Stéphane Oudard, MD, PhDHead of the Oncology and Innovative phase I Department

Georges Pompidou HospitalRené Descartes University, Paris, France

stephane.oudard@aphp.fr

Management of mCRPCState of the art in 2018

Disclosure

•Research grant agreement:– Sanofi, Janssen, Astellas

•Consulting agreements with:–Astellas AstraZeneca–Janssen Roche–MSD Sanofi

Castrate-resistant prostate cancer (CRPC)Definition

PSA: prostate-specific antigenEAU guidelines on prostate cancer (2014 update) – www.uroweb.org

Castrate serum testosterone

<50 ng/mL or 1.7 nmol/L

Biochemical progression

3 consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with PSA >2 ng/mL

Radiological progression

The appearance of ≥2 bone lesions on bone scan or enlargement of a soft tissue lesion using RECIST (Response Evaluation Criteria in Solid Tumors)

OR

+ either

Phase III clinical trials in mCRPC

Study Agents N Indication HR ∆ OS

TAX-3271 DOC/P vs mito/P 1,006 mCRPC 0.76 +2.9

IMPACT2 Sipuleucel-T vs pbo 512 mCRPC (pre-DOC) 0.78 +4.1

COU-AA-3023

COU-AA-3014

ABI/P vs P

ABI/P vs P

1,088

1,195

mCRPC (pre-DOC)

mCRPC (post-DOC)

0.81

0.74

+4.4

+4.6

PREVAIL5

AFFIRM6

ENZ vs pbo

ENZ vs pbo (or P)

1,717

1,199

mCRPC (pre-DOC)

mCRPC (post-DOC)

0.71

0.63

+2.2 (est)

+4.8

TROPIC7 CAB/P vs mito/P 755 mCRPC (post-DOC) 0.70 +2.4

ALSYMPCA8 Radium-223 vs pbo 921 mCRPC 0.70 +2.8

ABI: abiraterone; CAB: cabazitaxel; DOC: docetaxel; HR: hazard ratio; OS: overall survival; P: prednisone; pbo: placebo; mito: mitoxantrone 1. Tannock IA et al. NEJM2004;351:1502-12; 2. Kantoff PW et al. NEJM 2010;363:411-22; 3. Ryan C et al. Lancet Oncol 2015;16:152–60; 4. Fizazi K et al. Lancet Oncol 2012;13:983-92; 5. Beer TM et al. NEJM 2014;371:424-33; 6. Scher HI et al. NEJM 2012;367:1187-97; 7. De Bono J et al. Lancet 2010;376:1147-54; 8. Parker C et al. NEJM 2013; 369:213-23

Which drug for which patient?

Docetaxel rechallenge in mCRPC pts

1. Eymard JC et al. BJU Int 2010;106:974-8.2. Ansari J et al. Oncol reports 2008;20:891-6.3. Beer TM et al. Cancer 2008;112:326-30.

� In selected patients1-6 :

� Good initial responders (PSA decrease ≥ 50%)1-6

� With Long progression-free interval (≥ 6 months) since last docetaxel administration6

� In case of no cumulative toxicity5,6

� Increased toxicity with subsequent rechallenges6

� Asthenia and Peripheral neuropathy +++

4. Garmey EG et al. Clin Adv Hematol Oncol 2008;6:118-32.5. Loriot Y et al. Eur J Cancer 2010;46:1770-2.6. Oudard S. BJU Int. 2014 Jun 20. doi: 10.1111/bju.12845

Frozen gloves/socks can reduce docetaxel-induced nail and skin toxicity

Skin toxicity (P < 0.0001)

Nail toxicity (P < 0.0001)

GradeControl (n = 45)

Glove(n = 45)

0 49% 89%

1 29% 11%

2 22% 0

GradeControl (n = 45)

Glove(n = 45)

0 38% 67%

1 44% 22%

2 9% 2%

Lost 9% 9%

Scotté F et al, J Clin Oncol 2005;23:4424-9Scotté F et al, Cancer 2008;112:1625-31

Prostate cancer progression in low testosterone environment: 2 co-existing mechanisms

Luminal secretory cells (AR+)

Intermediate cells (AR-)

Prostate adultstem cells (AR-)

Transit amplifyingcells (AR-)

ADT

Massive apoptosisof luminal AR+ cells

ADAPTATIONAllows growth in low

testosterone environment

CLONAL PROLIFERATION(AR- cells)

Tombal B et al, Eur J Cancer 2011;47:S179-88

Co-existence of AR-positive and AR-negative tumour cells in the same patient

Beltran H. Cancer discovery 2011; 1: 487-95

AR-positive cellsAR-negative cells

• COU-AA-301 and AFFIRM primary endpoint was OS.

