Sequencing in Metastatic Prostate Cancer Treatment · sequencing in castration-resistant prostate cancer Reprinted from Cancer Treat Rev, 48, Seisen T, et al., A comprehensive review

SEQUENCING IN METASTATIC PROSTATE CANCER TREATMENT

Eleni Maragkouli, Medical Oncologist

Oncology Department

The University of Thessaly, Medical School

University Hospital of Larissa, Greece

PROSTATE CANCER

DRUG DEVELOPMENT

Chemotherapy

Tum

ou

rvo

lum

e an

d a

ctiv

ity

Docetaxel or

abiraterone

acetate (AA) + ADT

for mHSPC

AA 2013

Enzalutamide 2014

Sipeuleucel-T

Radium 223

Castration

M0 CRPC

(enzalutamide?

ARN509?)

Docetaxel AA 2011

Cabazitaxel 2010

Radium 223

Enzalutamide 2012

Image from http://prostatakrebs-tipps.de/prostata-krebswachstum-stadien/

DOCETAXEL PLUS PREDNISONE

OR MITOXANTRONE PLUS PREDNISONE

For advanced prostate cancer

Docetaxel

improved rates of

response in terms

of pain, serum

PSA level, and

quality of life

HR for death=0.76

(95% CI, 0.62–0.94;

p=0.009) OS = +2,9 m

From N Engl J Med, Tannock IF, et al., Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer, 351, 1502–12. Copyright © 2004

Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

N=1006 men with chemotherapy-naive mCRPC randomly assigned to docetaxel (75 mg/m2 q3w), docetaxel

(30 mg/m2 weekly) or mitoxantrone (12 mg/m2 q3w). All patients received prednisone 5 mg orally bd

Kaplan–Meier estimates of the probability of

overall survival in the three groups

Response to treatment, as measured by decreases in pain,

PSA level, and tumour burden and improvements in the QoL

THIS IS ALL EFFECTIVE IN THE

POST-DOCETAXEL SETTING

P, prednisone; CI, confidence interval; mths, months.

1. Bahl A, et al., Ann Oncol 2013;24:2402–8. Open Access article distributed under CC-BY-NC Licence (http://creativecommons.org/licenses/by-nc/3.0/); 2. Reprinted from

Lancet Oncol 13, 10, Fizazi K, et al., Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301

randomised, double-blind, placebo-controlled phase 3 study. 983–92, Copyright 2012, with permission from Elsevier; 3. From N Engl J Med, Scher H, et al., Increased Survival

with Enzalutamide in Prostate Cancer after Chemotherapy, 367, 11187–97. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts

Medical Society ; 4. From N Engl J Med, Parker C, et al., Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer, 369, 213–23. Copyright © 2013

Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

BUT ALSO EFFECTIVE

PRE-DOCETAXEL…

COU-AA-3021 PREVAIL2

ORR: 62%

1. From N Engl J Med, Ryan CJ, et al., Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy, 368:138-48. Copyright © 2013 Massachusetts Medical

Society. Reprinted with permission from Massachusetts Medical Society;

2. From N Engl J Med, Beer TM, et al., Enzalutamide in Metastatic Prostate Cancer before Chemotherapy, 371:424–33. Copyright © 2014 Massachusetts Medical

Society. Reprinted with permission from Massachusetts Medical Society.

ALGORITHM SEQUENCING IN mCRPC

WHICH DRUG

FOR

WHICH PATIENT

THERE ARE NO PROSPECTIVE SEQUENCING OR HEAD-TO-HEAD STUDIES TO GUIDE OUR TREATMENT CHOICE IN mCRPC

REGIMEN SEQUENCING

Laboratory parameters

PSA doubling time, LDH, ALP

Clinical Parameters

Symptomatic or asymptomatic disease

Response to previous chemo or hormone, lines of therapy

Radiographic parameters

High or low volume disease

Presence of visceral disease

Other parameters

Other medical history

Disease characteristics (SCPC, anaplastic features)

BIOMARKERS?

Other?

PATIENT AND (ONLY INDIRECTLY)

TUMOUR CHARACTERISTICS

INFLUENCING TREATMENT DECISIONS

Based on Level I evidence and adverse events

Performance status – symptomatic disease

Comorbidities

Based on retrospective experience, Phase 2 results

Time to CRPC

Prior therapy exposure and response

Tumour characteristics

SHORT RESPONSE TO FIRST ADT

(1 YEAR) MAY PREDICT POOR RESPONSE

TO AR-TARGETED THERAPIES

Docetaxel2

188 patients with mCRPC in

2 prospective databases

High Gleason score and visceral

metastases more common

if early CRPC (≤1 year)

Good response to docetaxel

irrespective of time to CRPC

AR-targeted agents1

Retrospective analysis in

108 patients with metastatic PCa

Poor response to subsequent

hormone therapies (including

abiraterone, enzalutamide)

if time to CRPC with first ADT

<16 months

Duration of

response

<16 mo ≥16 mo

↓ PSA ≥50% 18% 58%

Median TTP 3 mo 5 mo

Duration of

response

≤1yr >1yr

↓ PSA ≥50% 67% 81%

Median TTP 6.1 mo 7.1 mo

1. Loriot Y, et al., ASCO GU 2012 (abstract 213); 2. Huillard, ASCO 2013 (abstract 5075).

SEQUENTIAL ADMINISTRATION

OF NEW AGENTS – 1

Few clinical trials

Retrospective uncontrolled post-hoc analysis (inherent bias)

Small sample size

Short follow-up

Evaluation of objective responses not always comparable

Evaluation of cumulative results and not patients’ individual data

Prognostic variables that may influence the clinical outcomes

Not always available

OS since the first initiation of docetaxel never reported

Maines F, et al., Crit Rev Oncol Hematol 2015;96:498–506

PRE- AND POST-DOCETAXEL

SETTING OF ABI AND ENZA COMPARISON

OS in favour for ENZ both in chemotherapy

pretreated (HR 0.85) and naïve (HR 0.90) patients

OS identical in pts with visceral disease and >75 ys

OS relatively (ns) better with ENZ in pts without

visceral disease

ENZ provides a significantly longer time without

PSA progression

ENZ provides a significantly better

radiographic PFS

Zhang W, et al., Asian J Androl 2017;19:196–202. Open access article distributed under the terms of the CC BY-NC-SA 3.0 License

(https://creativecommons.org/licenses/by-nc-sa/3.0/)

It is a not direct comparison!

