Nuove strategie terapeutiche per il trattamento del cancro alla prostata refrattario alla castrazione: le più recenti evidenze cliniche sull’efficacia degli inibitori della biosintesi degli androgeni come Abiraterone Acetato e analoghi e degli antiandr
Similar to Nuove strategie terapeutiche per il trattamento del cancro alla prostata refrattario alla castrazione: le più recenti evidenze cliniche sull’efficacia degli inibitori della biosintesi degli androgeni come Abiraterone Acetato e analoghi e degli antiandr
Similar to Nuove strategie terapeutiche per il trattamento del cancro alla prostata refrattario alla castrazione: le più recenti evidenze cliniche sull’efficacia degli inibitori della biosintesi degli androgeni come Abiraterone Acetato e analoghi e degli antiandr (20)
Top Rated Hyderabad Call Girls Erragadda ⟟ 9332606886 ⟟ Call Me For Genuine ...
Nuove strategie terapeutiche per il trattamento del cancro alla prostata refrattario alla castrazione: le più recenti evidenze cliniche sull’efficacia degli inibitori della biosintesi degli androgeni come Abiraterone Acetato e analoghi e degli antiandr
2. 788 NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCER
table).1 However, the response and duration of benefit as well as a brief review of hormonal strategies in
tend to decrease with each successive hormonal manip- CRPC to date is summarized. To standardize the
ulation. Chemotherapy may be an option when hormone measurement and reporting of the PSA response
therapy fails. Docetaxel is currently the only agent to rate and TTPP clinical studies of these investiga-
show improvement in overall survival in these patients tional agents are reported using criteria specified in
as well as in pain and quality of life benefits.2,3 Still, the the Prostate-Specific Antigen Working Group and/or
incremental survival benefit with docetaxel is only about Prostate Cancer Clinical Trials Working Group 2
3 months.2–4 Currently median survival after failed ini- guidelines.7,8
tial ADT is approximately 18 months with fewer than
20% of patients surviving beyond 3 years.2–4 Prostate TRADITIONAL SECONDARY
cancer remains the second leading cause of cancer re- HORMONAL THERAPIES FOR CRPC
lated death in men in the United States and the need for
Cumulative experience with secondary hormonal
new treatment options is critical.
therapies provides substantial clinical evidence that
Disease progression despite medical or surgical
ligand mediated AR signaling remains functional in
castration signals the emergence of a prostate can-
a large proportion of CRPCs. However, except for
cer phenotype that can survive and proliferate in a
antiandrogens, current secondary hormonal strate-
low androgen environment.5 Although it was once
gies can be considered relatively nonspecific since
termed androgen independent or hormone refrac-
they suppress pituitary-gonadal axis function or
tory, it is now recognized that a significant propor-
nonselectively inhibit adrenal and gonadal steroid-
tion of these tumors continue to rely on AR signal-
ogenesis. Clinical outcomes of traditional secondary
ing6 and are more precisely characterized as CRPC.
hormonal therapies in CRPC are briefly summa-
Selective inhibition of persistent androgen produc-
rized.
tion in CRPC is emerging as a promising therapeutic
strategy. Novel antiandrogens that interfere di- Antiandrogens
rectly with AR mediated signaling pathways in The combination of an antiandrogen with gonadal
CRPC are also generating substantial clinical inter- androgen suppression (combined or maximal andro-
est. The current clinical development of these agents gen blockade) or after failed initial androgen sup-
Select clinical trials of second line therapy with antiandrogens, estrogens and glucocorticoids, and nonspecific androgen inhibitors
for CRPC
PSA Response
References Treatment (total daily mg) No. Pts % 50% or Greater Median Duration (mos)
2nd Line antiandrogens:
Fossa et al9 Flutamide (375), bicalutamide (80) 193, 39 34, 44 6.6*
Small et al10 High dose bicalutamide (150) 52 20 Not available
Suzuki et al11 High dose bicalutamide (150) 31 23 Not available
Scher et al12 High dose bicalutamide (200) 51 24 4.0
Kassouf et al13 Nilutamide (200 or 300) 28 28 7.0
Glucocorticoids:
Bubley et al7 Prednisone (10) 101 21 Not available
Small et al14 Prednisone (20) 29 34 2.0
Kantoff et al15 Hydrocortisone (40) 230 16 2.3
Storlie et al16 Hydrocortisone (40) 81 14 2.3
Robertson et al17 Dexamethasone (1.5) 27 59 Not available
Oh et al18 Dexamethasone (0.5-2) 37 62 9.0
Smith et al19 Dexamethasone (1.5) 38 61 Not available
Estrogens:
Kruit et al20 DES (3) 42 24 3.8
Figg et al21 DES (1) 21 43 Not available
Ketoconazole:
Scher et al8 Ketoconazole (1,200) hydrocortisone AAWD 128 27 8.6
Chen et al24 Ketoconazole (1,200) hydrocortisone 36 47 6.3
Linja et al25 Ketoconazole (600) hydrocortisone 28 46 7.5
Stanbrough et al26 Ketoconazole (1,200) hydrocortisone 45 31† Not available
Gregory et al27 Ketoconazole (1,200) hydrocortisone 50 63 3.5
Aminoglutehimide:
Small et al22 Aminoglutethimide (900) hydrocortisone AAWD 29 48† 4.0
Holzbeierlein et al23 Aminoglutethimide (1,000) hydrocortisone 35 37 9.0
* PSA responders combined.
