understanding the current prostate cancer treatment paradigm .pdf · understanding the current...

Understanding the Current Prostate Cancer Treatment Paradigm

Richard J. Lee, M.D., Ph.D. Assistant Professor of Medicine, Harvard Medical School

Mass General Hospital Cancer Center

PHEN Thirteenth Annual Summit

21 September 2017

2

Disclosures

2

Research funding •  Janssen

Advisory board •  Bayer

•  AstraZeneca

•  Genentech

3

The MGH Prostate Cancer Team

3

Richard Lee Dror Michaelson Philip Saylor Matthew Smith Carol Gurski Erika Meneely Kara Olivier

Our patients

Douglas Dahl Adam Feldman Niall Heney Scott McDougal Frank McGovern Aria Olumi Shahin Tabatabaei Matt Wszolek

Jason Efstathiou David Miyamoto Christine Olsen Bill Shipley Anthony Zietman

Kristina Braaten Esther Oliva Chin-Lee Wu Robin Young

Mukesh Harisinghani Peter Mueller Joe Simeone

Outline

An overview of major changes in prostate cancer care since 2010…

•  Hormone therapies

•  Chemotherapies

•  Immunotherapy

•  Radiation therapy

Outstanding questions

4

Treatment of prostate cancer 2009

5

Time

Tum

or B

urde

n / P

SA

Castration (ADT)

Secondary Hormone Rx

Castration-resistant

Highly variable

Castration-sensitive

Surgery or radiation

Localized cancer Recurrent or metastatic cancer

Docetaxel


6

Time

Tum

or B

urde

n / P

SA

Castration (ADT)


Docetaxel


Highly variable




Abiraterone

Cabazitaxel

Enzalutamide

Radium-223

Sipuleucel-T

Abiraterone

Enzalutamide

Docetaxel

Salvage RT + hormones

Docetaxel

Abiraterone

2017

2014-2017

2010-2014

FDA-approved drugs for mCRPC, 2010-2014

Improved Overall Survival

•  4/29/10: sipuleucel-T

•  6/17/10: cabazitaxel (post-docetaxel)

•  4/28/11: abiraterone (post-docetaxel)

•  8/31/12: enzalutamide (post-docetaxel)

•  12/10/12: abiraterone (pre-docetaxel)

•  5/15/13: radium-223 dichloride

•  9/10/14: enzalutamide (pre-docetaxel)

Supportive Care

•  11/18/10: denosumab (for prevention of skeletal problems)

•  9/19/11: denosumab (for fracture prevention)

7

First, some basics: Understanding the data: Things we care about in clinical trials

Number of patients What is the “treatment arm” compared against (“control

arm”)? Was there adequate follow-up? Were any findings statistically significant?

8

Understanding the data: “Survival curves” (Also called the Kaplan-Meier curve)

9

Perc

ent A

live

Time

100

50

0

Treatment B

Treatment A

And some way-way-way-background: Castration stops testosterone stimulation of

prostate cancer via the androgen receptor (AR)

10

AR DHT

AR DHT

DHT

testosterone

AR AR

h growth, survival, PSA

Nobel Prize in Physiology or Medicine, 1966 “for his discoveries concerning hormonal treatment of prostatic cancer”

Source: www.Nobelprize.org

Charles Huggins, M.D. (1901 – 1997)

1. Huggins C, Hodges CV. Cancer Res 1941; 1: 293-297. 2. Huggins C, R.E. Stevens J, Hodges CV. Arch Surg 1941; 43: 209-233.

Some definitions

Androgen deprivation therapy (ADT) = castration therapy

•  Goal: lower testosterone (T) to castrate levels

•  Surgical castration (bilateral orchiectomy)

•  Medical castration –  GnRH agonists (leuprolide,

goserelin, triptorelin, buserelin, histrelin)

–  GnRH antagonist (degarelix)

11


12

Time

Tum

or B

urde

n / P

SA

Castration (ADT)


Docetaxel


Highly variable




Docetaxel


Recurrent prostate cancer after prostatectomy

A detectable level of PSA indicates persistence or recurrence of prostate cancer

Some men may be cured with “salvage radiation therapy”