SEQUENTIAL ADMINISTRATION OF

NEW AGENTS – 2 A comprehensive review of genomic landscape, biomarkers and treatment

sequencing in castration-resistant prostate cancer

Reprinted from Cancer Treat Rev, 48, Seisen T, et al., A comprehensive review of genomic landscape, biomarkers and treatment sequencing in castration-resistant

prostate cancer, 25–33., Copyright2016, with permission from Elsevier.

HETEROGENEITY OF

CLINICAL TRIALS

Reprinted from Crit Rev Hem Oncol 96, 2015, Maines F, et al., Sequencing new agents after docetaxel in patients with metastatic castration-resistant prostate cancer,

498–506, Copyright 2015, with permission from Elsevier.

WHAT ABOUT EARLIER

CHEMOTHERAPY?

What if we start having patients that have already received chemotherapy and have

hormonosensitivity?

Things are changing, since they may have to go directly to second-line

chemotherapy with cabazitexel when disease progresses, or try a re-challenge

with docetaxel

How should we treat castration-resistant prostate cancer patients who have received

androgen deprivation therapy (ADT) plus docetaxel upfront for hormone-sensitive

disease?

Retrospective analysis of the GETUG-AFU 15 Phase 3 trial

Study design

THE FIRST DATA

Lavaud P, et al., ESMO 761P, 2016. Courtesy of Dr Lavaud.

PSA RESPONSE FOR

CRPC PATIENTS

Treated with docetaxel (first- or second-line)

according to time of relapse after upfront

ADT+D treatment (cut-off 13.6 months)

Treated with abiraterone or enzalutamide

(first- or second-line): Patients treated with

upfront ADT+D

Lavaud P, et al., ESMO 761P, 2016. Courtesy of Dr Lavaud.

KAPLAN–MEIER CURVES FOR bPFS

Survival after first-line docetaxel treatment for CRPC in patients treated

for mHSPC with upfront ADT and ADT-D

bPFS after docetaxel for first-line

CRPC was 6 months (95% CI 3.6–

7.7) in the ADT arm and 4.1 months

(95% CI 1.3-4.9) in the ADT+D arm

When used for first-line or second-

line CRPC treatments, next-

generation AR axis-targeted agents

(abiratone or enzalutamide) were

associated with a PSA decline of

more than 50% in 10/12 (83%)

evaluable patients in the ADT

control arm and 10/17 (59%) in

the ADT+D armMedian OS for CRPC

27.5 mo for ADT vs. 23.7 mo for ADT+D

Lavaud P, et al., ESMO 761P, 2016. Courtesy of Dr Lavaud

THERE ARE MORE CONSIDERATIONS…

Upfront metastatic, high-volume bone (lytic?), visceral, high GS

Anaplastic phenotype?

PSA high or low? PSA decline

CTCs?

Methodology of disease measurement

Search of biomarkers (clinical, pathological, molecular, to better identify patients

that may be helped by early chemotherapy)

ARE WE EVALUATING

DISEASE PROPERLY?

We need a more precise identification of disease distribution or volume to better

identify those who most benefit from chemotherapy

WHAT IS EXTENSIVE DISEASE?

Presented By Michael Morris at 2014 ASCO Annual Meeting. J Clin Oncol 32:5s, 2014 (suppl; abstr 5022)

≥4 lesions ≥4 lesions <4 lesions

DIFFERENT APPROACHES OF

DISEASE VOLUME

Disease extent is a powerful prognostic factor for OS

1. Crawford ED, et al., N Engl J Med. 1989;321(7):419–4; 2. rom N Engl J Med , Eisenberger MA, et al., Bilateral Orchiectomy with or without Flutamide for Metastatic

Prostate Cancer, 339, 1036–42; Copyright © 1998 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society; 3. Hussain M, et

al., N Engl J Med 2013;368(14):1314–25; 4. Millikan RE, et al., J Clin Oncol. 2008;26(36):5936–42.

1. First report on disease extent and OS

Minimal: Spine, pelvis and/or lymph nodes

versus

Extensive: Ribs, long bones and/or visceral

organs (liver, lung)

4. MDACC – High volume: ≥3 bone metastases or

visceral disease

Low: 7.8 yrs

High: 3.1 yrs

2. S8894 – Bilateral orchiectomy ± flutamide

3. S9346 – Survival by disease extent for CAD

arm only

24 48 72 9600

20

40

60

80

100

Months of follow-up

OS

(%

)

At risk Death Median (years)

Extensive 362 225 4.4

Minimal 403 220 6.9

5 10 1500

20

40

60

80

100

Years since randomisation

Sur

viva

l (%

)

Flutamide, extensive disease

Placebo, extensive disease

Flutamide, minimal disease

Placebo, minimal disease

Minimal: 51 mo

Extensive: 27.5 mo

Definition low volume disease

Imaging Modality Dependent

BS + SPECT NaF-PET WBMR_DWI

0-4

Bone scan

4-20

18F-choline-PET

>20

NaF-PET

This meta-analysis indicated that MRI was better than choline

PET/CT and BS on a per-patient basis (pooled sensitivities)3

BONE METASTASES

BS, bone scintigraphy.1. Kjölhede H, et al., BJU Int 2012;110:1501–6; 2. Jambor I, et al., Prospective evaluation of planar bone scintigraphy, SPECT, SPECT/CT, 18F-NaF PET/CT and

whole body 1.5T MRI, including DWI, for the detection of bone metastases in high risk breast and prostate cancer patients: SKELETA clinical trial. Acta Oncol

2016;55:59–67, copyright © Acta Oncologica Foundation reprinted by permission of (Taylor & Francis Ltd, http://www.tandfonline.com) on behalf of Acta Oncologica

Foundation; 3. Shen G, et al., Skeletal Radiol 2014;43:1503-13.

Choline PET/CT 0.91 (95% (CI): 0.83–0.96)

MRI 0.97 (95% CI: 0.91–0.99)

BS 0.79 (95% CI: 0.73–0.83)

Patient with prostrate cancer1 Patient with breast cancer2

IS PFS A SURROGATE FOR OS ?

Nx

Age

% M at

presentation

High risk /

Strata ?