† PSA decrease 80% or greater.
3. NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCER 789
pression is often an effective therapeutic maneuver, ticosteroid supplementation.20 Common adverse
although responsiveness is inversely related to dis- effects include lethargy, nausea, skin rash, pe-
ease extent. In this setting flutamide produces a ripheral edema, hypothyroidism and increased he-
50% or greater decrease in PSA in 80% of patients patic enzyme. Aminoglutethimide has largely
with localized disease, 54% with metastatic disease been supplanted by ketoconazole, an azole anti-
and 23% with symptomatic metastatic disease.9 fungal that inhibits multiple cytochrome p450 en-
Changes in PSA have also been seen upon AAWD, is zymes involved in androgen biosynthesis, including
likely related to the potential of these agents to show conversion of cholesterol to pregnenolone, 11 -hy-
partial agonist activity, particularly in the presence droxylation and 17 -hydroxylase/C17,20-lyase (CYP17)
of altered or mutated AR. In prospective studies activity.10 Ketoconazole produces a 50% or greater
AAWD was associated with a 50% or greater de- decrease in PSA in approximately 30% to 60% of
crease in PSA in 10% to 15% of patients with pros- CRPC cases with a median response duration of
tate cancer with responses lasting a median of about about 7 months.10,21,22 In the largest randomized
6 months.10,11 Changing to an alternate second line study to date the combination of high dose ketocona-
antiandrogen, such as high dose bicalutamide or zole with hydrocortisone and AAWD produced a 50%
nilutamide, is associated with a 50% or greater de- or greater decrease in PSA in 28% of CRPC cases
crease in PSA in about a third of patients, with a compared to 11% for AAWD alone.10 Deferred use of
median response duration of typically between 4 and ketoconazole after AAWD was associated with a 50%
7 months (see table).11–13 or greater decrease in PSA in 32% of patients. Cir-
Glucocorticoids culating androgen, which initially decreased on ke-
Glucocorticoids, which have a history of use as sup- toconazole therapy, increased at the time of disease
portive therapy with steroidogenesis suppressive progression, indicating failure of this agent to contin-
agents or as a control arm in chemotherapy trials, uously suppress androgen biosynthesis. Side effects of
have modest activity alone in prospective CRPC tri- ketoconazole, including lethargy, rash, gastrointesti-
als. A 50% or greater decrease in PSA was reported nal issues and potential adrenal suppression, can of-
in up to 20% of patients with CRPC on various ten limit treatment duration. Also, as a nonspecific
prednisone or hydrocortisone regimens and in up to p450 inhibitor ketoconazole has the potential to pro-
60% on dexamethasone with a response of typically voke drug-drug interactions by interfering with the
a median of about 2 months.9,14 –16 The mechanisms metabolism of other drugs, including warfarin and
underlying the glucocorticoid activity in CRPC are various statins.
