Upload
i3-health
View
78
Download
5
Embed Size (px)
Citation preview
Appraisal of Recent Progress in Metastatic
Castration-Resistant Prostate Cancer
Oliver Sartor, MD
Laborde Professor of Cancer Research
Medical Director, Tulane Cancer Center
Departments of Medicine and Urology
Assistant Dean for Oncology
Tulane Medical School
New Orleans, Louisiana
Disclosures
Dr. Sartor discloses the following commercial
relationships:
Consultant: AstraZeneca, Bayer, Bellicum, Bristol-Myers
Squibb, Celgene, Dendreon, EMD Serono, Johnson & Johnson,
Oncogenex, Pfizer, Sanofi-Aventis, and Tokai
Grants/research support: from Bayer, Endocyte, Innocrin,
Johnson & Johnson, and Sanofi-Aventis
Learning Objectives
Assess predictive and prognostic markers to refine
treatment planning for individual patients with
metastatic CRPC
Discuss the implications of drug resistance in
treatment selection for patients with metastatic
CRPC
Evaluate efficacy and safety data on novel
therapeutic regimens for metastatic CRPC
CRPC = castration-resistant prostate cancer.
Recurrent After Initial Hormonal Therapy
Deaths: 26,730
Radiographic
Metastases:
Castrate
1st-line
chemo
Docetaxel
Radiographic
Metastases:
Castrate
Post-chemo
Cabazitaxel
Abiraterone
Enzalutamide
Radium-223
Prostate Cancer Clinical States
PSA = prostate-specific antigen; ADT = androgen deprivation therapy.
NCCN, 2017.
Hormone Sensitive
Diagnoses: 161,360
Rising PSA
Salvage Rx,
ADT,
or no therapy
Localized
Disease
Local therapy
or no therapy
Rising PSA:
Castrate
No standard
of care
Overt
Metastases
ADT +
Docetaxel or
abirateroneFirs
t
Metastatic CRPC
Radiographic
Metastases:
Castrate
Pre-chemo
Sipuleucel-T
Abiraterone
Enzalutamide
Radium-223
Inherited DNA-Repair Gene Mutations
in Men With Metastatic PC
11.8% of men with metastatic prostate cancerBRCA2: 5.4%
CHEK2: 1.9%
ATM: 1.6%
BRCA1: 0.9%
RAD51D and PALB2: 0.4% each
4.6% of men with localized prostate cancer
PC = prostate cancer.
Pritchard et al, 2016.
Why Are Germline Mutations
Important?
Poor prognosis and early age of onset
Implications for future therapiesToday, PARP inhibitors, platinum agents, and PD1 inhibitors
Tomorrow, perhaps others
Implications for family members that may require careful
monitoring or even prophylactic surgery~70% of women with a BRCA2 pathologic mutation develop breast
cancer, ~40% for ovarian cancer
Pritchard et al, 2016; Mersch et al, 2015.
Prostate Cancer Clinical States
NCCN, 2017.
Recurrent After Initial Hormonal TherapyHormone Sensitive
Diagnoses: 161,360 Deaths: 26,730
Rising PSA
Salvage Rx,
ADT,
or no therapy
Radiographic
Metastases:
Castrate
1st-Line
Chemo
Docetaxel
Localized
Disease
Local therapy
or no therapy
Rising PSA:
Castrate
No standard
of care
Overt
Metastases
ADT +
Docetaxel or
Abiraterone
Radiographic
Metastases:
Castrate
Post-chemo
Cabazitaxel
Abiraterone
Enzalutamide
Radium-223
Therapy
Metastatic CRPC
Radiographic
Metastases:
Castrate
Pre-chemo
Sipuleucel-T
Abiraterone
Enzalutamide
Radium-223
Consensus, Controversy, and Change
in Hormone-Naive Metastatic PC
Consensus: High-volume metastatic disease is
suitable for ADT + 6 cycles of docetaxel
Controversy: Low-volume metastatic disease is
debatable given negative CHAARTED data and no
STAMPEDE data in this subset
Change: STAMPEDE and LATITUDE data are
game changersADT + abiraterone
Chemohormonal Therapy in Metastatic
Hormone-Sensitive Prostate Cancer
Sweeney et al, 2015.
