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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
Treatment of prostate cancer 2017
6
Time
Tum
or B
urde
n / P
SA
Castration (ADT)
Secondary Hormone Rx
Docetaxel
Castration-resistant
Highly variable
Castration-sensitive
Surgery or radiation
Localized cancer Recurrent or metastatic cancer
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
Treatment of prostate cancer 2017
12
Time
Tum
or B
urde
n / P
SA
Castration (ADT)
Secondary Hormone Rx
Docetaxel
Castration-resistant
Highly variable
Castration-sensitive
Surgery or radiation
Localized cancer Recurrent or metastatic cancer
Docetaxel
Salvage RT + hormones
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
Treatment of prostate cancer 2017
15
Time
Tum
or B
urde
n / P
SA
Castration (ADT)
Secondary Hormone Rx
Docetaxel
Castration-resistant
Highly variable
Castration-sensitive
Surgery or radiation
Localized cancer Recurrent or metastatic cancer
Docetaxel
Salvage RT + hormones
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
Treatment of prostate cancer 2017
22
Time
Tum
or B
urde
n / P
SA
Castration (ADT)
Secondary Hormone Rx
Docetaxel
Castration-resistant
Highly variable
Castration-sensitive
Surgery or radiation
Localized cancer Recurrent or metastatic cancer
Docetaxel
Salvage RT + hormones
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.
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
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.
Scher et al (2012) N Engl J Med 367: 1187-1197.
Ryan et al (2013) N Engl J Med 368: 138-148.
De Bono et al (2011) N Engl J Med 364: 1995-2005.
Treatment of prostate cancer 2017
33
Time
Tum
or B
urde
n / P
SA
Castration (ADT)
Secondary Hormone Rx
Docetaxel
Castration-resistant
Highly variable
Castration-sensitive
Surgery or radiation
Localized cancer Recurrent or metastatic cancer
Abiraterone
Cabazitaxel
Enzalutamide
Radium-223
Sipuleucel-T
Abiraterone
Enzalutamide
Docetaxel
Salvage RT + hormones
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-V2: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-V1:MTLGAVVVSERILRVFGVSEWOP stop
AR-V2: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
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
38 Saylor et al. Clin Cancer Res 2017; 23: 363-369.
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?
39 Saylor et al. Clin Cancer Res 2017; 23: 363-369.
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)
40 Saylor et al. Clin Cancer Res 2017; 23: 363-369.
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