not well defined and in the absence of comparative
randomized data no 1 particular agent or regimen is
considered preferable. INSIGHTS INTO ANDROGEN
PRODUCTION AND SIGNALING IN CRPC
Estrogens
Estrogens have long been known to be active against AR Signaling
prostate cancer. The synthetic estrogen DES sup- Prostate cancer gene expression studies revealed
presses testosterone by decreasing LH-releasing that AR activated genes that are initially down-
hormone secretion as well as directly affecting pitu- regulated during ADT become reactivated upon
itary LH production. Also, DES has direct cytotoxic transition to CRPC.23 Up-regulation of the AR gene
activity in prostate cancer cell lines.17 A 50% or coincides with this transition24 and AR gene ampli-
greater decrease in PSA was reported in 20% to 40% fication has been found in about 30% of CRPCs.25
of patients with CRPC treated with DES with a The importance of ligand mediated AR signaling in
median response duration of about 4 months (see CRPC is underscored by findings of frequent AR
table).18,19 However, a substantially increased risk over expression and heightened AR sensitivity re-
of cardiac and vascular toxicities, including myocar- lated to increased receptor stabilization, enhanced
dial infarction, stroke and pulmonary embolism, is nuclear localization and over expression of nuclear
known to occur with DES and concomitant antico- coactivators.23,25–27 Point mutations may confer AR
agulation therapy is recommended with its use in promiscuity, permitting activation by nonandro-
patients with CRPC.1 genic ligands such as progesterone and estradiol.6
These finding support the theory that ligand depen-
Steroidogenesis Inhibitors dent AR signaling may be a primary mediator of
Ketoconazole and aminoglutethimide, which are non- growth and survival among CRPCs. Ligand inde-
specific androgen synthesis inhibitors, have efficacy for pendent mechanisms may also have a role in persis-
CRPC (see table). By blocking the conversion of choles- tent AR signaling in CRPC, as evidenced by the
terol to pregnenolone, aminoglutethimide broadly inhib- recent identification of several constitutively active
its adrenal steroid synthesis and its use necessitates cor- AR splice variants.28
4. 790 NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCER
Persistent Androgen of patients with congenital CYP17 deficiency, a rare
Production in Castrate Environment disorder characterized by adrenal hyperplasia, and
With current ADT strategies the suppression of inadequate synthesis of cortisol, androgen and es-
gonadal androgen production results in castrate trogen, accompanied by impaired sexual develop-
testosterone, defined as less than 50 ng/dl (less ment.34 Because mineralocorticoid biosynthesis is
than 2.0 nM). Despite gonadal androgen suppres- not impaired and due to the weak glucocorticoid
sion, low levels of circulating androgens persist, activity provided by corticosterone, these patients do
mainly due to peripheral conversion of adrenal not have adrenocortical insufficiency. However, in
steroids, and circulating testosterone may be seen response to low circulating cortisol the cortisol-
at up to 10% of precastration levels.29 Recent find- ACTH feedback loop is stimulated, leading to in-
ings suggest that CRPCs acquire the ability to creased pituitary release of ACTH. This results in
convert adrenal steroids to androgens, in essence excess mineralocorticoid production and a clinical syn-
creating an intracrine signaling system. Gene up- drome characterized by hypertension, hypokalemia,
regulation and expression of enzymes involved in fluid overload and renin suppression. This syndrome is
androgen biosynthesis, including CYP17, have effectively managed by low dose glucocorticoids with
been documented in CRPC tissue23,26,30,31 with or without mineralocorticoid antagonists to suppress
evidence of intratumor conversion of upstream ACTH release.
precursors of testosterone and dihydrotestoster-
one present at concentrations sufficient to activate
AR.32,33 These findings have supported the clinical SELECTIVE TARGETING
development of novel agents that selectively tar- OF CYP17 FOR CRPC
get persistent androgen production and ligand me- Given its critical role in androgen biosynthesis,
diated AR binding in CRPCs. CYP17 has generated interest as a relevant biolog-
ical target for CRPC. Several novel therapeutic en-
Role of CYP17 in Androgen Biosynthesis tities that selectively inhibit CYP17 are currently
Cytochrome p450c17 (CYP17) catalyzes 2 essential under clinical evaluation for CRPC (see Appendix).
reactions in androgen biosynthesis, including 17 -
hydroxylation of C21 steroids and cleavage of the Abiraterone Acetate
C17,20 bond of C21 steroids.34 These reactions are key Abiraterone is a highly potent, selective, irreversible
in the biosynthesis of DHEA and androstenedione, inhibitor of CYP17.35 Abiraterone prevents conver-
precursors of testosterone and estradiol (see figure). sion of pregnenolone to DHEA and progesterone to
The biological consequences of CYP17 inhibition are androstenedione in the testes and adrenal glands.