Controversy as P = 0.11
High volume: visceral metastases and/or ≥4 bone metastases
(at least 1 beyond pelvis and vertebral column)
LATITUDE: Abiraterone + Prednisone in
Metastatic Castration-Sensitive PC
OS = overall survival; PFS = progression-free survival; NR = not reached.
Fizazi et al, 2017.
6/4/17 NEJM
Median OS: NR vs 34.7 months Median PFS: 33.0 vs 14.8 months
Inclusion criteria: At least 2/3: Gleason ≥8, ≥3 bone mets, visceral disease
LATITUDE: PSA Progression
Fizazi et al, 2017.
LATITUDE: Adverse Events
ALT = alanine aminotransferase; AST = aspartate aminotransferase.
Fizazi et al, 2017.
Abiraterone Placebo
STAMPEDE: Abiraterone for PC Not
Previously Treated With Hormone Therapy
James et al, 2017.
June 3, 2017
STAMPEDE: OS and FFS
FFS = failure-free survival; PSADT = prostate-specific antigen doubling time.
James et al, 2017.
June 3, 2017
Non-metastatic disease subset included:
At least 2/3: Gleason 8-10, T3/4, PSA>40 and intention to treat with radiation
OR
Previously treated with surgery and at least 1 of the following:
PSA ≥4 and PSADT <6 months, PSA ≥20, N+
Some Implications of LATITUDE
and the “New” STAMPEDE
Biology changes associated with relapse after upfront
abiraterone/prednisone and ADT
The effectiveness of subsequent therapies is likely
altered in (as yet) undefined waysCross-resistance between abiraterone and enzalutamide is well
documented in CRPC
The meaning of CRPC is now changing….Post-ADT or post-ADT + docetaxel or
post-ADT + abiraterone/prednisone?
Should we be using ADT + docetaxel or
ADT + abiraterone/prednisone or a triplet?
What Happens If You Have Very Few
Metastases? Oligometastatic?
Photo courtesy of Eugene Kwon.
Bone metastatic disease can lead to further metastatic
spread!
The Evolutionary History of Lethal
Metastatic Prostate Cancer
Gundem et al, 2015.
Approach to Oligomets: Treatment
of the Primary ± Surgery or Radiation?
Observation
SBRT to mets (delay systemic therapy)
ADT “old” or “new”……how long?New ADT to include abiraterone/prednisone?
ADT + SBRT to mets
ADT + docetaxel
ADT + docetaxel + SBRT to mets
Something for everyone…a true “dealer’s choice”
No one knows the right answer and
current trials are limited!
SBRT = stereotactic body radiation therapy.
Prostate Cancer Clinical States
NCCN, 2017.
Recurrent After Initial Hormonal TherapyHormone Sensitive
Diagnoses: 161,360 Deaths: 26,730
Rising PSA
Salvage Rx,
ADT,
or no therapy
Radiographic
Metastases:
Castrate
1st-Line
Chemo
Docetaxel
Localized
Disease
Local therapy
or no therapy
Rising PSA:
Castrate
No standard
of care
Overt
Metastases
ADT +
docetaxel or
abiraterone
Radiographic
Metastases:
Castrate
Post-chemo
Cabazitaxel
Abiraterone
Enzalutamide
Radium-223
Next
Metastatic CRPC
Radiographic
Metastases:
Castrate
No-chemo
Sipuleucel-T
Abiraterone
Enzalutamide
Radium-223
Prostate Cancer Clinical Trials
aFinal analysis.
BSC = best supportive care.
Berthold et al, 2008; Kantoff et al, 2010; Rathkopf et al, 2014. Beer et al, 2017; Scher et al, 2012; de Bono et al, 2010; Fizazi et
al, 2012; Parker et al, 2013.