RTOG 9601 asked whether anti-androgen therapy could improve outcomes (cancer control, overall survival) when added to radiation therapy

13

Bicalutamide + RT: better outcomes

14 Shipley et al. N Eng J Med 2017; 376: 417-428.

12y: 76% vs 71% alive

12y: 14.5% vs 23% with metastasis


15

Time

Tum

or B

urde

n / P

SA

Castration (ADT)


Docetaxel


Highly variable




Docetaxel


Docetaxel

Abiraterone

Newly diagnosed metastatic prostate cancer

ADT has been the standard approach

In 2004, docetaxel was FDA-approved for castration-resistant disease due to 2 studies that demonstrated a benefit in overall survival

Shortly thereafter, investigators tried giving docetaxel to newly-diagnosed, castration-sensitive prostate cancer patients

16

Tannock et al. N Engl J Med 2004; 351: 1502-1512. Petrylak et al. N Engl J Med 2004; 351: 1513-1520.

16.5 mos

17.4 mos

18.9 mos

What about earlier use of docetaxel in metastatic castration-sensitive prostate cancer?

17

Pros

•  Attack testosterone-independent clones early

•  Might allow ADT to keep disease in remission for longer period of time

•  Some patients at the time of progression are too frail for chemo

Cons

•  ADT may take cells out of cycle, making them less responsive to cytotoxics

•  Some patients response to ADT for a long time and never need chemotherapy (overtreatment)

2015/2016: CHAARTED and STAMPEDE

18

Sweeney et al. N Engl J Med 2015; 373: 737-746. James et al. Lancet 2016; 387: 1163-1177.

CHAARTED primary endpoint: Overall Survival

19 Sweeney et al. N Engl J Med 2015; 373: 737-746.

13.6mo improvement!

17mo improvement!

2017: LATITUDE and STAMPEDE

20

James et al. N Engl J Med 2017; 377: 338-351. Fizazi et al. N Engl J Med 2017; 377: 352-360.

Abiraterone studies: primary endpoint: Overall Survival

21

Fizazi et al. N Engl J Med 2017; 377: 352-360.

34.7 months vs not reached

James et al. N Engl J Med 2017; 377: 338-351.

LATITUDE STAMPEDE


22

Time

Tum

or B

urde

n / P

SA

Castration (ADT)


Docetaxel


Highly variable




Docetaxel


Docetaxel

Abiraterone Abiraterone

Cabazitaxel

Enzalutamide

Radium-223

Sipuleucel-T

Abiraterone

Enzalutamide

FDA-approved drugs for mCRPC, 2010-2014

Improved Overall Survival

•  4/29/10: Sipuleucel-T

•  6/17/10: Cabazitaxel (post-docetaxel)

•  4/28/11: Abiraterone (post-docetaxel)

•  8/31/12: Enzalutamide (post-docetaxel)

•  12/10/12: Abiraterone (pre-docetaxel)

•  5/15/13: Radium-223 dichloride

•  9/10/14: Enzalutamide (pre-docetaxel)

23

Overall survival curves

24

Kantoff et al (2010) N Engl J Med 363: 411-422.

25.8 mos 21.7 mos

p = 0.03

Sipuleucel-T

15.1 mos 12.7 mos

p < 0.0001

Cabazitaxel

De Bono et al (2010) Lancet 376: 1147-1154.

De Bono et al (2011) N Engl J Med 364: 1995-2005.

14.8 mos

10.9 mos

p < 0.001

Abiraterone post-docetaxel

Ryan et al. Lancet Oncol 2015; 16: 152-160.

34.7 mos 30.3 mos

Abiraterone pre-docetaxel

Scher et al (2012) N Engl J Med 367: 1187-1197.

Beer et al. N Engl J Med 2014; 371: 424-433.

30.2mos

29% reduction in risk of death

32.4mos

Enzalutamide pre-docetaxel

Parker et al. N Engl J Med 2013; 369: 213-223.