Primary resistance to AR-targeted agents

1. De Bono JS et al. N Engl J Med 2011;364:1995-2005; 2. Scher H et al. N Engl J Med 2012;367:1187-97

ABI+P(COU-AA-301)1

ENZ±P

(AFFIRM)2

Primary resistance1 out of 3 patients

Primary resistance1 out of 4 patients

Radiological progression-free survival (rPFS)

• Phase II trial in 62 patients with mCRPC treated with ABI + P• Transiliac bone marrow biopsies before, at 8 weeks and at end of treatment

Who are the non-responders to ABI?

Efstathiou E et al, J Clin Oncol 2011;30:637-43

Who are the non-responders?(defined as patients

treated for ≤4 months)

Bone marrow biopsy:- Intense AR nuclear expression- CYP17 expression

P<0.001

YES82% responders

(12/13)

NO18% responders

(2/12)

� No PSA decline ≥ 30%

at 1 month predicts poor

response to AR-targeted agents

1. Rescigno P et al. Eur Urol. 2016:724-731; 2. Fuerea A et al. Eur J Cancer. 2016;61:44-51.

No PSA Decline With ABI Associated WithPoor rPFS and Poor OS (COU-AA-302)

rPFS

Ryan et al, Clin Genitourin Cancer 2017 Jul 25. pii: S1558-7673(17) 30211-2

OSPSA decline with ABI

PSA decline with ABI

ABI, abiraterone; rPFS, radiographic progression

No PSA Decline With ENZA Associated With Poor rPFS, Poor Pain Relief and Worse OS (AFFIRM)

rPFS

Armstrong A et al, Cancer 2017;123:2303-2311

OS

No PSA decline

Lack of PSA decline by 80 days following ENZA initiationassociated with poor outcomes

ENZA, enzalutamide

Patients progressing with an AR-targeted agent poorly respond to a another one

Author Yearpublished

N pts Duration of 2nd

treatment

���� PSA≥ 50%

Median PFS

ENZ ����ABI

Loriot et al. 2013 38 3 mo 8% 2.7 mo

Noonan et al. 2013 30 13 wks 3% 3.6 mo

ABI ���� ENZ

Schrader et al. 2013 35 4.9 mo 29% -

Badrising et al. 2014 61 3 mo 21% -

Bianchini et al. 2014 39 2.9 mo 23% -

Schmid et al. 2014 35 2.8 mo 10% -

Brasso et al. 2014 137 3.2 mo 18% -

Retrospective trials based on a small number of patients

Zhang T et al, Expert Opin Pharmacotherap 2014;16:1-9

Combination of AR-targeted agents doesnot overcome primary resistance

� 3 different open-label phase II studies of 60 pts with bone mCRPC treated with ABI/P, ENZ, or combination of both

� Transiliac bone marrow biopsies before tt, at 8 weeks and at end of treatment

1. Efstathiou E et al, JCO 2011;30:637-43; 2. Efstathiou E et al, Eur Urol 2015;67:53-60; 3. Efstathiou E et al, JCO 2014;32(suppl):abstract 5000

ABI/P1 ENZ2 ENZ + ABI/P3

PSA C

hange (

%)

-100-90

-75

-50

-30

0

25

50

75

100

↓PSA ≥30%: 61% (34/56)↓PSA ≥50%: 50% (28/56)↓PSA ≥90%: 16% (9/56)

27%

29 %

PSA C

hange (

%)

-100-90

-75

-50

-30

0

25

50

75

100

29%↓PSA ≥30%: 55% (30/55)↓PSA ≥50%: 50% (25/55)↓PSA ≥90%: 20% (11/55)

PSA C

hange (

%)

-100-90

-75

-50

-30

0

25

50

75

100

12%↓PSA ≥30%: 83.6% (41/49)↓PSA ≥50%: 75.5% (37/49)↓PSA ≥90%: 44.9% (22/49)

• mPFS: 5.7 months in the combination group vs 5.6 months in the control group (HR: 0.83; P = 0.22).