Trial Frontline HR Survival (mo)
TAX 327Docetaxel/prednisone vs
mitoxantrone/prednisone0.79 19.2 vs 16.2a
IMPACT Sipuleucel-T vs control 0.78 25.8 vs 21.7a
COU-AA-302Abiraterone/prednisone vs
placebo/prednisone0.81 35.3 vs 31.1a
PREVAIL Enzalutamide vs placebo 0.77 35.3 vs 31.3a
Trial Post-Docetaxel HR Survival (mo)
TROPICCabazitaxel/prednisone vs
mitoxantrone/prednisone0.70 15.1 vs 12.7a
COU-AA-301Abiraterone/prednisone vs
placebo/prednisone0.74 15.8 vs 11.2a
AFFIRM Enzalutamide vs placebo 0.63 18.4 vs 13.6a
TrialFrontline and
Post-DocetaxelHR Survival (mo)
ALSYMPCARadium-223/BSC vs
placebo/BSC0.70 14.9 vs 11.3a
Sequencing, Combinations, and Utility
of Molecular Biomarkers
The Great Unknowns
Many Sequences Can Be Considered,
Not Just Abi/Enza and Vice-Versa
aLarge randomized trials show activity of abi/pred, enza, cabazitaxel, and radium post-docetaxel.
Abi 1st Enza 1st Docetaxel 1st Radium 1st
Abi 2nd ----------- +++ resistance Activea No data
Enza 2nd ++ resistance ------------ Activea No data
Docetaxel 2nd Some data Some data ------------ Some data
Cabazitaxel 2nd Some data Some data Activea No data
Radium 2nd Small data Small data Activea --------------
No randomized trials are available for the post-abi or post-enza space.
No randomized trial for any space except post-docetaxel.
Treatment Sequencing
Many articles can be cited, but huge cross-
resistance between abiraterone and enzalutamide
when used sequentially
Whichever you use first will likely last
Whichever you use second not likely to last
Back-to-back oral hormonal agents may not be the
best option
40% with
≥50 decline
Prospective 2nd-Line Therapy:
Abi > Docetaxel From COU-AA-302
de Bono et al, 2017.
Maximum PSA Decline
3rd-Line Enzalutamide Therapy:
Doc > Abi > Enza
Schrader et al, 2014.
Overall 10/35
(28.6%) with
PSA >50%
decline
17/35 (48.6%)
no response
3rd-Line Cabazitaxel Therapy:
Doc > Abi > Cabazitaxel
Pezaro et al, 2014.
15/37 (40.5%)
PSA ≥50% decline
10/37 (27%)
no response
3rd-Line Cabazitaxel Therapy:
Doc > Abi > Cabazitaxel
Al Nakouzi et al, 2015.
≥50% PSA decline: 28 pts
(35.0%); median OS: 14.3
mo
≥50% PSA decline in
TROPIC study: 39.2%
No correlation between
response to cabazitaxel and
duration on docetaxel or
abiraterone
Cabazitaxel remains active in patients progressing after docetaxel and
abiraterone.
N=79
Biomarkers:
Molecular Stratification
PSA Responses in Enza-Treated
Patients by AR-V7 RNA Status in CTCs
CTCs = circulating tumor cells.
Antonarakis et al, 2014.
PSA Responses in Abi-Treated
Patients by AR-V7 RNA Status in CTCs
Antonarakis et al, 2014.
Nuclear AR-V7 (Antibody) and
Abi/Enza Responsiveness
Scher et al, 2016.
Presence of AR-V7–Positive CTCs and Response to AR-Signaling Inhibitors
Nuclear AR-V7 and
Taxane Responsiveness
Scher et al, 2016.
Circulating-Free DNA Alterations
and Progression
Azad et al, 2015.
AR Copy Number Gain or Selected
Mutations in Cell-Free Plasma DNA in
Abiraterone-Treated Patients
Romanel et al, 2015.
OS: AR Copy Number Gain or Selected
Mutations in Cell-Fee Plasma DNA Prospectively
Tested With Abiraterone
Romanel et al, 2015.
AR 702/878
Which Agent for Which Patient?