illustrated by the clinical and biochemical features Abiraterone also appears to suppress de novo andro-
ACTH
Cholesterol
Pregnenolone Progesterone Corticosterone Aldosterone
(Mineralocortocoids)
CYP17
(17α-hydroxylase)
17α-hydroxypregnenolone 17α-hydroxyprogesterone Cortisol
(Glucocortocoids)
CYP17
(C17,20 lyase)
Testosterone 5α-dihydrotestosterone
Dehydroepiandrostenedione
(DHEA) Androstenedione
Estrogens
Steroid biosynthesis pathways and role of CYP17
5. NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCER 791
gen production in prostate tumors, as evidenced by greater decrease in PSA. Of 30 patients given dexa-
inhibition of CRPC growth in xenograft models de- methasone 0.5 mg at the time of progression, which
void of testicular and adrenal androgens.36 Unlike was permitted by protocol, a secondary PSA re-
nonspecific CYP17 inhibitors such as ketoconazole, sponse of 50% or greater was noted in 10 (33%). Of
abiraterone was not anticipated to impair mineralo- interest, steroid levels downstream of CYP17 did not
corticoid synthesis, providing potential improved increase at the time of disease progression, suggest-
clinical tolerability. ing sustained CYP17 inhibition.38
Early clinical evaluation of oral abiraterone ac- Prior ketoconazole was permitted in the phase I
etate in noncastrate men showed that initial an- portion of the second phase I/II study.39 Of 33
drogen suppression was soon overcome by a com- phase I patients 19 (58%) had a 50% or greater
pensatory surge in luteinizing hormone and, as decrease in PSA, including 10 of 19 (53%) with
such, development focused on a castrate popula- prior ketoconazole exposure. These findings sug-
tion.37 In phase I studies abiraterone acetate fur- gested a potential lack of cross resistance with
ther decreased castrate testosterone to concentra- prior ketoconazole. The phase II portion of this
tions below detection limits.38,39 Other systemic study added prednisone 5 mg twice daily to abi-
effects consistent with selective CYP17 inhibition raterone acetate 1,000 mg daily and excluded pa-
included stimulation of ACTH release in response tients with prior ketoconazole exposure.41 Prelim-
to decreased cortisol and resulting increases in inary findings indicated a 50% or greater PSA
mineralocorticoid precursors (deoxycorticosterone decrease in 29 of 33 patients (88%) with a median
and corticosterone) with little effect on aldoste- TTPP of 337 days (95% CI 280 days, never at-
rone due to a negative feedback loop. As learned in tained). The use of prednisone markedly de-
patients with congenital CYP17 deficiency, adding creased the incidence and severity of hypokale-
a supplemental glucocorticoid such as dexameth- mia, hypertension and fluid retention. Except for
asone or prednisone suppresses ACTH release and single incidences of grade 3 hypertension and hy-
is often effective for signs of mineralocorticoid ex- pokalemia, most adverse events were grade 1 and
cess, including hypertension, hypokalemia and no grade 4 events attributable to mineralocorti-
fluid retention. Pharmacokinetic analysis sug- coid excess were seen.
gested that interaction with food, such as a high Phase II studies have evaluated abiraterone ace-
fat meal, tended to increase drug exposure, al- tate as monotherapy and combined with low dose
though these findings were quite variable. As prednisone in men with CRPC and disease progres-
such, abiraterone acetate is given in a fasting sion after docetaxel chemotherapy. In each study
state to maintain drug exposure as consistently as patients were heavily pretreated, and multiple hor-
possible. monal therapies and up to 2 prior chemotherapies
In phase I/II studies in men with chemotherapy had failed. With abiraterone acetate monotherapy a
naïve CRPC in whom multiple prior hormonal ther- 50% or greater decrease in PSA was seen in 24 of 47
apies had failed the pharmacodynamic effects of abi- patients (51%) with a median TTPP of 169 days
raterone acetate appeared to plateau at a dose of 750 (95% CI 130 to 281).42 Objective partial responses
to 1,000 mg, leading to the selection of 1,000 mg for were seen in 6 patients (13%) and disease stabiliza-
continued phase II evaluation.38 – 41 Common ad- tion was noted in 25 (53%). In 11 patients (23%)
verse events of consistent mineralocorticoid excess there was improved performance status, a potential
included hypertension, hypokalemia and edema, surrogate indicator of clinical benefit. Consistent
which responded to management by the selective with expectations, adverse events included hypoka-
mineralocorticoid receptor antagonist eplerenone or lemia in 55% of cases, hypertension in 17% and fluid
low dose corticosteroids. Spironolactone was specif- retention in 15%, which responded to management
ically avoided because of its potential androgenic by eplerenone or low dose corticosteroids. Abi-
properties. Other common adverse events were fa- raterone acetate combined with prednisone pro-
tigue, headache, nausea and diarrhea. No dose lim- duced a 50% or greater decrease in PSA in 24 of 58
iting toxicity was seen with the administration of up patients (41%), including 8 of 27 (30%) who were
to 2,000 mg abiraterone acetate daily. ketoconazole pretreated and 16 of 31 (52%) who
In a cohort of 42 patients treated with abiraterone were ketoconazole naïve.43 Median TTPP was 99
acetate at the phase II dose of 1,000 mg 28 (67%) had days (95% CI 57 to 169) in patients with prior keto-
a 50% or greater PSA decrease with a greater than conazole exposure and 198 days (95% CI 82 to not
90% decrease in 8 (19%).40 Objective partial re- evaluable) in ketoconazole naïve patients. The com-
sponses were seen in 9 of 24 patients (37.5%) with bination was well tolerated with adverse events con-
measurable disease. Median TTPP overall was 225 sisting of primarily grade 1 or 2 hypokalemia, hy-
days (95% CI 162 to 287) with a median TTPP of 253 pertension and fluid retention. Abiraterone acetate
days (95% CI 122 to 383) in patients with a 50% or is currently being evaluated in 2 randomized, mul-
6. 792 NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCER
ticenter, phase III studies of CRPC and accrual to cantly down-regulated AR protein expression, in
these studies is complete. contrast to findings with castration alone or bicalu-
Features and characteristics that may predict re- tamide, which showed up-regulation of AR expres-
sponse to abiraterone acetate are under evaluation. sion. Phase I/II evaluation of TOK-001 in CRPC was
Pretreatment serum DHEA, DHEA-sulfate andro- initiated in late 2009.