• Secondary end points: no difference.

• Tolerability: Grade 3 hypertension (10% v 2%) and increased ALT (6% v 2%) or AST (2% v 0%) more frequent in the combination than the control group.

Attard G et al, JCO 2018; Sep 1;36(25):2639-2646

1. Tannock et al, Lancet Oncol 2013; 14:760-8; 2. Mezynski H et al, Ann Oncol 2012. 23: 2943–2947; 3. Schweizer MT et al, Eur Urol 2014; 66:646-52; 4. Azad et al, The Prostate 2014; 74:1544-1550; 5. De Bono et al. Eur Urol 2016 (epub ahead of print)

VENICE1

DOC/Pbon=612

De Bono2

ABI→DOCn=35

Schweizer3

Azad4

ABI→DOCn=86

De Bono5

(COU-AA-302)ABI→DOC

n=261

DOCn=95

ABI→DOCn=24

DOC therapy line 1 2 1 2 2 2

Visceral mets YES YES YES YES YES NO

� PSA ≥50% 63.5%* 25.7%* 63.0%* 38.0%* 35.0%* 27%*

Median PSA-PFS(mths)

8.1 4.6 6.7 4.1 4.0 (TTP 7.6**)

OS, median (mths) 21.2 12.5 - - 11.7 NA

[2-5] = retrospective analyses; *confirmed PSA responses; **TTPP: time to PSA progression (not PSA- PFS) was obtained in only100 patients

Impaired activity of docetaxel Post ABI?

ABI or ENZA Prior to CABA – No impact?

1. De Bono JS et al, Lancet. 2010;376:1147-54; 2. Pezaro CJ et al.,Eur Urol.2014;66:459-65; 3. Al Nakouzi N et al.,Eur Urol. 2015;68:228-35; 4. Sella A et al.,Clin GU Cancer. 2014;12:428-32; 5. Wissing MD et al, Int J Cancer. 2015;136:E760-72.

AuthorYear

PublishedN pts

VisceralMets, %

���� PSA≥50%

Median PFS

No prior ABI or ENZA

De Bono1 2010 378 25% 39.2% 2.8 mo

ABI or ENZA ���� CABA

Pezaro2 2012 37 35% 41% 5.5 mo

Al Nakouzi3 2014 79 14% 35% 4.4 mo

Sella4 2014 24 29% 31.5% -

Wissing5 2014Prior ABI, 69No ABI, 63

--

31.9%49.2%

6.5 mo8.1 mo

[1] is a prospective randomized study of CABA/P vs Mito/P in mCRPC (post-DOC); [2 and 5] trials are retrospective studies in mCRPC pts (post-DOC)

ABI: abiraterone acetate; ENZA: enzalutamide; CABA: cabazitaxel;P: prednisone; Mito: mitoxantrone

mCRPC with primary resistance toan AR-targeted agent

(progression ≤ 12 months on ABI or ENZA) before or after

Docetaxel

CABAZITAXEL

1:1

R

A

N

D

O

M

I

Z

E

Swith to another AR-targeted agent

(ABI or ENZA depending of first therapy)

Sponsor: Sanofi

n=324

n=162

n=162

CARD studyA ‘practice changing’ trial

Stratification factors: � ECOG PS (0/1 vs 2),

� Time to progression (≤6 vs 6–12 mo),

� Timing of AR-targeted agent (before vs after DOC) Primary endpoint: radiographic PFS

Secondary endpoints: PSA response, ECOG PS, PFS (clinical or radiological), objective tumor response,

pain, QoL, time to SSEs, OS, safety, biomarkers

NCT02485691. ClinicalTrials.gov.

How to identify patients poorlyresponding to AR-targeted agents?