Chemo at PD

Control armF/up

Difference

of PFS / OS

CHAARTED 790 63 73% 65% / YES 40% (60%?) 29 mos YES / YES

GETUG-15 385 64 71% 48% / NO 63% 85% 83 mos YES / NO

STAMPEDE 2962 65 61% ?? / NO 44% 43 mos YES / YES

FOLLOW-UP ?

SUBSEQUENT TREATMENTS ?

Consider the total treatment given to patients in each arm of the study:

Intent-to-treat

Presented By Howard Scher at 2015 ASCO Annual Meeting

GETUG-15 CHAARTED

ADT + D ADT ADT + D ADT

Total enrolled 192 193 397 393

Total failed 142 (74%) 146 (81%) 145 (36%) 174 (44%)

Post-prot. docetaxel 54 (28%) 120 (62%) 49 (12%) 129 (32%)

Post-prot. cabazitaxel 3 (2%) 2 (1%) 43 (11%) 29 (7%)

Post-prot. ABI or placebo 19 (10%) 21 (11%) 92 (23%) 79 (20%)

Post-prot. ENZ or placebo 9 (5%) 7 (4%) 0 0

Post-prot. sipuleucel-T 0 0 20 (8%) 20 (8%)

Non-life prolonging 106 (55%) 131 (69%) 49 (12%) 129 (32%)

Courses life prolonging rx. 277 (144%) 150 (78%) 603 (151%) 255 (65%)

Taxane only 249 (130%) 122 (63%) 489 (123%) 158 (40%)

DOCETAXEL (DOC) POST AR

INHIBITION WITH AA

Baseline characteristics and

outcome measures

DOC post-ΑA1

(n=86)

DOC post-AA2

(n=38)

DOC post-ΑA3

(n=23)

DOC post-ΑA4

(n=23)

DOC post-ΑA5

(n=365)

Median age, years (range) 71 (52–85) 71 (46–87) 67 69

ECOG performance status

0–1

≥2

91%

9%

68%

29%

-

-

-

-

Gleason score ≥8 43% 37% 74%

PSA (median, ng/mL) – - 260

Metastatic sites, %

Bone

Lymph node

Visceral

94

23

11

-

-

-

94

23

9

94

23

9

Efficacy endpoints

≥50% PSA, %

≥30% PSA, %

Median OS, months

Median PFS, months

Response, %

26

37

11.6

4.0

9

8

18

7.2

2.7

8

48

65

12.4

4.0

-

40

53

12.4

4.4

-

40Suggestion of lower

efficacy of

subsequent taxanes

1. Mezynski J, Ann Oncol 2012;23:2943-7; 2. Azad AA, The Prostate 74:1544-50(2014); 3. Aggarwal R, Clin Genitourin Cancer. 2014 Oct;12(5):e167-72; 4. Suzman

DL, Prostate 2014 Sep;74(13):1278-85; 5. Flaig TW, et al., ASCO 2015 Abstr. 168.

IMPACT OF PRIOR RESPONSE TO

AA ON DOCETAXEL EFFICACY

86 patients (37 docetaxel naïve)

PSA response rates were not

linked to prior response to AA

No differences in patients

receiving docetaxel for

• PSA response rates

• Median PFS

• Median OS

Azad AA, et al., A retrospective, Canadian multi-center study examining the impact of prior response to abiraterone acetate on efficacy of docetaxel in metastatic

castration-resistant prostate cancer. Prostate 2014;74:1544–50. © 2014 Wiley Periodicals, Inc.

CABAZITAXEL POST-(DOC+AR-

INHIBITION)


outcome measures

CABA

post-DOC-AA/ENZ1

(n=37)

CABA

post-DOC-AA2

(n=24)

CABA

post-DOC-AA3

(n=79)

CABA

post-DOC-AA4

(n=65)

Median age, years (range) 62 65 69


0–1

≥2

83

11

–

–

59

38

PSA (median, ng/mL) 717 128 307

Metastatic sites %

Bone

Lymph node

Visceral

86

54

35

91

66.6

29

71

-

14

Efficacy endpoints

≥50% PSA, %

≥30% PSA, %

Median OS, months

Median PFS, months

Response

41

-

15.8

4.6

15%

31.5

–

8.4

–

15.3%

35

62

10.9

4.4

NR

47

7

24

14.4% in TROPIC

TRIAL

1. Pezzaro CJ, et al., Eur Urol 2014;66:459–465; 2. Sella A, et al., Clin Genitourin Cancer 2014;12(6):428–32;

3. Al Nakouzi N, et al., Eur Urol 2014;68(2):228–35; 4. Caffo O, et al., J Clin Oncol 2014;32:Abstract 5089.

AA POST-ENZ IN mCRPC

POST-CHEMO

Baseline characteristics and outcome measures

AA post-ENZ1

(n=30)AA post-ENZ2

(n=38)AA post-DOC3

(n=103)

Median age, years (range) 70 (56–84) 71 (52–84) 67 (45–85)

ECOG performance status0–1≥2

70%23%

68%29%

66%34%

Gleason score ≥8 43% 37%

PSA (median, ng/mL) – 232 61.7 ng/dL (3-3,000)

Metastatic sites, %BoneLymph nodeVisceral

876030

973926

50.55.8

43.7

Efficacy endpoints≥50% PSA, %≥30% PSA, %Median OS, monthsMedian PFS, monthsResponse, n

311

11.5 3.50

8187.22.78

16.27.06

≥50% PSA response: 3–8%

1. Noonan KL, et al., Ann Oncol 2013;24:1802–7; 2. Loriot Y, et al., Ann Oncol 2013;24:1807–12;

3. Demirci E, et al., J Clin Oncol 32, 2014 (suppl; abstr e16094).

ENZALUTAMIDE POST-AA IN

mCRPC POST-CHEMO (1)


outcome measures

ENZ

post-AA1

(n=79*)

ENZ

post-AA2

(n=26)

ENZ

post-AA3

(n=35)

ENZ

post-AA

(n=150†)

ENZ

post-AA4

(n=24)

ENZ

post-AA

(n=61)

ENZ

post-AA

(n=23)

Median age, years (range) 74 (55–87) 72 (56–88) 72 (60–83) 70 (44–90) 72 (57–82) 69 (64–74) 70 (57–94)