stenedione and estradiol correlate with the proba-
bilities of a 50% or greater PSA decrease and
NOVEL AR ANTAGONISTS FOR CRPC
TTPP.44 In patients with a baseline circulating tu-
mor cell count of 5/7.5 ml or greater a decrease to Second Generation Antiandrogen MDV3100
less than 5/7.5 ml was associated with a 50% or AR over expression is known to be a mechanism of
greater decrease in PSA.42,43 Correlations between antiandrogen resistance in CRPC. Also, the partial
serum testosterone levels and those in the tumor agonist activity of current first generation antian-
microenvironment in patients with CRPC with bone drogens such as bicalutamide can be a factor in
metastasis are also being explored.44 Preliminary tumor progression. MDV3100 is a novel second gen-
findings suggest that higher testosterone in the tu- eration antiandrogen that shows selective, potent
mor microenvironment (bone marrow) may correlate affinity for AR while being devoid of any agonist AR
with an increased likelihood of a response. These activity in CRPC models.47 Compared to bicaluta-
observations support a role for intracrine androgen mide MDV3100 has greater binding affinity for AR.
production and persistent AR signaling in CRPC, In CRPC cell lines MDV3100 effectively inhibits nu-
and suggest a possible predictive indicator for re- clear translocation and DNA binding to androgen
sponse. response, leading to the induction of apoptosis. In
tumor xenograft models known to over express AR
CYP17 Inhibitors TAK-700 and TOK-001 treatment with MDV3100 led to substantial tumor
TAK-700 and TOK-001 (formerly VN/124-1) are se- regression while growth suppression was more mod-
lective CYP17 inhibitors currently in phase I/II de- est.
velopment (see Appendix). Preliminary phase I re- MDV3100 was clinically evaluated in a phase I/II
sults with TAK-700, an oral selective C17,20-lyase multicenter study in 140 patients with progressive
inhibitor, summarized findings with dose levels of metastatic CRPC with oral dose escalations of 30 to
100 through 600 mg twice daily as well as 400 mg 600 mg daily.48 The study population was relatively
twice daily combined with low dose prednisone in 26 heavily pretreated with failure of at least 2 prior
patients with metastatic CRPC.45 No dose limiting hormonal therapies in most patients, prior keto-
toxicity was seen. Fatigue was the most common conazole exposure in 63 (45%) and failure of at least
treatment related adverse event, as seen in 16 pa- 1 prior chemotherapy in 75 (54%). The most common
tients (62%), including 3 with grade 3 or greater treatment related adverse event with MDV3100 was
events at the 600 mg dose. Other common treatment fatigue, which had an onset of approximately 4
related adverse events were nausea in 38% of cases, weeks with timing that corresponded to the achieve-
constipation in 35%, anorexia in 35% and vomiting ment of steady-state drug concentrations. Grade 3/4
in 30%. Decreases in median testosterone from 4.9 adverse events were seen predominantly at a dose of
to 0.6 ng/dl and in DHEA-sulfate androstenedione 360 mg or greater, including fatigue in 11% of pa-
from 53.8 to less than 0.1 g/dl were seen at the 400 tients, which generally responded to dose reduction,
mg dose. A blunted cortisol response after ACTH asthenia in 2% and seizures in 2%. Due to tolerabil-
stimulation was seen in 2 of 7 patients at the 400 mg ity issues at doses above 360 mg and the potential
dose and in all 5 at the 600 mg dose. Doses at or concern for seizures a maximum tolerated dose of
above 300 mg twice daily produced a 50% or greater 240 mg was selected for sustained treatment. Effi-
decrease in PSA in 11 of 14 patients (70%), of whom cacy was observed across all dose levels and ap-
4 (29%) had a 90% or greater PSA decrease. Contin- peared to be dose dependent, attaining a plateau at
ued phase II evaluation of TAK-700 at the 400 mg between 150 and 240 mg daily. Overall a 50% or
twice daily dose, including the need for concomitant greater PSA decrease was seen in 78 patients (56%)
prednisone, in men with metastatic CRPC is ongo- with objective partial responses in 13 (22%) with
ing. Also, a phase II study of TAK-700 in men with measurable disease. A similar 50% or greater PSA
nonmetastatic CRPC with increasing PSA has be- decrease was seen in patients parsed by prior che-
gun accrual. motherapy exposure and extent of prior hormonal
In preclinical experience TOK-001 selectively in- therapy, although a lower rate was seen in patients
hibited 17 -hydroxylase/C17,20-lyase activity and previously treated with ketoconazole. Overall me-
down-regulated AR expression.46 In the LAPC4 dian TTPP was 224 days (95% CI 147 to 315) with a
prostate cancer xenograft model TOK-001 combined median of 147 (95% CI 140 to 231) and 287 days
with castration inhibited tumor growth and signifi- (95% CI 203 to 427) in patients with and without
7. NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCER 793
prior chemotherapy exposure, respectively. Also, survival. Adaptive mechanisms, including up-regu-
49% of patients with an unfavorable circulating tu- lation of AR expression and enhanced receptor sen-
mor cell count (5/7.5 ml or greater) at baseline had sitivity, permit tumor growth in the castrate envi-
conversion to favorable counts, of whom 19 (76%) ronment. In castration resistant prostate tumor
also had a 50% or greater maximum PSA decrease. tissues the expression of enzymes involved in andro-
Currently MDV3100 at a dose of 160 mg is under gen biosynthesis suggests that these tumors may
phase III evaluation in patients with CRPC who also develop intracrine signaling mechanisms.