Loriot Y et al. Eur J Cancer 2015 sept ; 51(14): 1946-52

• Retrospective cohort of 173 patients, including 57 treated with enzalutamide in AFFIRM phase III trial

PFS

TTCRPC

P<0.001

PSA decrease ≥ 50%

8%

58%

TTCRPC: time to castration resistance; PFS: progression-free survival

TTCRPC ≥12 months

TTCRPC <12 months

HR: 0.58 (95% CI: 0.42-0.82)Median PFS: 5.8 mo vs 2.8 mo

Log-rank P =0.002

Surv

ival (%

)Months

1.0

0.8

0.6

0.4

0.2

0

10 20 25 301550

Short response to 1st ADT may predict poorresponse to Enza

Optimal management of mCRPC: highlightsfrom a European Expert Consensus Panel

• Early imaging should be performed to detect primary resistance to novel agents targeting the AR pathway

Fitzpatrick JM et al. Eur J Cancer 2014;50:1617-27

% o

f vo

ting e

xpert

s

21 EU expertsStrong consensus

3 months recommended as the appropriate minimum time point based on the imaging modalities currently available

Bryce AH et al, Prostate Cancer Prostatic Dis 2017; 20: 221-227

Of 265 chemonaive mCRPC patients with radiological progression and evaluable PSA levels on ENZA,

65 (24.4%) had a non rising PSA

Monitoring mCRPC patients by PSA alone is not enough

mCRPC, metastatic prostate cancer

Patients with Radiological Progression & No PSA Progression Have a Worse Prognosis (PREVAIL)

100

90

80

70

60

50

40

30

20

10

0

PFS

(%

)

Time (months)0 3 6 9 12 15 18 21 24 27 30 33

Non rising PSA

Median 8.3 mo

[95% CI, 8.0-10.3]

Rising PSA

Median 11.1 mo

[95% CI, 11.0-13.4]

HR=1.78 (95% CI: 1.26-2.23)

P=0.0003

No. at risk

Non-rising PSA 65 63 43 25 15 10 5 4 2 1 0 0

Rising PSA 200 200 180 141 89 57 33 19 11 4 2 0

Monitoring mCRPC patients by PSA alone is not enough

Bryce AH et al, Prostate Cancer Prostatic Dis 2017; 20: 221-227

Timing of Progression Events with First-Line AR-Targeted Agents (COU-AA-302 or PREVAIL)

Bony mCRPCABI or ENZA

Initiation PSA ���� Radiological

Progression

ClinicalProgression

11 mths1-3 5-9 mths1-4 8-9 mths1-3

Insidious PSA Low Progression(25%)5

Most patients unfitto receive chemo

at that stage

1. Ryan CJ et al, NEJM 2013;368:138-48; 2. Ryan CJ et al. Lancet Oncol 2015;16:152-60; 3. Beer TM et al, NEJM 2014;371:424-33; 4. Beer TM et al, Eur Urol 2017;71:151-4; 5. Bryce AH et al, Prostate Cancer Prostatic Dis 2017; 20: 221-227

No symptoms(BPI-SF 0-1)

Mild symptoms(BPI-SF 2-3)

ABI

P

ABI

P

COU-AA-302 – Post-Hoc AnalysisPain Associated with Worse Prognosis with ABI

Miller K et al, Eur Urol. 2018 Jul;74(1):17-23.

Switch to another life-extending therapy before symptom progression ���� Regular radiological monitoring

ABI, abiraterone; BPPI-SF, Brief Pain Inventory- Short Form; P, prednisone

Mild pain associated with worse OS in mCRPC treated with 1Line Chemotherapy

Median 21.4 mths[95% CI, 16.0-26.8]

Median 15.0 mths[95% CI, 8.2-21.8]

Median 13.1 mths[95% CI, 9.8-7.5]

Oudard S et al. BJU Int 2009; 103: 1641-46

Retrospective analysis of 145 mCRPC pts treated with first-line chemotherapy at HEGP from 2000 to 2002

CATS international database

Delanoy N et al, Eur Urol Oncol 2018 (epub ahead of print); Oudard S et al, ASCO 2018 (abstract e17007)

• Retrospective review of 669 consecutive mCRPC patients treated in daily

practice with 3 LETs in 7 countries (France, Austria, Greece, Italy, Israel, Spain,

UK) from 2012 to 2016

• Type of progression at initiation of LETs [PSA only, radiological (± PSA), clinical

(± PSA ± Radiological)*] evaluable in 661 patients

669 mCRPC patients

DOC/P ���� CABA/P ����ART (N=158)DOC/P ���� CABA/P ����ART (N=158)