Radium-223

Sipuleucel-T (Provenge)

A vaccine delivered via intravenous infusion Mechanism / logistics: •  “Autologous active cell immunotherapy”: a patient’s own

blood cells are removed, “activated” with a protein (PA2024, prostatic acid phosphatase fused to GM-CSF), and re-infused

•  Requires 3 rounds of pheresis and re-infusion 3 days later

25 Kantoff et al. N Engl J Med 2010; 363: 411-422.

Cabazitaxel (Jevtana)

An intravenous chemotherapy like docetaxel Mechanism: interferes with cell division, but may be less

likely to be pumped out of cancer cells than docetaxel

Phase III trial design •  Patients who have progressed on docetaxel therapy

26

Why bother with hormone therapies if the disease is “castration resistant”?

Mechanisms of resistance to hormone therapy •  Androgen production from non-testicular sources

–  Adrenal glands

–  Tumor cells themselves

•  AR gene mutations (18-50%)

•  AR gene amplification (up to 30%)

•  Other ways to activate the AR without testosterone (ligand-independent)

27

Abiraterone acetate (Zytiga)

Oral medication, taken daily, with prednisone (steroid) Mechanism: •  A steroidogenesis inhibitor

•  Irreversible inhibitor of 17α-hydroxylase and C17,20-lyase CYP17 activity, two enzymes that are important for testosterone production in the adrenal glands

28

Enzalutamide (Xtandi)

Oral medication, taken daily Mechanism of action •  An anti-androgen

•  Competes for androgen binding to AR

•  Inhibits AR translocation to the nucleus

•  Inhibits binding to DNA

29

AR DHT

AR DHT

DHT

testosterone

AR AR

h growth, survival, PSA

X X

X X

Radium-223 dichloride (Xofigo)

An intravenous radiation treatment

Mechanism •  A radioisotope containing an α-emitting nuclide

•  Targets bone metastases with high-energy α radiation of extremely short range that spares bone marrow, limiting toxic effects

•  For patients with bone-only or bone-dominant disease

Logistics: monthly infusions x 6 months

30

Overall survival curves

31

Kantoff et al (2010) N Engl J Med 363: 411-422.

25.8 mos 21.7 mos

p = 0.03

Sipuleucel-T

15.1 mos 12.7 mos

p < 0.0001

Cabazitaxel

De Bono et al (2010) Lancet 376: 1147-1154.


14.8 mos

10.9 mos

p < 0.001

Abiraterone post-docetaxel

Ryan et al. Lancet Oncol 2015; 16: 152-160.

34.7 mos 30.3 mos

Abiraterone pre-docetaxel


Beer et al. N Engl J Med 2014; 371: 424-433.

30.2mos

29% reduction in risk of death

32.4mos

Enzalutamide pre-docetaxel

Parker et al. N Engl J Med 2013; 369: 213-223.

Radium-223

mCRPC and overall survival

32

Agent(s) N OS improvement P

Docetaxel-Naive

Mitoxantrone + hydrocortisone 119 12.3mo 0.3mo 0.77

Hydrocortisone 123 12.6mo

Docetaxel/estramustine 338 17.5mo 1.9mo 0.02

Mitoxantrone 336 15.6mo

Docetaxel/prednisone q3wk 335 18.9mo

2.4mo 0.009

0.36 Docetaxel/prednisone q1wk 334 17.4mo

Mitoxantrone/prednisone q3wk 337 16.5mo

Abiraterone acetate/prednisone 546 34.7mo 4.4mo 0.01

Placebo/prednisone 542 30.3mo

+/- Docetaxel

Sipuleucel-T 341 25.8mo 4.1mo 0.03

Placebo 171 21.7mo

Radium-223 chloride 541 14.0mo 2.8mo 0.00046

Placebo 268 11.2mo

Docetaxel-

pretreated

Cabazitaxel/prednisone 378 15.1mo 2.4mo <0.0001

Mitoxantrone/prednisone 377 12.7mo

Abiraterone acetate/prednisone 797 14.8mo 3.9mo <0.001

Prednisone 398 10.9mo

Enzalutamide 800 18.4mo 4.8mo <0.001

Placebo 399 13.6mo

(1) Kantoff et al. (1999) J. Clin Oncol. 17: 2506 – 2513. (2) Petrylak et al. (2004) N. Engl. J. Med 351: 1513 - 1520. (3) Tannock et al. (2004) N. Engl. J. Med 351: 1502 – 1512. (4) De Bono et al (2010) Lancet 376: 1147-1154.


