Targeting androgen pathways in prostate cancer
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prostate cancer Targeting androgen pathways in prostate cancer prostate cancer prostate cancer
Transcript of Targeting androgen pathways in prostate cancer
Targeting androgen pathways in prostate cancer
Targeting androgen pathways in prostate cancerprostate cancerprostate cancer
Androgen deprivativeTherapy
WHY?
HOW?
WHEN?
Prostate cells are physiologically dependent on androgensto stimulate growth, function and proliferation.
Testosterone, although not tumorigenic, is essential for the growth and perpetuation of tumour cells(Berman DM, Rodriguez R, Veltri RW. Development, molecular biology and physiology ofthe prostate. In: Wein AJ, et al (eds). Campbell-Walsh Urology. 10th edn. Elsevier 2012, pp. 2533-69).
If prostate cells are deprived of androgenic stimulation, they undergo apoptosis .
Charles Brenton Huggins
Nobel Prize 1966He found out that castration or estrogen administration led to glandular atrophy, which could be reversed by re-administration of androgen. In 1941 the beneficial effect of androgen ablation on metastatic prostate cancer was realised when Huggins and Clarence Hodges treated patients by either castration or estrogen therapy.
Any treatment that results ultimately in suppression of androgen activity is referredto as Androgen Deprivation Therapy (ADT).
ADT can be achieved by:
Suppressing the secretion of testicular androgens Bilateral OrchiectomyLong acting LHRH agonists or antagonists
Inhibiting the action of circulating androgens at the level of their receptor using competing compounds Non steroidal antiandrogensNon steroidal antiandrogensSteroidal antiandrogens
In addition, these two methods can be combined to achieve what is known as complete (or maximal or total) androgen blockade (CAB).
New Dugs for castration resistance prostate cancerAbiraterone – Taestosterone synthesis inhibition at the adrenal level as inside the cancer cells (intracrine mechanism)Enzalutamide- a novel antiandrogen with higher receptor affinity than bicalutamide
Castration levelsCastration levels
• < 50 ng/dl (1.7 nmol/l)
Conventional value to define effective castration(established more than 40 years ago)
• < 20 ng/dl (1 nmol/l)
Contemporary and more appropriate definition ofcastration 1, 2, 3
1) Oefelein MG et al Urology 2000; 56: 1021. 2) Morote J et al BJU Int 2009; 103:332. 332. 3) Pickels T et al BJU Int 2012; 110: E500 1) Oefelein MG et al Urology 2000; 56: 1021. 2) Morote J et al BJU Int 2009; 103:332. 332. 3) Pickels T et al BJU Int 2012; 110: E500
Long-acting LHRH agonists are currently the main forms of ADT
MAB Uncertain clinical advantage , incremental costs of therapy
LHRH antagonists are an alternative to LHRH agonists . Probably agonists have less side effects in particular cardiovascular effects
Non -steroidal antiandrogen monotherapy is less effective than LHRH analogues . Its use in advanced prostate cancer is not indicated
Intermittent MAB – Should be considered only in selected patients. Recent studies do not shows advantages in quality of life for intermittent treatment
Timing
Localized disease
Immediate therapy only in high risk tumors
Locally advanced
N-Adjuvant radiotherapy
N+Immediate therapy in presence of >2 positive nodes
Expectant management is optional in presence of ≤2 positive nodes
BCR Evaluation of prognostic factors
Metastatic disease
Immediate therapy in symptomatic patients
Deferred therapy (optional) only in asymptomatic patients with
limited metastatic disease and important comorbidity
Prostate cancer becomes refractory to ADT
CASTRATION RESISTANT PROSTATE CANCER (CRPC)
CASTRATION RESISTANT PROSTATE CANCER (CRPC)
Mechanisms
Increased expression of AR
Increased expression of enzymes that synthesize androgens
Utilization of other pathways to activate AR
HORMONE REFRACTORY PROSTATE CANCER HRPCHRPC
Local Therapy
Androgen Deprivation
Therapies After LHRH Agonists
and Anti-androgens
Chemotherapy
Postchemotherapy
Death
Tu
mo
r V
olu
me &
Ac
tivit
y
Castration Sensitive
Asymptomatic
Nonmetastatic
Castration Resistant
Metastatic
Symptomatic
Time
Tu
mo
r V
olu
me &
Ac
tivit
y
tumor burden(PSA levels)
100
150
Testosteroneserum levels
(ng/dl)
Disease progression
CASTRATE RESISTANT PROSTATE CANCERCRPCCRPC
De Bono ESMO Educational Program, Genitourinary Cancers 2010 modified
Serum testosterone50
100
time
20
Castrationthreshold
0
Stimulation of Tumor Growth
Androgen Depletion/Blockade
“mCRPC remains androgen-sensitive despite castrate levels of testosterone...”