DOC/P ���� ART ���� CABA/P (N=456)DOC/P ���� ART ���� CABA/P (N=456)

ART ���� DOC/P ���� CABA/P (N=55)ART ���� DOC/P ���� CABA/P (N=55)

ART: next generation AR-targeted agent (abiraterone acetate or enzalutamide) ; LET: Life-extending Therapy

*Clinical progression defined by worsening of cancer related pain or symptoms as per physician judgment

Type of progression First LETN = 661 pts

Second LETN = 630 pts

Third LET

N = 617 pts

PSA rise only 151 (22.8%) 142 (22.5%) 91 (14.7%)

Radiological progression

- No PSA rise

225 (34%)35/225 (15.6%)

140 (22.2%)26/140 (18.6%)

107 (17.3%)

22/107 (20.6%)

Clinical progression- No PSA rise

285 (43.1%)24/285 (8.4%)

348 (55.2%)79/348 (22.7%)

419 (67.9%)85/419 (20.3%)

Clinical progression at LET initiation increases with the number of lines

LET: life-extending therapies

Progression type at initiation of each LET

Oudard et al, ASCO 2018 (abstract e17007)

OS by progression type at initiation of 1st LET in the CATS study

Median 44.9 mths[95% CI, 38.0; 49.4]

Median 37.85 mths[95% CI, 35.1; 44.2]

Median 30.7 mths[95% CI, 27.5; 32.9]

N=151 N=225 N=285

Log rank p<0.001

Ove

rall

surv

ival

Clinical progression associated with worse OS Oudard et al, ASCO 2018 (abstract e17007)

LET: life extending therapy

AR-FL

ARv7

Constitutively active splice variant

Antonarakis et al. N Engl J Med. 2014;371:1028-1038.Guo Z et al. Int J Biol Sci. 2011;7:815-822.

AR-FL: Full-Length Androgen Receptor; NTD: N-Terminal Domain; DBD: DNA-Binding Domain; LBD: Ligand-Binding Domain; U: Unique N- or C-terminal sequence

AR-V7 in CTCs seems a promising predictorof treatment response

Antonarakis ES et al, NEJM 2014;371:1028-38; Antonarakis ES et al, JAMA Oncol 2015;1:582-91

Abiraterone Enzalutamide Taxane*

PSA response rate:AR-V7 positive: 0% (95% CI: 0-26%)AR-V7 negative: 52.6% (95%CI: 29-76%)P=0.004

PSA response rate:AR-V7 positive: 0% (95% CI: 0-46%)AR-V7 negative: 68.0% (95% CI: 46-85%)P=0.004

PSA response rate:AR-V7 positive: 41% (95% CI: 18-67%)AR-V7 negative: 65% (95%CI: 41-85%)P=0.19

AR-V7 positive AR-V7 negative

Data support an association between AR-V7 and resistance to abiraterone and to enzalutamide

PS

A c

ha

ng

e,

%

100

50

–50

–100

*

†

* * *

†

††

100

50

0

–50

–100

†

*

†

*

†

* †

† †

††

† † ††

†

††

† † †

† †

100

50

0

–50

–100

*Docetaxel, N=30Cabazitaxel, N=7

CTC: circulating tumour cell

Is there an optimal sequenceof life-extending therapies?

Systematic review of 13 published retrospective studies in mCRPC (n=1016)

ART: Androgen receptor targeted agents; CABA: cabazitaxel

ART����ART (n=469)

CABA����ART (n=229)

ART����CABA (n=318)

Su

rviv

al

%

Months

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12

12-month OS rate by sequence in post-Docetaxel

Poor outcome when ART are prescribed in sequence

Mayne F et al, Crit Rev Hematol Oncol 2015; 96: 498-506

FLAC International database (HEGP)

• Records of 387 consecutive mCRPC patients treated with cabazitaxel after docetaxel in 5 countries (France, Greece, Spain, Turkey)

• Retrospective data collection:– Disease history (duration and response to 1st ADT), treatment sequences received, clinical

characteristics at initiation of the next life-extending therapy post-docetaxel (ie cabazitaxel or ART)– Efficacy of cabazitaxel (PSA response, radiological and/or clinical PFS) – Overall survival