0–1

≥2

–

–

85%

–

77%

23%

–

–

67%

33%

57%

43%

–

–

PSA (median, ng/mL) – – – 102 578 267 144

Metastatic sites %

Bone

Lymph node

Visceral

–

–

–

96

73

3

100

71

17

88

–

19

–

–

–

79

54

21

100

61

48

Efficacy endpoints

≥50% PSA, %

≥30% PSA, %

Median OS, months

Median PFS, months

Response, n

–

–

–

3.6

–

27

54

–

4.9

–

10

13

7.5

3.1

–

–

39

–

–

–

–

46

4.8

–

–

21

46

7.3

2.8

–

17

–

–

1.4

0

*75 post-abiraterone, 62 of whom received abiraterone as last treatment before enzalutamide, †122 patients had prior post-chemotherapy

abiraterone and 28 received. †pre-chemotherapy abiraterone.1. Stevenson R, et al., J Clin Oncol 2014;32(Suppl 4): Abstract 125; 2. Vera-Badillo FE, et al., J Clin Oncol 2014;32(Suppl 4): Abstract 159;

3. Schmid SC, et al., Adv Ther 2014;31:234–41; 4. Thomsen FB, et al., Scand J Urol 2013;48(3):268-75

ENZALUTAMIDE POST-AA IN

mCRPC POST-CHEMO (2)


outcome measures

ENZ

post-AA1

(n=35)

ENZ

post-CYP17i2

(n=20)

ENZ

post-AA3

(n=39)

ENZ

post-AA4

(n=23)

ENZ

post-AA5

(n=24)

ENZ

post-AA6

(n=66)

Median age, years (range) 70 (57–81) 76 (64–84) 70 (54–85) 76 (65–82) 72 (57–82) 74.8 (56–94)


0–1

≥2

–

–

–

–

64.2%

35.8%

65.2%

34.8%

66.7%

33.3%

–

–

PSA (median, ng/mL) – 120 500 – 578 22

Metastatic sites %

Bone

Lymph node

Visceral

–

–

–

65

40

20

84.6

53.8

15.3

95.6

–

17.4

–

–

–

89.4

–

–

Efficacy endpoints

≥50% PSA, %

≥30% PSA, %

Median OS, months

Median PFS, months

Response, n

28.6

37.1

7.1

4.0

1

40

–

–

–

–

12.8

41.1

Not reached

2.8

–

39

–

–

–

–

54.2

45.8

4.8

–

–

–

29

–

–

–

≥50% PSA response: 12–54%

1. Schrader AJ, et al., Eur Urol 2014;65:30–6; 2. Bournakis E, et al., ECC 2013. Poster presentation P413; 3. Bianchini D, et al., Eur J Cancer 2014;50:78–84; 4.

Thomson D, et al., J Clin Oncol 2014;32(Suppl 4): Abstract 188; 5. Thomsen FB, et al., Scand J Urol 2013;48(3):268-75; 6. Scholz MC, et al., J Clin Oncol

2014;32(Suppl 4): Abstract 247.

COMPLETED RETROSPECTIVE

STUDIES OF SEQUENCING AA AND ENZ

Analysis of patients who received AA followed by ENZ in pre-chemotherapy setting

Median duration of ENZ therapy was around 4 months

Similar to the low response rates detected in the post-chemotherapy sequencing studies, Suzman et al.

found that only 34% of patients had >50% PSA decline on ENZ, whereas Azad et al. found that only 25% of

patients had a >50% PSA decline on ENZ

Zhang T, et al., Expert Opin Pharmacother. 2015;16(4):473–85.

In the post-chemotherapy setting

Completed retrospective studies of sequencing AA and ENZ in patients with mCRPC

In the pre-chemotherapy settingAuthors Year published No. of pts Duration of ENZ treatment >50% decline in PSA Median PFS

ENZ → AA

Suzman DL, et al. 2014 30 4 months 34% 4.1 months

Azad AA, et al. 2014 47 4.1 months 25% 4.6 months

Authors Year published No. of pts Duration of 2nd treatment >50% decline in PSA Median PFS

ENZ → AA Loriot Y, et al. 2013 38 3 months 3% 2.7 months

Noonan KL, et al. 2013 30 13 months 3% 3.8 months

AA → ENZ

Schrader AJ, et al. 2013 35 4.9 months 29%

Badrising S, et al. 2014 61 3 months 21%

Bianchini D, et al. 2014 39 2.9 months 23%

Schmid SC, et al. 2014 35 2.8 months 10%

Brasso K, et al. 2014 137 3.2 months 18%

The Hellenic experience of the Name Patient Access Program (NPAP)

ENZALUTAMIDE IN HEAVILY

PRE-TREATED PATIENTS

With bone mCRPC resistant to Androgen Biosynthesis Inhibitor (ABI)

treatmentP

SA

cha

nge

(%)

-100-90

-75

-50

-30

0

25

50

75

100≥50% PSA decline: 40% (8/20)

≥90% PSA decline: 5% (1/20)

Bournakis E, et al., ESMO 2013. Poster presentation P413. Courtesy of Dr Bournakis.

Retrospective study – 47 patients mCRPC

All patients were treated with D and AA

42 patients (89%) CAB

Median age: 69 years (IQR, 63–73.5)

79% had bone metastases; 55% had lymph node metastases; 17% had

visceral metastases

Median duration of ENZ treatment was 12.0 weeks (IQR, 8.3–20.4)

11 patients (23%) responded to ENZ (maximum PSA decline ≥50%)

Median OS: 40.1 weeks (95% CI, 25.4–61.4)

Median PFS: 12.1 weeks (95% CI, 9.9–14.0)

Median time to PSA progression:15.7 weeks (95% CI, 14.0–28.7)

ENZ is well tolerated and there is a 23% response rate in heavily pre-treated

CRPC patients, which is comparable with third-line treatment outcomes

ENZALUTAMIDE AS A FOURTH- OR

FIFTH-LINE TREATMENT OPTION

Badrising SK, et al., Oncology 2016;91(5):267–27

AA VS. ENZALUTAMIDE BEFORE

AND AFTER DOCETAXEL

Median PFS: 19.5 m (AA) vs. 13 m (ENZ)

Median OS: 33.3 m (AA) vs. 30 m (ENZ)

Median PSA-PFS: 29.5 m (AA) vs. 12.3 m (ENZ)

Chance of achieving PSA response to both

1st and 2nd hormonal therapy is significantly

higher in the AA ENZ group (33.8% vs. 6.3%)

Maughan BL, et al., Comparing Sequencing of Abiraterone and Enzalutamide in Men With Metastatic Castration‐Resistant Prostate Cancer: A Retrospective Study.