were previously treated with docetaxel. Novel agents that target CYP17 and selectively in-
hibit persistent androgen production show promise
AR Inhibitor BMS-641988 for CRPC treatment. Also, second generation anti-
BMS-641988 is a highly potent AR inhibitor that androgens such as MDV3100 offer another means to
was specifically designed based on AR crystal struc- address persistent AR signaling in CRPC. Based on
ture.49 Compared to bicalutamide BMS-6410988 encouraging clinical results to date it seems likely
showed higher binding affinity and greater inhibi- that these new classes of agents will substantially
tion of AR mediated signaling in preclinical models. change the treatment and clinical outlook in many
Two phase I studies of BMS-641988 in CRPC are men with CRPC, particularly those unwilling to ac-
complete but results have not yet been reported. cept or unable to tolerate cytotoxic chemotherapy.
CONCLUSIONS ACKNOWLEDGMENTS
A significant proportion of CRPCs continue to rely Christine Gutheil and Karim Chamie assisted with
on ligand mediated AR signaling for growth and the manuscript.
APPENDIX
Clinical development status of novel androgen synthesis inhibitors and second generation antiandrogens for CRPC
Class/Agent Target Phase Status
Androgen biosynthesis inhibitors:
Abiraterone acetete CYP17 (17- -hydroxylase/C17,20-lyase) III
TOK-001 (formerly VN/124-1) CYP17 (17- -hydroxylase/C17,20-lyase), selective AR modulator I/II
TAK-700 CYP17 (C17,20-lyase) I/II
Antiandrogens:
MDV3100 AR binding/nuclear translocation I/II
BMS-641988 AR binding I
REFERENCES
1. Lam JS, Leppert JT, Vemulapalli SN et al: Sec- 6. Scher HI and Sawyers CL: Biology of progressive, 10. Small EJ, Halabi S, Dawson NA et al: Antiandro-
ondary hormonal therapy for advanced prostate castration resistant prostate cancer: directed gen withdrawal alone or in combination with
cancer. J Urol 2006; 175: 27. therapies targeting the androgen-receptor signal- ketoconazole in androgen-independent prostate
ing axis. J Clin Oncol 2005; 23: 8253. cancer patients: a phase III trial (CALGB 9583).
2. Tannock IF, de Wit R, Berry WR et al: Docetaxel J Clin Oncol 2004; 22: 1025.
plus prednisone or mitoxantrone plus prednisone 7. Bubley GJ, Carducci M, Dahut W et al: Eligibility
and response guidelines for phase II clinical trials 11. Suzuki H, Okihara K, Miyake H et al: Alternative
for advanced prostate cancer. N Engl J Med
in androgen-independent prostate cancer: recom- nonsteroidal antiandrogen therapy for advanced
2004; 351: 1502.
mendations from the Prostate-Specific Antigen prostate cancer that relapsed after initial maxi-
Working Group. J Clin Oncol 1999; 17: 3461. mum androgen blockade. J Urol 2008; 180: 921.