DOC ART* CAB

DOC ART*CAB

*ART: Enzalutamide or Abiraterone

DOC CAB

Angelergues A et al, Clin Genitourin Cancer 2018 Aug;16(4):e777-e784

FLAC study - OS from diagnosis of mCRPC

Angelergues A et al, Clin Genitourin Cancer 2018 Aug;16(4):e777-e784

FLAC - OS from First life-extending therapy received in mCRPC

Angelergues A et al, Clin Genitourin Cancer 2018 Aug;16(4):e777-e784

669 mCRPC pts treated

with DOC, CABAand ART

• Retrospective analysis of 669 consecutive patients treated with DOC, CABA and one ART in 34 centers in 8 countries (France, Austria, Greece, Italy, Israel, Denmark,Spain, UK)

CATS International Database

DOC ���� CABA ����ART (N=158)

DOC ���� ART ���� CABA (N=456)

ART ���� DOC ���� CABA (N=55)

Delanoy N et al. Eur Urol Oncol 2018 (In press)Doc: docetaxel; CABA: Cabazitaxel; ART: Androgen Receptor–Targeted agent

Delanoy N et al. Eur Urol Oncol 2018 (In press)Doc: docetaxel; CABA: Cabazitaxel; ART: Androgen Receptor–Targeted agent

Delanoy N et al. Eur Urol Oncol 2018 (In press)Doc: docetaxel; CABA: Cabazitaxel; ART: Androgen Receptor–Targeted agent ; LET: first life-extending

� PSA response on DOCETAXEL was lower in post ART than upfront (p=0.02)

59.8%

64.3%

44.0%

Delanoy N et al. Eur Urol Oncol 2018 (In press)Doc: docetaxel; CABA: Cabazitaxel; ART: Androgen Receptor–Targeted agent ; LET: first life-extending

� PSA response on DOC was lower in post ART than upfront (p = 0.02)

� PSA response on CABA was higher in 2nd than 3rd line (p = 0.001)

56.1%

40.2%

30.2%

Overall Survival by treatment sequencein the CATS study

Delanoy N et al, Eur Urol Oncol 2018 (epub ahead of print)

� mOS was longer in DOC starting sequence compared to ART (p= 0.007).� CABA seemed to retain its activity regardless of treatment sequence.

• 2 teams have evaluated adapted schedules of administration of Cabazitaxel 16 mg/ m2/ 2 weeks with Prednisone:

– A French monocenter study (EGP)1: 27 pts with G-CSF

– A Finnish multicenter (Prosty II)2: 40 pts wo G-CSF

• Safety profile:– Good tolerability with less diarhea

– Lower hematotoxicity than

in the TROPIC trial.

• Efficacy1:– PSA response > 50%: 42.3%

– Time to PSA progression: 3.4 mths

Cabazitaxel every two weeks: is it not a new drug?

1Clément-Zhao A et al, BJU Int. 2018 Feb;121(2):203-2082Kellokumpu-Lehtinen PL et al, abstract 276, ASCO GU 2015

Grade ¾ toxicity Prosty French trial

Asthenia 3 (7.5%) 4 (16.7%)

Neutropenia 6 (15%) 4 (16.7%)

Thrombocytopenia NR 3 (12,5%)

Anemia NR 2 (8.3%)

Febrile neutropenia 1 (2.5%) 1 (4.2%)

Diarrhea NR 1 (4.2%)

sepsis 1 (2.5%) 1 (4.2%)

Pulmonary embolism 1 (2.5%) /

CABASTY phase III randomized trial in mCRPC

• Progressive mCRPC patients

• Age ≥70 years

• Prior DOC

• ECOG PS status: 0-2

CABAZITAXEL/P

25 mg/m2 q3w

1:1

Primary endpoint: incidence of grade ≥3 neutropenia

and/or neutropenic infection

Secondary endpoints: dose intensity, PSA response, PFS,

OS, quality of life, geriatric evaluation

R

A

N

D

O

M

I

Z

E

Countries: France, Germany,

Finland, Sweden

N=170 pts

N=85

Prophylactic G-CSF in all patients

CABAZITAXEL/P

16 mg/m2 q2w

N=85

https://clinicaltrials.gov/ct2/show/NCT02961257

Prior abi or enza abi or enza naïve

with abi or enza Concurent abi or enza as 2nd line

mOS : 17 months TEAE: 93/184 (51%) pts during treatment and 11 (6%) during FUPost hoc analyses: pts with 3 prior anticancer medications, baseline ECOG PS 2, and lower baseline hemoglobin received less cycle of radium 223 and unlikely to benefit from radium-223. Tolerability: Radium-223 well tolerated regardless of concurrent or prior abiraterone or enzalutamide.