Prostate 2017;77(1):33–40. © 2014 Wiley Periodicals, Inc.

Enza–Abi sequence

(N=16)

Abi–Enzasequence

(N=65)P-

value

Age (years), median 62 63 0.83

Race, % CaucasianAfrican-AmericanAsian

88120

78167

0.76

Metastatic disease at diagnosis, % 29 30 0.99

PSA (ng/mL) at diagnosis, median 18.9 11.3 0.71

Gleason score, % <88–10

5050

3466

0.36

Prior prostatectomy, % 69 44 0.10

Prior ketoconazole, % 31 25 0.75

Prior docetaxel, % 12 32 0.21

ECOG PS, % 0–1>1

937

964

0.50

Bone pain present, % 13 31 0.33

Visceral disease present, % 19 11 0.42

PSA (ng/mL), prior to first agent in sequence, median

33.1 29.8 0.40

Alkaline phosphate (U/L), median 83 88 0.40

Hb (g/dL), median 12.6 12.2 0.20

Albumin (g/dL), median 4.2 4.1 0.17

Number of bone lesions, % <9≥9

6931

6238

0.77

RESISTANCE MECHANISMS

Prognostic markers

Multiple clinical nomograms

CALGB: LDH, haemoglobin (Hb), albumin, alkaline phosphatase, PSA,

VISCERAL metastases, pain/opioids, PS

Neutrophil:Lymphocyte ratio

CTC enumeration (CellSearch)

cfDNA quantification

What about predictive markers?

Can we interrogate tumour to assess response based upon MOA?

PRIMARY RESISTANCE

1. From N Engl J Med, de Bono JS, et al., Abiraterone and Increased Survival in Metastatic Prostate Cancer, 364:1995-2005. Copyright © 2011 Massachusetts

Medical Society. Reprinted with permission from Massachusetts Medical Society.

2. From N Engl J Med, Scher H, et al., Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy;367:1187-97. Copyright © 2012 Massachusetts


AS SECOND-LINE CHEMO IN

mCRPC

PSA response rates for cabazitaxel (post-docetaxel) are quite similar

pre- and post-abiraterone

Post-abiraterone Pre-abiraterone

Saad F, et al., Can Urol Assoc J.2016;10:102–9. © 2016 Canadian Urological Association. With permission from Can Urol Assoc J.

LDH ???

Predictive markers of PSA response to AA in mCRPC

Leibowitz-Amit R and Templeton AJ, J Clin Oncol 2013;31(15S):322s(abs.5058).

60 5645

27

00

20

40

60

80

100

0 1 2 3 4

Res

pons

e ra

te (

%)

Composite score

PSA response according to total score

Multivariable analyse

Variable P Comparison OR 95% CI

NLR 0.04‘0’ vs ‘1’

‘2’ vs ‘1’

1.07

0.24

0.4–3.1

0.07–0.8

LDH 0.33 ‘0’ vs 1.58 0.6–4.0

Met extension 0.02 ‘0’ vs ‘1’ 2.83 1.2–6.9

Elevated LDH

increases risk

of non-response

CLINICAL OUTCOME OF TAXANE

TREATMENT VS. AR-TREATMENT

ACCORDING TO AR-V7 STATUS

PSA response: 65% Taxane,

64% ENZA/AA, p=0.60, adjusted p=0.36

Cox model adjusting for: AR-FL

level, prior use of ENZA/AA

Antonarakis ES, et al.. JAMA Oncol 2015;1(5):582–91

0 3 6 9 12 15Time (months)

18 210.0

0.2

0.4

0.6

0.8

1.0

PS

A P

FS

No. at risk

Taxane 17 9 3 0 0 0 0 0

ENZA or AA 18 2 0 0 0 0 0 0

Adjusted p=0.001

Taxane, AR-V7 positive

ENZA or AA, AR-V7 positive

0 3 6 9 12 15Time (months)

18 210.0

0.2

0.4

0.6

0.8

1.0

PF

S

17 11 2 0 0 0 0 0

18 6 1 0 0 0 0 0

Adjusted p=0.003

0 3 6 9 12 15Time (months)

18 210.0

0.2

0.4

0.6

0.8

1.0

OS

17 15 7 5 2 1 0 0

18 14 11 10 5 2 0 0

Adjusted p=0.06

0 3 6 9 12 15Time (months)

18 210.0

0.2

0.4

0.6

0.8

1.0

No. at risk

Taxane 20 12 7 3 0 0 0 0

ENZA or AA 44 36 23 16 10 1 0 0

Adjusted p=0.83

0 3 6 9 12 15Time (months)

18 210.0

0.2

0.4

0.6

0.8

1.0

PF

S

20 16 8 4 0 0 0 0

44 41 30 20 16 3 0 0

Adjusted p=0.96

0 3 6 9 12 15Time (months)

18 210.0

0.2

0.4

0.6

0.8

1.0

OS

20 16 10 8 5 2 0 0

44 43 43 41 31 15 4 0

Adjusted p=0.46

Taxane, AR-V7 negative

ENZA or AA, AR-V7 negativePS

A

PF

S

OUTCOMES: AR-V7

“CONVERSIONS”

Clinical outcomes of AR-V7– to AR-V7+ men were intermediate

Outcome AR-V7– AR-V7–

(n=36/42)

AR-V7– AR-V7+

(n=6/42)

AR-V7+ AR-V7+

(n=16)

PSA response68%

(95% CI, 52–81%)

17%

(95% CI, 4–58%)

0%

(95% CI, 0–19%)

PSA PFS6.1 months

(95% CI, 5.9 mo – NR)

3.0 months (95% CI, 2.3 mo – NR)

1.4 months (95% CI, 0.9–2.6 mo)

PFS6.5 months

(95% CI, 6.1 mo – NR)

3.2 months

(95% CI, 3.1 mo – NR)

2.1 months

(95% CI, 1.9–3.1 mo)

Antonarakis ES, ASCO 2014, A 5001.