Choosing Which Agent May Be Effective,
Not Just Predicting Resistance
DNA-Repair Defects Can Be Inherited,
Somatic, or Both
Robinson et al, 2015.
DNA-Repair Defects and Olaparib
in Metastatic Prostate Cancer
Mateo et al, 2015.
DNA-Repair Defects and Olaparib
in Metastatic Prostate Cancer (cont.)
Mateo et al, 2015.
Biallelic Inactivation of BRCA2 in
Platinum-Sensitive Metastatic CRPC
Cheng et al, 2016.
Cabazitaxel/Carboplatin/G-CSF in
“Aggressive Variant” Prostate Cancer
G-CSF = granulocyte colony-stimulating factor.
Corn et al, 2016.
Incidence of MMR Mutations in
Autopsy CRPC Specimens: 12%
MMR = mismatch repair.
Pritchard et al, 2014.
Pembrolizumab + Enza in CRPC:
Mismatch Repair or More?
MSI = microsatellite instability.
Graff et al, 2016.
MSI
Noted
FDA Announcement May 2017
Pembrolizumab awarded accelerated approval for
cancers with high MSI or DNA mismatch repair-
deficient
No companion diagnostic specified
Estimates 10% of all cancers worldwide?
PTEN Loss as Predictive Biomarker for
Akt Inhibitor Ipatasertib + Abi
rPFS = radiographic progression-free survival; HR = hazard ratio; CI = confidence interval.
de Bono et al, 2016.
PTEN
Loss
PTEN
Loss
PTEN
Loss
No PTEN
Loss
No PTEN
Loss
No PTEN
Loss
N=253
Ipat-
400 + Abi
(n=25)
Ipat-
200 + Abi
(n=25)
Pbo + Abi
(n=21)
Ipat-
400 + Abi
(n=32)
Ipat-
200 + Abi
(n=27)
Pbo + Abi
(n=35)
rPFS events,
n (%)15 (60) 16 (64) 18 (86) 20 (63) 20 (74) 26 (74)
Median PFS
(mo)11.5 11.1 4.6 7.5 4.6 5.6
Unstratified HR 0.39 0.46 0.84 1.13
90% CI 0.22-0.70 0.25-0.83 0.51-1.37 0.69-1.85
P Value 0.0064 0.0285 0.5647 0.6762
PSMA Upregulation With Abi/Enza
PSMA = prostate-specific membrane antigen.
Murga et al, 2015.
PSMA Binding Molecules Can Be Linked to
Therapeutic Isotopes Via a Chelator
Isotopes:
Lu-177
Bi-213
Ac-225
Chatalic et al, 2016.
PSMA Lu-177 Clinical Trials:
Waterfall Plots for PSA
Rahbar et al, 2016.
Multimodality Skills to Optimally
Manage PC in the Near Future
Hormonal therapy
Targeted therapy
Immunotherapy
Chemotherapy
Surgery
Radiation oncology
Nuclear medicine
Molecular pathology
Genetics
Genetic counseling
Case 1
84-year-old frail patient with a history of diabetes,
hypertension, hyperlipidemia, and obesity presents to
the clinic with increasing rib pain
S/p ADT and local radiotherapy for initial diagnosis of
prostate cancer 2 years ago (T3b N1 M0)
Initial PSA was 52 ng/mL and decreased to 2.2 ng/mL,
then despite ongoing ADT, PSA increased to 15 ng/mL
and mild diffuse bone pain
Bone scan reveals metastasis in multiple ribs and
several pelvic lesions. CT reveals 1.5 cm nodes in the
pelvis
Case 1 (cont.)
How would you treat this patient?a. Abiraterone/prednisone
b. Enzalutamide
c. Radium-223
d. Zoledronate/denosumab
e. Combination
Case 2
59-year-old patient with a history of surgery,
Gleason 7, PSA failure, intermittent ADT then bone
metastatic CRPC
Treated initially with abiraterone/prednisone
PSA rise and no symptoms
Case 2 (cont.)