Sartor O et al, Oncologist. 2018 Feb;23(2):193-202.

Phase III randomized studies on radium 223 in mCRPC pts with abiraterone + Prednisone or enzalutamide

Planned evaluations

• OS• Time to opiate use for

cancer pain• Time to cytotoxic

chemotherapy• rPFS

• QoL

Statistical analysis

• 389 events to detect a 39%

increase in SSE-FS

• 90% power

• 8.2 month difference (29.2 vs 21

months)

• 2-sided type 1 error 0.05

Abiraterone/P

1000 mg QD+ ADT

n=806 pts

Asymptomatic/mildly symptomatic chemo-naïve

Metastatic CRPC (≥2 bone mets)

No visceral or brain mets

WHO performance 0–1

Stratification factors:

-Use of bone health agents

-Total alkaline phosphatase

-Geographic region

• Phase III, multicenter study, placebo-controlled• Primary endpoint: symptomatic skeletal event-free survival (SSE-FS)

Radium-223

50 kBq/kg monthly, for 6 months +

Abiraterone/P 1000

mg QD+ ADT

Close for inclusion

R 2:1

Planned evaluations

• rPFS

• OS

• TT first SRE

• Subsequent therapy

• Pain

• QoL

Statistical analysis

• 233 events (Month 51)

• 90% power

• 9 month difference (17 vs. 26 months)

• 1-sided type 1 error 0.025

Enzalutamide

160 mg QD+ ADT

n=560

Asymptomatic/mildly symptomatic

Metastatic CRPC(≥2 bone mets)

Visceral metastases

negative

Lymph node

negative/positive

WHO performance 0–1

No significant CVD

• A Phase 3, randomised, multicentre study• Primary endpoint: rPFS

Radium-223 50

kBq/kg monthly, for 6 months +

enzalutamide

160 mg QD+ ADT

Recruiting

R 2:1

EORTC PEACE III studyPhase III ERA223 trial

Bayer, the manufacturer of radium-223, reported that the unblinding follows the recommendation of an IDMC, which observed more fractures and deaths in patients receiving both radium-223 and abiraterone

acetate compared with patients receiving abiraterone alone (1 december 2017, press release).

PTEN Loss as a Predictive Biomarker for the Akt Inhibitor Ipatasertib + Abiraterone Acetate in mCRPC pts

• Co-Primary Endpoint: rPFS With 400 mg Ipatasertib or Placebo + Abiraterone by ICR IHC

HRa, 0.39 (0.22-0.70)

HRa, 0.84 (0.51-1.37)

ICR IHC PTEN Loss ICR IHC PTEN Non-Loss

Pbo + Abi

Pbo + Abi

Ipat 400 mg + Abi Ipat 400 mg + Abi

Median 4.6 mo Median 11.5 mo Median 7.5 moMedian 5.6 mo

► rPFS was prolonged in the ipatasertib 400 mg + abiraterone arm vs the placebo + abirateronearm in the primary analysis

De Bono J et al, ESMO 2016, abstract 718O Dx, diagnostic.a Unstratified HR; 90% CI; P value from log-rank test.

intention-to-treat population

HRR mutation-positive subgroup wild-type HRR subgroup

Olaparib + AAP: clinical efficacy benefit in mCRPC compared to AAP alone

Clarke N et al, Lancet Oncol 2018;19:975-85.

Conclusions

• Prostate cancer is a heterogeneous disease

• Short response to ADT in 1st-line seem prognostic and predictive of lower response to AR-targeted agents

• AR-V7 splice variant evaluation in CTCs is promising but requires validation

• Cross resistance between new hormonal treatments (abi-enza; enza-abi)

• Survival benefit is related to the number of life-extending therapies received

• Do not miss the window of opportunity for chemotherapy

• Personalized medecine (PARP and pTEN inhibitors) seem promosing

• Treatment choice should be based on MDT

• Patients should be put into clinical trials