30 achieved a sustained PSA response (>50%) for over 24w, correlated

with radiological response

Toxicity :

- Mild acute hematotoxicity (more often if diffuse bone marrow involvement)

- Xerostomia, nausea and fatigue : <10%

Kratochwil et al. Cancer J Nuclear Medicine 2016.


Comparison with Radium-223


Proof of concept in two patients

Actinium-225 linked to PSMA

225Actinium-PSMA: Alpha radionuclide labeled PSMA-ligand

(less penetration into normal tissue than 177Lu)

Bi-monthly administrations

Two patients showed complete PSA and radiological response

without serious side effects (mainly xerostomia)



Proof of concept in two patients

Actinium-225 linked to PSMA


Take home messages

Rapid evolution in systemic therapies for prostate cancer

Most men with metastatic disease still die from their cancer

Chemotherapy maintains an important position in the

armamentarium against mCRPC

Improving outcomes requires new drugs/targets…

- AR non-ligand binding domain

- PARP inhibitor

… or new combinations

- including immunotherapy or radioimmunotherapy


Summary

What’s new - AFPHB in prostate.pdf · What’s new in prostate cancer therapy ? Page 7 ......

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