How would you treat this patient?a. Abiraterone/dexamethasone
b. Enzalutamide
c. External beam radiation
d. Zoledronate/denosumab
e. Radium-223
f. Docetaxel
g. Combination
Case 3
61-year-old patient with metastatic CRPC treated
with ADT alone in 2012, then with rising PSA and
multiple bone lesions on bone scan (total >20)
Treated initially with docetaxel with good response
Now progression in bone again with severe focal
hip pain
Germline testing revealed a BRCA2 mutation
No soft tissue lesion
Case 3 (cont.)
How would you treat this patient?a. External beam radiation
b. Abiraterone
c. Enzalutamide
d. Radium-223
e. Cabazitaxel
f. Zoledronic acid/denosumab
g. Carboplatin
h. Combination
Key Takeaways
CRPC is evolving into a molecularly targeted
disease for a growing subset of patients
AR remains our most proven target and much can
be gained by CRPC treatment with the new AR-
targeted agents, but cross-resistance is a major
issue
Much progress has been made, but we have a long
way to go, especially for those progressing after
AR-targeted therapy and taxanes
Questions?
References
Al Nakouzi N, Le Moulec S, Albiges L, et al (2015). Cabazitaxel remains active in patients progressing after docetaxel followed by novel
androgen receptor pathway targeted therapies. Eur Urol, 68(2):228-235. DOI:10.1016/j.eururo.2014.04.015
Antonarakis ES, Changxue L, Wang H, et al (2014). AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med,
371(11):1028-1038. DOI:10.1056/nejmoa1315815
Azad AA, Volik SV, Wyatt AW, et al (2015). Androgen receptor gene aberrations in circulating cell-free DNA: biomarkers of therapeutic
resistance in castration-resistant prostate cancer. Clin Cancer Res, 21(10):2315-2324. DOI:10.1158/1078-0432.ccr-14-2666
Beer TM, Armstrong AJ, Rathkopf D, et al (2017). Enzalutamide in men with chemotherapy-naïve metastatic castration-resistant prostate
cancer: extended analysis of the phase 3 PREVAIL study. Eur Urol, 71(2):151-154. DOI:10.1016/j.eururo.2016.07.032
Berthold DR, Pond GR, Soban F, et al (2008). Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer:
updated survival in the TAX 327 study. J Clin Oncol, 26(2):242-245. DOI:10.1200/JCO.2007.12.4008
Chatalic KL, Heskamp S, Konijnenberg M, et al (2016). Towards personalized treatment of prostate cancer: PSMA I&T, a promising prostate-
specific membrane antigen-targeted theranostic agent. Theranostics, 6(6):849-861. DOI:10.7150/thno.14744
Cheng HH, Pritchard CC, Boyd T, et al (2016). Biallelic inactivation of BRCA2 in platinum-sensitive metastatic castration-resistant prostate
cancer. Eur Urol, 69(6):992-995. DOI:10.1016.j.eururo.2015.11.022
Corn PG, Ning Tapia EL, Xiao L, et al (2016). Confirmatory analysis to determine associations between platinum-sensitivity, molecular signature
of combined tumor suppressor defects and aggressive variant prostate carcinomas (AVPC). J Clin Oncol, 34(Suppl 15). Abstract 5020.
de Bono JS, de Giorgi, Massard C, et al (2016). PTEN loss as a predictive biomarker for the Akt inhibitor ipatasertib combined with abiraterone
acetate in patients with metastatic castration-resistant prostate cancer (mCRPC). Ann Onc, 27(Suppl 6). Abstract 7180.
DOI:10.1093/annonc/mdw372.02
de Bono JS, Oudard S, Ozguroglu M, et al (2010). Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate
cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet, 376(9747):1147-1154. DOI:10.1016/s0140-
6736(10)61389-x
de Bono JS, Smith MR, Saad F, et al (2017). Subsequent chemotherapy and treatment patterns after abiraterone acetate in patients with
metastatic castration-resistance prostate cancer: post hoc analysis of COU-AA-302. Eur Urol, 71(4):656-664.