Ryan et al (2013) N Engl J Med 368: 138-148.



33

Time

Tum

or B

urde

n / P

SA

Castration (ADT)


Docetaxel


Highly variable




Abiraterone

Cabazitaxel

Enzalutamide

Radium-223

Sipuleucel-T

Abiraterone

Enzalutamide

Docetaxel


Docetaxel

Abiraterone

Despite all the progress, there’s work to be done

Outstanding questions •  With so many drugs, what is the optimal sequence?

•  What do we know about resistance to therapies?

•  Can we identify cellular changes (genetic or other) that may explain more aggressive cancer behavior in black patients?

•  What is the role for immunotherapy? Who benefits?

Outstanding needs •  Predictive biomarkers for aggressive disease, treatment

response, intermediate endpoints

•  New imaging techniques

34

One example of a potential biomarker that could tell us about treatment response and aggressive behavior

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med nejm.org6

men). In the enzalutamide cohort, the PSA re-sponse rate among AR-V7–positive patients was 0% (95% CI, 0 to 26; 0 of 12 men), and the rate among AR-V7–negative patients was 53% (95% CI, 29 to 76; 10 of 19 men; P = 0.004). The best PSA re-sponses are shown in Figure 2A. In linear regres-

sion modeling, AR-V7 status remained predictive of PSA response after adjustment for the expression of full-length androgen receptor mRNA (P<0.001).

The overall proportion of patients who had a PSA response while receiving abiraterone was 55% (95% CI, 36 to 73; 17 of 31 men). In the abir-aterone cohort, the PSA response rate among AR-V7–positive patients was 0% (95% CI, 0 to 46; 0 of 6 men), and the rate among AR-V7–negative patients was 68% (95% CI, 46 to 85; 17 of 25 men; P = 0.004). The best PSA responses are shown in Figure 2B. In linear regression modeling, AR-V7 status remained predictive of PSA response after adjustment for the expression of full-length an-drogen receptor mRNA (P = 0.02).

Secondary End PointsPSA Progression–free SurvivalAmong enzalutamide-treated patients, PSA pro-gression–free survival was shorter among men with detectable AR-V7 at baseline than among those with undetectable AR-V7 (P<0.001 in a uni-variate analysis) (Fig. 3A). In a multivariable Cox model adjusted for the expression of full-length androgen receptor mRNA and prior abiraterone use, the detection of AR-V7 remained indepen-dently predictive of shorter PSA progression–free survival (hazard ratio for PSA progression, 3.1; 95% CI, 1.0 to 9.2; P = 0.046); the level of full-length androgen receptor mRNA was also pre-dictive of shorter PSA progression–free survival (hazard ratio, 1.4; 95% CI, 1.0 to 1.9), but previ-ous abiraterone use was not (hazard ratio, 2.5; 95% CI, 0.4 to 14.5). Results of the propensity-score–weighted multivariable model are shown in Table S3A in the Supplementary Appendix.

Among abiraterone-treated patients, PSA pro-gression–free survival was shorter among men with detectable AR-V7 at baseline than among those with undetectable AR-V7 (P<0.001 in a univariate analysis) (Fig. 3B). In a multivariable Cox model adjusted for the expression of full-length androgen receptor mRNA and prior enzalutamide use, the detection of AR-V7 was the only independent predictor of shorter PSA progression–free survival (hazard ratio for PSA progression, 15.7; 95% CI, 2.1 to 117.5; P = 0.007); neither the level of full-length androgen receptor mRNA (hazard ratio, 1.0; 95% CI, 0.8 to 1.2) nor previous enzalutamide use (hazard ratio, 0.9; 95% CI, 0.1 to 5.2) was predictive. Results of the propensity-score–weighted multivariable model

† † ††

† †

†

†† † †

††

††

† † †

† †

* * *

†

†

†

†

* * * *

Best

PSA

Res

pons

e (%

cha

nge)

100

−100

50

−50

0

B Abiraterone-Treated Patients

A Enzalutamide-Treated Patients

Best

PSA

Res

pons

e (%

cha

nge)

100

−100

50

−50

0

AR-V7 positive AR-V7 negative

AR-V7 positive AR-V7 negative

Figure 2. Waterfall Plots of Best Prostate-Specific Antigen (PSA) Responses According to AR-V7 Status.