N=37 patients, starting taxane Rx, prior AA/ENZA allowed, 1º: PSA response

17/37 (46%) AR-V7+ CTCs (25% in NO prior AA/ENZA, 50% in either, 53% in both)

AR-V7+: Younger, GS >8, prior ENZA/AA, >bone, PSA, ALkP, AR-FL

PSA responses (54%, 41% in AR-V7+, 65% in AR-V7–), PSA PFS, PFS

numerically better in AR-V–, but NS

AR-V7– : 11% +, 89% remained – Low conversion rate with taxanes?

AR-V7+ : 58% –, 42% remained + CTC disappearance?

If so, could taxane Rx restore sensitivity to secondary hormonal therapies?

BUT clinical info is NOT supporting this now

AR-V7 AND EFFICACY OF TAXANE

CHEMOTHERAPY IN PATIENTS WITH mCRPC

Compared with 62 patients from previous trial

In AR-V7+ men, taxanes appear to be more efficacious than ENZA or AA

(PSA response, PSA PFS, cPFS)

In AR-V7– men, taxanes and ENZA or AA may have comparable efficacy

Antonarakis ES, et al., JAMA Oncol 2015;1(5):582–91

RESISTANT REVERSIONS

THROUGH TIME POST TREATMENTS LINES

(A) AR-V7– at BASELINE (n=15)

TreatmentRemained

AR-V7–"Conversions" to

AR-V7+

First-line ADT (n=2) 1 1

Abiraterone (n=4) 3 1

Enzalutamide (n=4) 1 3

Docetaxel (n=3) 0 3

Cabazitaxel (n=2) 0

Total (n=15) 7 8

(B) AR-V7+ at BASELINE (n=22)

TreatmentRemained

AR-V7+"Reversions" to

AR-V7–

First-line ADT (n=0) 0 0

Abiraterone (n=5) 4 0

Enzalutamide (n=4) 4 0

Docetaxel (n=9) 4 5

Cabazitaxel (n=4) 1 1

Total (n=22) 13 6

(A) Number of baseline

AR-V7– individuals that either remained

AR-V7– or converted to AR-V7+

during treatment

(B) Number of baseline

AR-V7+ individuals that either remained

AR-V7+ or reverted back to AR-V7–

during treatment

AR-V7+ may be associated with primary and acquired resistance to ENZA and AA

If validated AR-V7+ patients could be steered away from receiving AR-targeting drugs

and could be offered alternative treatments

CABAZITAXEL RETAINS ACTIVITY

IN AR-V7+

Reprinted from European Urology 68(2015), Onstenk W, et al., Efficacy of Cabazitaxel in Castration-resistant Prostate Cancer Is Independent of the Presence of AR-

V7 in Circulating Tumor Cells, 939–945, Copyright (2015), with permission from Elsevier.

Detection of AR-V7 in CTCs from men with mCRPC is not associated with

primary resistance to taxane agents

AR-V7–positive patients may retain sensitivity to taxanes

In AR-V7–positive men:

Taxanes may be more efficacious than AR-directed therapies

In AR-V7–negative men:

Taxanes may have comparable efficacy to AR-directed agents

AR-V7 may be a treatment-selection marker in mCRPC

CLINICAL CONCLUSIONS

CTCs COLLECTIONS POST

THERAPY LINES

161 patients

Reproduced with permission from JAMA Oncol 2016;2(11):1441–9. Copyright © 2016 American Medical Association. All rights reserved.

LIQUID BIOPSY AND CELL-FREE

DNA TO GUIDE THERAPY

Hegemann M, et al., Liquid biopsy: ready to guide therapy in advanced prostate cancer? BJU International 2016;118(6):855–86. © 2016 BJU International

Compensate for the heterogeneity between different cancer foci

Easier to obtain

Can be repeated at different time points

Stage dependent

“AR ON” cells (PSA+ and PSMA–) are mostly found in hormone-naïve patients changing to

“AR OFF” after induction of androgen deprivation

Transition from “AR ON” to “ AR mixed” or ‘”AR OFF” during treatment with AA was prognostic

Detection of ARVs

The blood of a proportion of patients can contain CTCs derived from the primary

tumour and different metastatic sites (CellSearch)

75% of pts with advanced PrCa

≥5 CTCs in 7.5 mL has been validated as a prognostic marker in mCRPC receiving

docetaxel or AA

Increase in CTCs at any point under treatment was associated with reduced OS

More prognostic than PSA

CTCs with stem cell features contribute to metastases

However, lack of sensibility within CRPC

LIQUID BIOPSY TO GUIDE

THERAPY

Scher HI, at al., Nat Rev Clin Oncol 2013;10:225–34.

“MUTATION GUIDED” THERAPY

Overall, 16 patients (33%) had tumour aberrations in DNA-repair genes. BRCA2 aberrations were

detected in 7 patients

Other:

BRCA1

ATM

Fanconi’s anaemia genes

CHEK2

Mateo J, et al., N Engl J Med 2015;373(18):1697–708.

Platinum sensitivity?

From N Engl J Med, Mateo J, et al., DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer, 373, 1697–708. Copyright © 2015 Massachusetts Medical

Society. Reprinted with permission from Massachusetts Medical Society

PLATINUM-BASED THERAPY IN

HEAVILY PRETREATED mCRPC PATIENTS

Platinum-based therapy plus oral cyclophosphamide is a tolerable and promising regimen for heavily

pretreated poor PS mCRPC patients with some “anaplastic” disease features as opposed to best supportive care.

Carboplatin seems to be more effective in terms of time to response and response rates

Bournakis E, et al., Abstract Medical Oncology ESMO 2015. Reproduced courtesy of Dr Bournakis.

AT FIRST LINE IN SPECIAL

POPULATIONS

Cabazitaxel + carboplatin with G-CSF

1. Corn PG, et al., J Clin Oncol 2016;33 suppl; abstr 5010; 2. Corn PG, et al. J Clin Oncol 2016;34 suppl; abstr 5020. Courtesy of Dr PG Corn

Loriot Y, et al., Ann Oncol 2009;20(4):703-8; Rechon A, et al. Ann Oncol 2011;22(11):2476-81, both by permission of Oxford University Press on behalf of the

European Society for Medical Oncology.