“….In metastatic hormone-resistant/refractory prostate cancer, tumor growth is no longer sensitive to androgen….”
levels of testosterone...”
Intracrine steroidogenesis may permit tumors tocircumvent low levels of circulating androgens.
Enzyme expression of the main steroidogenesis enzymes in CPRC vs primary tumor
CRPC expresses more AR than benign prostatic tissue and hormone-naïve prostate cancers in and hormone-naïve prostate cancers in immunohistochemical studies
While absent in hormonally untreated prostate cancer, in≈ 30% of CRPC, AR amplification is reported
As a consequence, even very low levels of intracellular testosterone and/or DHT might cause androgen signalling and AR –regulated transcription
Abiraterone Acetate: An Androgen Biosynthesis Inhibitor
Abiraterone Acetate plus Pdn vs Placebo plus Pdn in Docetaxel progressive mCRPC pts. Results of the phase III Randomized Study AA-
301.
Abiraterone acetate 1000 mg daily
(147 sites in 13 countries; USA, Europe, Australia, Canada)
• 1195 pts with progressive mCRPC
• Failed 1 or 2 CT Regimens, one of which contained Docetaxel
• Randomised 2:1
• Stratification by:
TREAT
UNTI
Prednisone 5mg twice daily
Placebo daily
OS (25% improvement; HR 0.8)Primary endpoint:
• Stratification by:
• ECOG PS (0-1 vs. 2)
• Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs. 4-10 [present])
• Prior CT (1 vs. 2)
• Type of progression (PSA only vs. Rx PD with or without PSA PD)
IL
PROGRESSION
Prednisone 5mg twice daily
Prednisone 5mg twice daily
de Bono et al. Ann Oncol 2010: Abstract LBA5 (Oral presentation at ESMO)Scher et al. J Clin Oncol 2011; 29(7S):Abstract 4 (Oral presentation at ASCO GU )
Abiraterone Acetate: Improved OS in mCRPC
Hazard ratio = 0.646 (0.54-0.77) P < 0.0001
Placebo:
Abiraterone acetate: 14.8 months (95% CI, 14.1-15.4)
100
80
60
40
Surv
ival
(%
)
AA 797 736 657 520 282 68 2 0
Placebo 398 355 306 210 105 30 3 0
21
Placebo: 10.9 months (95% CI, 10.2-12.0)
40
20
Surv
ival
(%
)
00 3 6 9 12 15 18
Placebo
AA
Time to Death (Months)
de Bono et al. Ann Oncol 2010: Abstract LBA5 (Oral presentation at ESMO)Scher et al. J Clin Oncol 2011; 29(7S):Abstract 4 (Oral presentation at ASCO GU )
Study 301. second pre-planned analysis (775 Events): median OS Increase from 3.9 to 4.6 Months
AA median OS (95% CI):15.8 mos (14.82-17.02)
HR (95% CI): 0.74 (0.638-0.859) P < 0.0001
Surv
ival
(%
) 60
80
100
Placebo median OS (95% CI): 11.2 mos (10.41-13.14)
AA
Placebo 398 306 183 100 6 0
797 657 473 273 15 0
Surv
ival
(%
)
0
20
40
Time to Death (Months)
0 6 12 18 24 30
Placebo AA
Scher et al. J Clin Oncol 2012; 29 (suppl): Abs A4517 (oral presentation)
Abiraterone Acetate - Study 301: OS Benefit across Patient Subgroups
Variable Subgroup N HR 95% CIAll subjects All 1195 0.66 0.56-0.79Baseline ECOG 0-1 1068 0.64 0.53-0.78
2 127 0.81 0.53-1.24
Baseline BPI < 4 659 0.64 0.50-0.82
4 536 0.68 0.53-0.85No of prior chemotherapy regimens 1 833 0.63 0.51-0.78
2 362 0.74 0.55-0.99
Type of progression PSA only 363 0.59 0.42-0.82
24
Type of progression PSA only 363 0.59 0.42-0.82
Radiographic 832 0.69 0.56-0.84Age, years 65 0.66 0.48-0.91
≥ 65 0.67 0.55-0.82Visceral disease at entry Yes 353 0.70 0.52-0.94Baseline PSA above median
Yes 591 0.65 0.52-0.81
Baseline LDH above median
Yes 581 0.71 0.58-0.88
Baseline ALK-P above median
Yes 587 0.60 0.48-0.74
Region N America 652 0.64 0.51-0.80Other 543 0.69 0.54-0.90
0.5 0.75 1 1.5Favors AA Favors placebo
Abiraterone (COU-301) : Tempo al primo SRE