Panel A shows the 31 enzalutamide-treated patients, and Panel B the 31 abiraterone-treated patients. The dotted line shows the threshold for defin-ing a PSA response (≥50% reduction in PSA level from baseline). Asterisks indicate an increase of more than 100% in best PSA response. Daggers in-dicate patients in the enzalutamide cohort who had previously received abir aterone and patients in the abiraterone cohort who had previously re-ceived enzalutamide.

The New England Journal of Medicine Downloaded from nejm.org at Harvard Library on September 4, 2014. For personal use only. No other uses without permission.

Copyright © 2014 Massachusetts Medical Society. All rights reserved.

•  AR-V7 mRNA splice variant:

–  Missing Ligand Binding Domain (LBD)

–  Constitutively active

–  Associated with resistance to abiraterone and enzalutamide in mCRPC

Antonarakis et al. N Engl J Med 2014; 371: 1028-1038.

AR: Xq11-12

179Translational Andrology and Urology, Vol 2, No 3 September 2013

© AME Publishing Company. All rights reserved. Transl Androl Urol 2013;2(3):178-186www.amepc.org/tau

docetaxol (14), with expanded indication approved on

%FDFNCFS�� UP� JODMVEF�QBUJFOUT�XIP�EJE�OPU� SFDFJWF�QSJPS�EPDFUBYPM� ��&O[BMVUBNJEF �B�NPSF�QPUFOU�BOUJ�androgen, was approved on August 2012 for post-docetaxol

metastatic CRPC (16). The successful clinical development

of these two new agents (14-16) underscores the importance

of understanding the mechanism of sustained AR signaling

JO�$31$��*O�UIJT� MJHIU �NPTU�"3�TQMJDF�WBSJBOUT� JEFOUJGJFE�so far do not contain the intended therapeutic target, the

"3�MJHBOE�CJOEJOH�EPNBJO�-#% � GPS�BOZ�PG�UIF�FYJTUJOH�hormone therapy regimens including the two new agents.

*O�UIJT�SFWJFX �XF�XJMM�EJTDVTT�EJTDPWFSZ�BOE�DIBSBDUFSJ[BUJPO�of the structural and functional diversity of AR splice

WBSJBOUT�GPS�XIJDI�UIF�LFZ�GFBUVSFT�IBWF�CFFO�EPDVNFOUFE�JO�UIF�MJUFSBUVSF�LFZ�GFBUVSFT�PG�UIF��"3�TQMJDF�WBSJBOUT�

are summarized in Figure 1), their potential roles in

NFEJBUJOH�DPOTUJUVUJWFMZ�BDUJWF�"3�TJHOBMJOH �BOE�LFZ�BSFBT�of investigation to establish them as a mechanism of CRPC,

particularly in the setting of resistance to abiraterone and

enzalutamide.

The canonical AR-FL

*O�B�OPSNBM�NBMF�HFOPNF �UIFSF�JT�POMZ�POF�DPQZ�PG�UIF�"3�gene located on Xq11-12. The AR gene is considered the most

JNQPSUBOU�HFOF�JO�QSPTUBUF�DBODFS��5IF�"3�'-�D%/"�XBT�òSTU�DMPOFE�JO��4USVDUVSBMMZ�"3�'-�SFTFNCMFT�PUIFS�OVDMFBS� SFDFQUPST � DPOUBJOJOH�B�IJHIMZ� DPOTFSWFE�%/"�CJOEJOH�EPNBJO� %#%�FODPEFE�CZ�&YPO�� B� MJHBOE�CJOEJOH�EPNBJO�-#%�FODPEFE�CZ�&YPO��BU�$�UFSNJOVT�

Figure 1�%FDPEJOH�UIF�BOESPHFO�SFDFQUPS�TQMJDF�WBSJBOU�USBOTDSJQUT��"��"3�HFOF�TUSVDUVSF�XJUI�DBOPOJDBM�BOE�DSZQUJD�FYPO�TQMJDF�KVODUJPOT�NBSLFE�BDDPSEJOH� UP�(3$I��IH��IVNBO�HFOPNF�TFRFVODFT� OPU�ESBXO�UP� TDBMF��#��/PNFODMBUVSF � GVODUJPOBM�BOOPUBUJPO �FYPO�DPNQPTJUJPOT �BOE�WBSJBOU�TQFDJòD�N3/"�DPMPS�NBUDIFE�UP�Figure 1A) and peptide sequences (in gray)