Bournakis E, et al., Abstract Medical Oncology ESMO 2015. Reproduced courtesy of Dr Bournakis

AA WITHDRAWAL TO AVOID

RESISTANCE

AA withdrawal seems to be a safe and promising choice for

a carefully chosen cohort of mCRPC patients with common

characteristics such as slow-rising PSA values, slow PSA-DT

(>3 m) under treatment, asymptomatic status and no radiological

progression. Probably, patients with bone metastases only or LN

might be the ones to whom such a choice could apply

Molecular stratification – Somatic and germline DNA analyses

DNA repair defective mCRPC – treatment with PARP inhibitors

PTEN loss mCRPC – combined AR and AKT blockade

High mutational load mCRPC – immunotherapy

Better treatment of local disease for M1 at diagnosis patients

Radiation? Surgery?

Predictive biomarkers for established drugs

Abiraterone and enzalutamide AR-aberrations

Taxane therapy

WHAT MAY COME NEXT FOR

TREATING M-PC?

SEQUENCING DECISIONS BASED ON OVERALL THERAPEUTIC PLANIn hormone sensitive patients

new data arise

In hormone-naïve prostate cancer, AA + prednisolone improves

Overall survival by 37%

Failure-free survival by 71%

Symptomatic skeletal events by 55%

Treatment was well tolerated

AA + prednisolone should be part of the standard of care for men starting

long-term androgen-deprivation therapy

WHAT ABOUT EARLIER NEW

AR-AGENTS? SUCH AS ABIRATERONE

Fizazi K, et al., N Engl J Med 2017;377(4):352–60

STUDY DESIGN

Efficacy end points

Co-primary:

OS

rPFS

Secondary: time to

Pain progression

PSA progression

Next symptomatic

skeletal event

Chemotherapy

Subsequent PC therapy

ADT + AA 1000 mg QD

+ prednisone 5 mg QD

(n=597)

ADT

+ placebos

(n=602)

Patients

Newly diagnosed adult

men with high-risk mHNPC

Meets at least 2 of 3

high-risk criteria

Gleason score of ≥8

Presence of ≥3 lesions on bone scan

Presence of measurable visceral lesion

Stratification factors

Presence of visceral disease (yes/no)

ECOG PS (0, 1 vs. 2)

Conducted at 235 sites in 34 countries in Europe, Asia-Pacific, Latin America,

and Canada

Designed and fully enrolled prior to publication of CHAARTED/STAMPEDE results

R

1:1

Fizazi K, et al., N Engl J Med 2017;377(4):352–60

THE FIRST DATA

At a median follow-up of 30.4 months (48% of total deaths), the addition of AA and prednisone

to ADT significantly improved OS, with a 38% reduction in the risk of death

The 3-year OS rate was 66% in the ADT-AA-prednisone group compared with 44% in the

ADT-placebos group

From N Engl J Med, Fizazi K, et al., Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer, 377, 352–60, Copyright © 2017


– Not reached

34.7 mo

How should we treat castration-resistant prostate cancer patients who have received

androgen deprivation therapy (ADT) plus docetaxel upfront for hormone-sensitive disease?

Retrospective analysis of the GETUG-AFU 15 Phase 3 trial

Study design

THE FIRST DATA

Lavaud P, et al., ESMO 761P, 2016.

CHAARTED

Hazard Ratio 0.61

(95% CI 0.47–0.80; p<0.0001)

Median overall survival

ADT + DOC

57.6 mos

ADT alone

44.0 mos

ADT: androgen deprivation therapy; DOC: docetaxel; OS: overall survival; mths: monthsFrom N Engl J Med, Sweeney C, et al., Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer, 373, 737-46. Copyright © 2015 Massachusetts


Hazard Ratio 0.60

(95% CI 0.45-0.81) P=0.0006

Hazard Ratio 0.63

(95% CI 0.34-1.17) P=1398

17-month benefit in median OS (from 32.2 to 49.2 months) for high volume

We projected 33 months in ADT arm with collaboration of SWOG9346 team

High volume Low volume

ADT alone

32.2 mths

ADT + DOC

49.2 mths

ADT alone

Not reached

ADT + DOC

Not reached

OVERALL SURVIVAL BY EXTENT OF

METASTATIC DISEASE AT START OF ADT

ADT: androgen deprivation therapy; DOC: Docetaxel 75 mg/m2

From N Engl J Med, Sweeney C, et al., Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer, 373, 737-46. Copyright © 2015 Massachusetts


287/700 pts became CRPC: 50% docetaxel

28% AA or enzalutamide

CHAARTED: SUBGROUPS BENEFIT

FROM DOCETAXEL

ADT: androgen deprivation therapy; DOC: Docetaxel 75 mg/m2

From N Engl J Med, Sweeney C, et al., Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer, 373, 737-46. Copyright © 2015 Massachusetts


SOC 405 deaths

SOC+DOC 165 deaths

HR (95% CI) 0.76 (0.63, 0.91)

P-value 0.003

Non-PH p-value 0.51

Restricted mean OS time

SOC 58.8 m

SOC+DOC 63.4 m

Diff (95% CI) 4.6 m (1.8, 7.3 m)

NOT HIGH AND LOW BURDEN

DISEASE OR OTHER PROGNOSTIC

STRATIFICATION

James N, et al., J Clin Oncol 2015;33(15_suppl):5001

Median OS (95% CI)

SOC: 67m (60, 91m)

SOC+DOC: 77m (70, NR)

SOC+Doc

SOC

Docetaxel: Survival

0 12 24 36 48 60

Time from randomisation (months)

72 84

0.0

0.2

0.4

0.6

0.8

1.0

Ove

rall

surv

ival

At risk (events)

SOC 1184 (73) 1092 (130) 860 (89) 521 (59) 310 (33) 156 (17) 81 (2) 36

SOC+DOC 592 (33) 545 (51) 437 (32) 283 (19) 180 (12) 91 (12) 48 (6) 18

Reprinted from Eur Urol 69, 4, Tucci M, et al., Addition of Docetaxel to Androgen Deprivation Therapy for Patients with Hormone-sensitive Metastatic Prostate

Cancer: A Systematic Review and Meta-analysis, 563–73. Copyright 2015, with permission from European Association of Urology.