Phase III Trial of Abiraterone Acetate in
asymptomatic or mildly symptomatic
metastatic chemotherapy-naïve CRPC
• 1000 patients withasymptomatic or mildly
RANDO
Abiraterone acetate 1000mg
Prednisone 5mg BID
Treat until progression
Primary end point:
• 25% improvement in
symptomaticmetastatic CRPC• Chemotherapy naïve
Stratified by:
OMIZED
1:1
Placebo
Prednisone 5mg BID
radiologic progression-free
survival
• 50% improvement in overallsurvival
ECOG performance status (0 vs 1)
Accrual completed 4/2009 www.clinicaltrials.gov Identifier: NCT00887198
Abiraterone Delays Progression in Patients with Chemotherapy-Naïve CRPC
Simvastatin suppresses biochemical recurrence (BCR) incastrated mice bearing LNCaP xenografts.
Simvastatin suppresses intratumoral and serum steroid accumulation in castrated mice bearing LNCaP xenografts
DHT
1. Blocks AR binding 3. Blocks DNA binding and activation
EnzalutamideEnzalutamide AR
Cytoplasm Nucleus
2. Impairs nuclear translocation
Enzalutamide
2–3 fold lower affinity than DHT
ENZALUTAMIDE
DHT
1. Blocks androgen (dihydrotestosterone) binding to the AR.
2. Impairs the movement of the complex formed when androgen binds to the AR into the nucleus of the cell (nuclear translocation).
3. Inhibits the binding of the androgen–AR complex to DNA.
Enzalutamide reduced risk of death by 29%
AR-mediated Mechanisms of“Castration Resistance” in P.Ca
• Non-androgen ligands• Steroids
• Anti-androgens
AR point
Hypersensitivity to low levels of ligand1
Sensitivity to other ligands1
Overamplification of the AR or increased 5α-reductase enzyme
levels may result in hypersensitivity
Large Part of Resistance Mechanism in Prostate
Cancer due to AR events
CRPC
AR point mutations1
1. Dutt & Gao. Future Oncol 2009;5:1403–13.; Newmark et al. Proc Natl Acad Sci USA 1992;89:6319–23.
AR splice variants1
AR over-expression1
Transcription of non-AR mRNAinto AR peptides, e.g.
• ARDLBD variant includes90–120 bp insertion from a
non-AR gene• A3 variant appears to constitutively
target Akt• A23 variant has a 23-amino-acid
insertion and impairs AR nuclear localisation
Single amino-acid substitutions, e.g.
• Codon 730 valine
methionine2
• Codon 89 leucine valine1
Prostate cancer pts feature overexpression of AR
independent of ligand levels
levels may result in hypersensitivity of AR to low levels of androgens
the generation of ARv567es is especially sensitive tosuppression of intratumoral androgens, suggesting growth ofthese tumors is associated with generation of AR variants inthe presence of castrate levels of androgen
Detection of AR-V7 in CTCs from men with metastatic CRPC is not associated with primary resistance to taxane with primary resistance to taxane chemotherapy. In AR-V7-positive men, taxanes appear to be more efficacious than enzalutamide or abiraterone therapy, whereas in AR-V7-negative men, taxanes and enzalutamide or abiraterone may have comparable efficacy.
In AR-V7-positive patients, PSA responses were higher in taxane-treated vs enzalutamide- or abiraterone-treated men (41% vs 0%; P < .001), and PSA PFS and PFS were significantly longer in taxane-treated men (HR, 0.19 [95% CI, 0.07-0.52] for PSA PFS, P = .001; HR, 0.21 [95% CI, 0.07-0.59] for PFS, P = .003).
BIOLOGIC CLASSIFICATION OFPROSTATE CANCER
ENDOCRINE-DRIVEN PHASE
MICROENVIRONMENT-DEPENDENT PHASE(ENDOCRINE-TO-PARACRINE TRANSITION)
TUMOR CELL AUTONOMOUS PHASE
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