A

B

AR-V13

AR-V1

AR-V2

AR-V3

AR-V4

AR-V5

AR-V6

AR-V7

AR-V8

AR-V9

AR-V12

AR-V14

AR-FL

AR-45

AR-V10

AR-V11

31 7 82 4

66948516

6691451566905968

669418056686324966941675

5 6 9

6694352866944119

66931244

66931531

66942669

6694282666905852

66937320

66937464

CE4

6690084566900562

CE1

66909400

CE2

66912029

CE5

6691341266863098

1b

66915918

4155 nts

8753 nts

CE3

66763874

66766604

66788683

66788864

AR-V9:MTLGDNLPEQAAFWRHLHIFWDHVVKK stop

Transcripts Proteins

AR-V12:KALPDCERAASVHF Stop

AR-V13:LFSINHT Stop

AR-V14:SVQPITPDAMYL Stop

1 2 3 CE1

1 2 3 CE13

1 2 CE13CE4

1 2 CE13CE43

1 2 CE23

1 2 CE23

1 2 CE33

1 2 3

1 2 CE53

1 2 93 4 8

1 2 93 4 5 6

1 2 93 4 5 6

1 2 83 4 5 6 7

1b 2 83 4 5 6 7

AR-FL:MTLGDNLPEQAAFWRHLHIFWDHVVKK stop

AR-V1:MTLGAVVVSERILRVFGVSEWOP stop


AR-V3:RAAEGFFRMNKLKESSDTNPKPYCMAAPMGLTENNRNRKKSYRETNLKAVSWPLNHT stop

AR-V4:MTLGGFFRMNKLKESSDTNPKPYCMAAPMGLTENNRNRKKSYRETNLKAVSWPLNHT stop

AR-V5:MTLGD stop

AR-V6:MTLGAGSRVS stop

AR-V7:MTLGEKFRVGNCKHLKMTRP stop

AR-V8:MTLGGFDNLCELSS stop

1 2 3 AR-V10:MTPSSGTNSVFLPHRDVVRTGCRSNSGYHSCSCEYHDYCFL stop

1 2 3 AR-V11:MTLGGKILFFLFLLLPLSPFSLIF stop (EXON RUNON)

AR45: start MILWLHSLETARDHVLPIDYY---FHTQ stop

AR4

AR1/2/2b

AR1/2/3/2b, AR5

AR3

ARv567es

Alternative names AR-Vs

Transcriptional activity

Inactive

Conditional

Unknown

Constitutive

Constitutive

Unknown

Unknown

Constitutive

Unknown

Conditional

Constitutive

Unknown

Ligand-stimulated

Conditional

Unknown

Unknown

7

AR: Xq11-12

AR-23

69 nts

1 2 83 4 5 6 7Ligand-stimulated

AR23: KVFFKRAAEEIPEERDSGNSCSELSTLVFVLPGKQKYLCA---FHTQ stop

AR-8 1 CE33 AR8: YSGPYGDMRNTRRKRLWKLIIRSINSCICSPRETEVPVRQQK stopInactive

AR-V7

35 Lu and Luo. Transl Androl Urol 2013; 2: 178-186.

179Translational Andrology and Urology, Vol 2, No 3 September 2013

© AME Publishing Company. All rights reserved. Transl Androl Urol 2013;2(3):178-186www.amepc.org/tau

docetaxol (14), with expanded indication approved on

%FDFNCFS�� UP� JODMVEF�QBUJFOUT�XIP�EJE�OPU� SFDFJWF�QSJPS�EPDFUBYPM� ��&O[BMVUBNJEF �B�NPSF�QPUFOU�BOUJ�androgen, was approved on August 2012 for post-docetaxol

metastatic CRPC (16). The successful clinical development

of these two new agents (14-16) underscores the importance

of understanding the mechanism of sustained AR signaling

JO�$31$��*O�UIJT� MJHIU �NPTU�"3�TQMJDF�WBSJBOUT� JEFOUJGJFE�so far do not contain the intended therapeutic target, the

"3�MJHBOE�CJOEJOH�EPNBJO�-#% � GPS�BOZ�PG�UIF�FYJTUJOH�hormone therapy regimens including the two new agents.