3. Petrylak DP, Tangen CM, Hussain MH et al:
Docetaxel and estramustine compared with mi- 12. Scher HI, Liebertz C, Kelly WK et al: Bicalutamide
8. Scher HI, Halabi S, Tannock I et al: Design and
toxantrone and prednisone for advanced refrac- for advanced prostate cancer: the natural versus
end points of clinical trials for patients with
tory prostate cancer. N Engl J Med 2004; 351: treated history of disease. J Clin Oncol 1997; 15:
progressive prostate cancer and castrate levels
1513. 2928.
of testosterone: recommendations of the Prostate
Cancer Clinical Trials Working Group. J Clin On- 13. Kassouf W, Tanguay S and Aprikian AG: Nilut-
4. Berthold DR, Pond GR, Soban F et al: Docetaxel col 2008; 26: 1148. amide as second line hormone therapy for pros-
plus prednisone or mitoxantrone plus prednisone
tate cancer after androgen ablation fails. J Urol
for advanced prostate cancer: updated survival in 9. Fossa SD, Slee PH, Brausi M et al: Flutamide 2003; 169: 1742.
the TAX327 study. J Clin Oncol 2008; 26: 242. versus prednisone in patients with prostate cancer
symptomatically progressing after androgen-abla- 14. Small EJ, Meyer M, Marshall ME et al: Suramin
5. Pienta KJ and Bradley D: Mechanisms underlying tive therapy a phase III study of the European therapy for patients with symptomatic hormone-
the development of androgen-independent pros- Organization for Research and Treatment of Cancer refractory prostate cancer results of a randomized
tate cancer. Clin Cancer Res 2006; 12: 1665. Genitourinary Group. J Clin Oncol 2001; 19: 62. phase III trial comparing suramin plus hydrocor-
8. 794 NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCER
tisone to placebo plus hydrocortisone. J Clin gens to testosterone in androgen-independent 39. Ryan CJ, Smith MR, Fong L et al: Phase I clinical
Oncol 2000; 18: 1440. prostate cancer. Cancer Res 2006; 66: 2815. trial of the CYP17 inhibitor abiraterone acetate
demonstrating clinical activity in patients with
15. Kantoff PW, Halabi S, Conaway M et al: Hydro- 27. Gregory CW, Johnson RT, Mohler JL et al: An- castration-resistant prostate cancer who received
cortisone with or without mitoxantrone in men drogen receptor stabilization in recurrent prostate prior ketoconazole. J Clin Oncol 2010; 28: 1481.
with hormone-refractory prostate cancer: results cancer is associated with hypersensitivity to low
of the cancer and leukemia group B 9182 study. androgen. Cancer Res 2001; 61: 2892. 40. Attard G, Reid AHM, A’Hern R et al: Selective
J Clin Oncol 1999; 17: 2506. inhibition of CYP17 with abiraterone acetate is
28. Hu R, Dunn TA, Wei S et al: Ligand-independent
16. Storlie JA, Buckner JC, Wiseman GA et al: Pros- androgen receptor variants derived from splicing highly active in the treatment of castration-resis-
tate specific antigen levels and clinical response of cryptic exons signify hormone-refractory pros- tant prostate cancer. J Clin Oncol 2009; 27: 3742.
to low dose dexamethasone for hormone-refrac- tate cancer. Cancer Res 2009; 69: 16.
41. Ryan C, Efstathiou E, Smith M et al: Phase II
tory metastatic prostate carcinoma. Cancer 1995;
29. Puche C, Jose M, Cabero A et al: Expression and multicenter study of chemotherapy (chemo)-naïve
76: 96.
enzymatic activity of the P450c17 gene in human castration resistant prostate cancer (CRPC) not
17. Robertson CN, Roberson KM, Padilla GM et al: adipose tissue. Eur J Endocrinol 2002; 146: 223. exposed to ketoconazole (keto), treated with abi-
Induction of apoptosis by diethylstilbestrol in hor- raterone acetate (AA) plus prednisone. J Clin
30. Montgomery RB, Mostaghel EA, Vessella R et al: Oncol, suppl., 2009; 27: 15s, abstract 5046.
mone-insensitive prostate cancer cells. J Natl
Maintenance of intratumoral androgens in meta-
Cancer Inst 1996; 88: 908.
static prostate cancer: a mechanism for castration- 42. Reid AH, Attard D, Danila D et al: Significant and
18. Oh WK, Kantoff PW, Weinberg V et al: Prospec- resistant tumor growth. Cancer Res 2008; 68: 4447. sustained antitumor activity in post-docetaxel,
tive, multicenter, randomized phase II trial of the castration-resistant prostate cancer with the
31. Locke JA, Fazli L, Adomat H et al: Androgen
herbal supplement, PC-SPES, and diethylstilbes- CYP17 inhibitor abiraterone acetate. J Clin Oncol
levels increase by intrarumoral de novo steroid-
trol in patients with androgen-independent pros- 2010; 28: 1489.
ogenesis during progression of castration-resis-
tate cancer. J Clin Oncol 2004; 22: 3705.
tant prostate cancer. Cancer Res 2008; 68: 6407. 43. Danila DC, Morris MJ, de Bono J et al: Phase II
19. Smith DC, Redman BG, Flaherty L et al: A phase multicenter study of abiraterone acetate plus
32. Mohler JL, Gregory CW, Ford OH 3rd et al: The
II trial of oral diethylstilbestrol as a second-line prednisone in patients in patients with docetaxel-
androgen axis in recurrent prostate cancer. Clin
hormonal agent in advanced prostate cancer. treated castration-resistant prostate cancer.