No heterogeneity between trials1

27% reduction in the risk of death in metastatic patients (HR 0.73; p=0.002)1

33% reduction in the risk of death in metastatic patients with high volume metastatic

disease (HR 0.67)1

No significant interaction between docetaxel and the disease volume (p=0.5)1

Low powered statistical calculation due to the low number of events and limited

follow-up?1

23% reduction in the risk of death2

META-ANALYSIS

1. Tucci M, et al., Eur Urol 2016;69:563–73; 2. Vale CL, et al., Lancet Oncol 2016;17(2): 243–56.

OS – STAMPEDE “ABIRATERONE

PLUS PREDNISONE COMPARISON”

HR 0.63

95% CI 0.52 to 0.76

p-value 0.00000115

This represents a 37% improvement in survival

James ND, et al., N Engl J Med 2017;377:338–51

Trt = SOC by Kaplan–Meier

Trt = SOC + AAP by Kaplan–Meier

SOC by flexible parametric model

SOC + AAP by flexible parametric model

SOC + AAP

6 24 30 360

0.2

0.4

0.6

0.8

1.0

Time from randomisation (months)

Ove

rall

surv

ival

0.0

12 18 42 48 54

No. of pts (events)

SOC 957 (37) 909 (88) 806 (92) 491 (36) 123

SOC + AAP 960 (26) 917 (63) 840 (67) 541 (25) 161



Time period (co-recruiting arms)

Recurrent disease

Is radiotherapy planned?

NSAID/Aspirin use

WHO PS 0 vs 1-2

Age at randomisation (cats)

Gleason Sum Score (cats)

Nodal status

Mets status

Subgroup

Overall

A-----GH--

ABC-E-GH--

ABC-E-G---

Yes

No

RT planned

No RT planned

Uses either

No use

1-2

0

70 or over

Under 70

unknown

8-10

<=7

NX

N+

N0

M1

M0

Dths/N

SOC-only

123/580

17/49

122/328

8/38

254/919

36/396

226/561

71/239

191/718

80/213

182/744

82/361

180/596

6/13

216/721

40/223

15/36

164/483

83/438

218/502

44/455

Dths/N

SOC+AAP

79/583

10/47

95/330

13/60

171/900

24/396

160/564

52/246

132/714

47/215

137/745

74/357

110/603

7/24

144/715

33/221

10/42

113/484

61/434

150/500

34/460

p-value

Interaction

0.62

0.19

0.89

0.35

0.11

0.0026

0.57

0.8

0.37

(95% CI)

Haz. Ratio

0.63 (0.52, 0.76)

0.59 (0.44, 0.78)

0.60 (0.27, 1.33)

0.69 (0.53, 0.90)

0.94 (0.35, 2.52)

0.61 (0.50, 0.74)

0.64 (0.38, 1.08)

0.63 (0.51, 0.77)

0.71 (0.50, 1.02)

0.59 (0.47, 0.74)

0.50 (0.35, 0.72)

0.69 (0.56, 0.87)

0.94 (0.69, 1.29)

0.51 (0.40, 0.65)

0.47 (0.11, 1.91)

0.59 (0.48, 0.73)

0.76 (0.48, 1.23)

0.68 (0.29, 1.57)

0.61 (0.48, 0.77)

0.69 (0.49, 0.96)

0.61 (0.49, 0.75)

0.75 (0.48, 1.18)

Favours: abiraterone SOC-only

.2 .4 .6 .8 1 1.2 1.4

SOC vs SOC+AAP

From N Engl J Med, James ND, et al., Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy, 377:338–51. Copyright © 2017


LATITUDE RESULTS

OS rate at 3 years:

ADT+AA+P: 66%

ADT+PBOs: 49%

These findings indicate that

the addition of AA + P to ADT

can potentially be considered

a new standard of care for

patients with high-risk, newly-

diagnosed mCNPC

From N Engl J Med, Fizazi K, et al., Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer, 377, 352–60, Copyright © 2017 Massachusetts

Medical Society. Reprinted with permission from Massachusetts Medical Society

Significantly significant 38% risk reduction of death

Significantly significant 70% risk reduction of time to PSA progression

[ADT+AA+Pred, not reached]

[ADT+PBOs, 34.7 mo]No. events: 406 (48% of 852)

ADT+AA+P: 169

ADT+PBOs: 237

Median follow-up:

30.4 mo

[ADT+AA+Pred, 33.2 mo]

[ADT+PBOs, 7.4 mo]

status

Mets

Overall

M1

M0

Dths/N

SOC-only

218/502

44/455

Dths/N

SOC+AAP

150/500

34/460

(95% CI)

Haz. Ratio

0.63 (0.52, 0.76)

0.61 (0.49, 0.75)

0.75 (0.48, 1.18)

Favours: abiraterone SOC-only

.2 .4 .6 .8 1 1.2 1.4

SOC vs SOC+AAP



Overall survival by metastatic status – pre-planned analysis

Mets * treatment interaction

P-value 0.37

No good evidence of heterogeneity by metastatic status

0.63

From N Engl J Med, James ND, et al., Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy, 377:338–51. Copyright © 2017


In hormone-naïve prostate cancer, abiraterone acetate + prednisolone

improves: Overall survival and failure-free survival

When

Meets at least 2 of 3 high-risk criteria

Gleason score of ≥8

Presence of ≥3 lesions on bone scan

Presence of measurable visceral lesion

…is a possible option

Who is the early-chemo candidate patient ?

Maybe when we have the clinical presentation of a more aggressive disease,

such as multiple visceral lesions or rapidly progressive in restaging, before any

treatment in hormone-naïve patients

NOT really clear yet!

WHAT MAY COME NEXT FOR

TREATING HSPC?

mCRPC

Ideal treatment sequence NOT known

Resistance mechanisms and biomarkers, if better elucidated, could provide

insight into treatment selection

Upon clinical suspicion of anaplastic/NePC

Short response (<1 year) to 1st-line ADT, lack of undetectable PSA with 1st ADT

High Gleason score (8–10), short PSA doubling time (<4–6 mo)

Visceral metastases, predominantly lytic bone metastases

Disproportionally low PSA to tumour burden, presence of B symptoms

See a medical oncologist and discuss it early…

SCPC and “anaplastic” “IAC” share neuroendocrine pathways and their

reliance on AR is little, if any – treatments aiming at AR are not efficacious

TAKE HOME MESSAGES

THANK YOU!

Documents

Sequencing in Metastatic Prostate Cancer Treatment · sequencing in castration-resistant prostate cancer Reprinted from Cancer Treat Rev, 48, Seisen T, et al., A comprehensive review