*O�UIJT�SFWJFX �XF�XJMM�EJTDVTT�EJTDPWFSZ�BOE�DIBSBDUFSJ[BUJPO�of the structural and functional diversity of AR splice

WBSJBOUT�GPS�XIJDI�UIF�LFZ�GFBUVSFT�IBWF�CFFO�EPDVNFOUFE�JO�UIF�MJUFSBUVSF�LFZ�GFBUVSFT�PG�UIF��"3�TQMJDF�WBSJBOUT�

are summarized in Figure 1), their potential roles in

NFEJBUJOH�DPOTUJUVUJWFMZ�BDUJWF�"3�TJHOBMJOH �BOE�LFZ�BSFBT�of investigation to establish them as a mechanism of CRPC,

particularly in the setting of resistance to abiraterone and

enzalutamide.

The canonical AR-FL

*O�B�OPSNBM�NBMF�HFOPNF �UIFSF�JT�POMZ�POF�DPQZ�PG�UIF�"3�gene located on Xq11-12. The AR gene is considered the most

JNQPSUBOU�HFOF�JO�QSPTUBUF�DBODFS��5IF�"3�'-�D%/"�XBT�òSTU�DMPOFE�JO��4USVDUVSBMMZ�"3�'-�SFTFNCMFT�PUIFS�OVDMFBS� SFDFQUPST � DPOUBJOJOH�B�IJHIMZ� DPOTFSWFE�%/"�CJOEJOH�EPNBJO� %#%�FODPEFE�CZ�&YPO�� B� MJHBOE�CJOEJOH�EPNBJO�-#%�FODPEFE�CZ�&YPO��BU�$�UFSNJOVT�

Figure 1�%FDPEJOH�UIF�BOESPHFO�SFDFQUPS�TQMJDF�WBSJBOU�USBOTDSJQUT��"��"3�HFOF�TUSVDUVSF�XJUI�DBOPOJDBM�BOE�DSZQUJD�FYPO�TQMJDF�KVODUJPOT�NBSLFE�BDDPSEJOH� UP�(3$I��IH��IVNBO�HFOPNF�TFRFVODFT� OPU�ESBXO�UP� TDBMF��#��/PNFODMBUVSF � GVODUJPOBM�BOOPUBUJPO �FYPO�DPNQPTJUJPOT �BOE�WBSJBOU�TQFDJòD�N3/"�DPMPS�NBUDIFE�UP�Figure 1A) and peptide sequences (in gray)