Cancer Res 2004; 10: 440.
Urology 1998; 52: 257. J Clin Oncol 2010; 28: 1486.
33. Mostaghel EA, Page ST, Lin DW et al: Intrapros-
20. Kruit WH, Stoter G and Klijn JG: Effect of com-
tatic androgens and androgen-regulated gene ex- 44. Logothetis CJ, Wen S, Molina A et al: Identifi-
bination therapy with aminoglutethimide and hy-
pression persist after testosterone suppression: cation of an androgen withdrawal responsive
drocortisone on prostate-specific antigen re-
therapeutic implications for castration-resistant phenotype in castrate resistant prostate cancer
sponse in metastatic prostate cancer refractory to
prostate cancer. Cancer Res 2007; 67: 5033. (CRPC) patients (pts) treated with abiraterone
standard endocrine therapy. Anticancer Drugs
acetate (AA). J Clin Oncol, suppl., 2008; 26:
2004; 15: 843. 34. Auchus RJ: The genetics, pathophysiology, and abstract 5017.
management of human deficiencies of P450c17.
21. Figg WD, Liu Y, Arlen P et al: A randomized,
Endocrinol Metab Clin North Am 2001; 30: 101. 45. Dreicer R, Agus DB, MacVicar GR et al: Safety,
phase II trial of ketoconazole plus aledronate
versus ketoconazole alone in patients with an- pharmacokinetics, and efficacy of TAK-700 in cas-
35. Barrie SE, Potter GA, Goddard PM et al: Pharma-
drogen independent prostate cancer and bone tration-resistant metastatic prostate cancer: a
cology of novel steroidal inhibitors of cytochrome
metastases. J Urol 2005; 173: 790. phase I/II open label study. Genitourin Cancer
P450 (17)alpha (17 alpha-hydroxylase/C17-20
Symp Proc 2010; 89: abstract 103.
lyase). J Steroid Biochem Mol Biol 1994; 50: 267.
22. Small EJ, Baron A, Fippin L et al: Ketoconazole
retains activity in advanced prostate cancer pa- 36. Montgomery B, Mostaghel E, Nelson P et al: 46. Vasaitis T, Belosay A, Schayowitz A et al: Androgen
tients with progression despite flutamide with- Abiraterone suppresses castration resistant hu- receptor inactivation ncontributes to antitumor effi-
drawal. J Urol 1997; 157: 1204. man prostate cancer growth in the absence of cacy of 17 -hydroxylase/17,20-lyase inhibitor 3 -
testicular and adrenal androgens. Presented at hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene
23. Holzbeierlein J, Lal P, LaTulippe E et al: Gene in prostate cancer. Mol Cancer Ther 2008; 7: 2348.
American Association for Cancer Research Spe-
expression of human prostate carcinoma during
cial Conference: Advances in Prostate Cancer
hormonal therapy identifies androgen-responsive 47. Tran C, Ouk Sm Clegg NJ et al: Development of
Research, San Diego, California, January 21–24,
genes and mechanisms of therapy resistance. a second-generation antiandrogen for treatment
2009.
Am J Pathol 2004; 164: 217. of advanced prostate cancer. Science 2009; 324:
37. O’Donnell A, Judson I, Dowsett M et al: Hor- 787.
24. Chen CD, Welsbie DS, Tran C et al: Molecular
monal impact of the 17alpha -hydroxylase/
determinants of resistance to antiandrogen ther- 48. Scher HI, Beer TM, Higano CS et al: Antitumour
C(17,20)-lyase inhibitor abiraterone acetate
apy. Nat Med 2004; 10: 33. activity of MDV3100 in castration-resistant pros-
(CB7630) in patients with prostate cancer. Br J
25. Linja MJ, Savinainen KJ, Saramäki OR et al: Cancer 2004; 90: 2317. tate cancer: a phase 1-2 study. Lancet 2010; 375:
Amplification and overexpression of androgen re- 1437.
38. Attard G, Reid AHM, Yap TA et al: Phase I clinical
ceptor gene in hormone-refractory prostate can-
trial of a selective inhibitor of CYP17, abiraterone 49. Attar RM, Jure-Kunkel M, Balog A et al: Discov-
cer. Cancer Res 2001; 61: 3550.
acetate, confirms that castration-resistant pros- ery of BMS-641988: a novel and potent inhibitor
26. Stanbrough M, Bubley GJ, Ross K et al: Increased tate cancer commonly remains hormone driven. of androgen receptor signaling for the treatment
expression of genes converting adrenal andro- J Clin Oncol 2008; 28: 4563. of prostate cancer. Cancer Res 2009; 69: 6522