DOI:10.1016/j.eururo.2016.06.033
References
Fizazi K, Scher HI, Molina A, et al (2012). 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. Lancet Oncol, 13(10):983-992.
DOI:10.1016/S1470-2045(12)70379-0
Fizazi K, Tran N, Fein L, et al (2017). Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med, 377(4):352-
360. DOI:10.1056/nejmoa1704174
Graff JN, Alumkal JJ, Drake CG, et al (2016). Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget,
7:52810-52817. DOI:10.18632/oncotarget.10547
Gundem G, Van Loo P, Kremeyer B, et al (2015). The evolutionary history of lethal metastatic prostate cancer. Nature, 520(7547):353-357.
DOI:10.1038/nature14347
James ND, de Bono JS, Spears MR, et al (2017). Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med,
377(4):338-351. DOI:10.1056/nejmoa1702900
Kantoff PW, Higano CS, Shore ND, et al (2010). Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med,
363(5):411-422. doi:10.1056/NEJMoa1001294
Mateo J, Carreira S, Sandhu S, et al (2015). DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med, 373(18):1697-1708.
DOI:10.1056/nejmoa1506859
Murga JD, Moorji SM, Han AQ, et al (2015). Synergistic co-targeting of prostate-specific membrane antigen and androgen receptor
in prostate cancer. Prostate, 75(3):242-254. DOI:10.1002/pros.22910
National Comprehensive Cancer Network (2017). NCCN Clinical Practice Guidelines in Oncology: prostate cancer. Available at:
http://www.nccn.org
Parker C, Nilsson S, Heinrich D, et al (2013). Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med, 369(3):213-
223. DOI:10.1056/nejmoa1213755
Pezaro CJ, Omlin AG, Altavilla A, et al (2014). Activity of cabazitaxel in castration-resistant prostate cancer progressing after docetaxel and
next-generation endocrine agents. Eur Urol, 66(3):459-465. DOI:10.1016/j.eururo.2013.11.044
Pritchard CC, Mateo J, Walsh MF, et al (2016). Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med,
375(5):443-453. DOI:10.1056/nejmoa1603144
Pritchard CC, Morrissey C, Kumar A, et al (2014). Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced
prostate cancer. Nat Commun, 5:4988. DOI:10.1038/ncomms5988
References
Rahbar K, Ahmadzadehfar H, Kratochwil C, et al (2016). German multicenter study investigating 177Lu-PSMA-617 radioligand therapy in
advanced prostate cancer patients. J Nucl Med, 58(1):85-90. DOI:10.2967/jnumed.116.183194
Rathkopf DE, Smith MR, de Bono JS, et al (2014). Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic
castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302). Eur Urol, 66(5):815-825.
DOI:10.1016/j.eururo.2014.02.056
Robinson D, Van Allen EM, Wu YM, et al (2015). Integrative clinical genomics of advanced prostate cancer. Cell, 161(5):1215-1228.
DOI:10.1016/j.cell.2015.05.001
Romanel A, Gasi Tandefelt D, Conteduca V, et al (2015). Plasma AR and abiraterone-resistant prostate cancer. Sci Transl Med,
7(312):312re10. DOI:10.1126/scitranslmed.aac9511
Scher HI, Fizazi K, Saad F, et al (2012). Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med,
367(13):1187-1197. DOI:10.1056/nejmoa1207506
Scher HI, Lu D, Schreiber NA, et al (2016). Association of AR-V7 on circulating tumor cells as a treatment-specific biomarker with outcomes and
survival in castration-resistant prostate cancer. JAMA Oncol, 2(11):1441-1449. DOI:10.1001/jamaoncol.2016.1828
Schrader AJ, Boegemann M, Ohimann CH, et al (2014). Enzalutamide in castration-resistant prostate cancer patients progressing after
docetaxel and abiraterone. Eur Urol, 65(1):30-36. DOI:10.1016/j.eururo.2013.06.042
Sweeney CJ, Chen YH, Carducci M, et al (2015). Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med,
373:737-746. DOI:10.1056/nejmoa1503747