A

B

AR-V13

AR-V1

AR-V2

AR-V3

AR-V4

AR-V5

AR-V6

AR-V7

AR-V8

AR-V9

AR-V12

AR-V14

AR-FL

AR-45

AR-V10

AR-V11

31 7 82 4

66948516

6691451566905968

669418056686324966941675

5 6 9

6694352866944119

66931244

66931531

66942669

6694282666905852

66937320

66937464

CE4

6690084566900562

CE1

66909400

CE2

66912029

CE5

6691341266863098

1b

66915918

4155 nts

8753 nts

CE3

66763874

66766604

66788683

66788864

AR-V9:MTLGDNLPEQAAFWRHLHIFWDHVVKK stop

Transcripts Proteins

AR-V12:KALPDCERAASVHF Stop

AR-V13:LFSINHT Stop

AR-V14:SVQPITPDAMYL Stop

1 2 3 CE1

1 2 3 CE13

1 2 CE13CE4

1 2 CE13CE43

1 2 CE23

1 2 CE23

1 2 CE33

1 2 3

1 2 CE53

1 2 93 4 8

1 2 93 4 5 6

1 2 93 4 5 6

1 2 83 4 5 6 7

1b 2 83 4 5 6 7

AR-FL:MTLGDNLPEQAAFWRHLHIFWDHVVKK stop



AR-V3:RAAEGFFRMNKLKESSDTNPKPYCMAAPMGLTENNRNRKKSYRETNLKAVSWPLNHT stop

AR-V4:MTLGGFFRMNKLKESSDTNPKPYCMAAPMGLTENNRNRKKSYRETNLKAVSWPLNHT stop

AR-V5:MTLGD stop

AR-V6:MTLGAGSRVS stop

AR-V7:MTLGEKFRVGNCKHLKMTRP stop

AR-V8:MTLGGFDNLCELSS stop

1 2 3 AR-V10:MTPSSGTNSVFLPHRDVVRTGCRSNSGYHSCSCEYHDYCFL stop

1 2 3 AR-V11:MTLGGKILFFLFLLLPLSPFSLIF stop (EXON RUNON)

AR45: start MILWLHSLETARDHVLPIDYY---FHTQ stop

AR4

AR1/2/2b

AR1/2/3/2b, AR5

AR3

ARv567es

Alternative names AR-Vs

Transcriptional activity

Inactive

Conditional

Unknown

Constitutive

Constitutive

Unknown

Unknown

Constitutive

Unknown

Conditional

Constitutive

Unknown

Ligand-stimulated

Conditional

Unknown

Unknown

7

AR: Xq11-12

AR-23

69 nts

1 2 83 4 5 6 7Ligand-stimulated

AR23: KVFFKRAAEEIPEERDSGNSCSELSTLVFVLPGKQKYLCA---FHTQ stop

AR-8 1 CE33 AR8: YSGPYGDMRNTRRKRLWKLIIRSINSCICSPRETEVPVRQQK stopInactive

RNA in situ hybridization (RNA ISH)

•  Note: Need 20mer probes across transcript with 500-1000 base pairs of unique target (not possible for ARv567es)

Saylor et al. Clin Cancer Res 2017; 23: 363-369. 36

Cell line controls: (+) VCAP, 22Rv1 (-) RWPE-1, PC3

Pre-treatment prostate: 1+(Gleason 4+5)

During ADTBladder TUR: 2+

Autopsy lung 2+adrenal 2+soft tissue 3+

Case: Serial tissue AR-V7 RNA ISH, 40X H&E, 20X Time

37 Saylor et al. Clin Cancer Res 2017; 23: 363-369.

Results for metastatic castration-sensitive prostate cancer cohort

•  AR-V7 detectable in some patients in both groups –  “Brief response”: 6/9 –  “Sustained response”: 4/13

•  Prognostic:

0 20 40 60 80 100

0.0

0.2

0.4

0.6

0.8

1.0

AR-V7 negativeAR-V7 positive

Months From ADT Start

OS

0 20 40 60 80 100

0.0

0.2

0.4

0.6

0.8

1.0

AR-V7 negativeAR-V7 positive

Months From ADT Start

PFS

OS: NR vs 33 mo; p=0.044 PFS: 94 vs. 6.5 mo; p=0.055


RNA ISH: Conclusions / Other directions

•  Automated RNA-ISH assay is feasible

•  Archival FFPE prostate cancer tissue can be used to assess AR-V7 RNA

•  Institutional cohort suggests baseline AR-V7 by this method is a negative prognostic marker

•  Validation in larger cohorts is needed

•  Other directions?


Archival Cohorts

•  “Low clinical likelihood” –  Gleason 6 prostatectomy (n=10)

–  Also: Gleason 7 and ≥8 (n=10 each)

•  “High clinical likelihood” –  mCRPC after multiple lines of therapy (n=12)

•  Castration-sensitive metastatic prostate cancer (ADT) –  “Sustained response” (> 2.5 years; n=13)

–  “Brief response” (< 9 months; n=9)


Ongoing collaboration

41

MGH Pathology -  Chin-Lee Wu -  Kshitij Arora -  Rong Hu -  Vikram Deshpande -  Miguel Rivera

MGH Cancer Center -  Phil Saylor -  Rick Lee -  David Miyamoto -  David Ting -  Kara Olivier -  Erika Meneely

BMC -  Rawad Elias -  Gretchen Gignac -  Jennifer Rider

Thank you for your attention!

42

Questions? Contact:

Richard J. Lee, MD PhD MGH Cancer Center

t: 617-724-4000 f: 617-726-8685

e: [email protected]

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