Review ArticleNovel Therapeutic Strategies for Castration Resistant ProstateCancer: Inhibition of Persistent Androgen Prod...
NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCER                              789pression is often an...
NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCER                       791gen production in prostate ...
NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCER                                                     ...
794                   NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCER    tisone to placebo plus hydr...
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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


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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

  1. 1. Review ArticleNovel Therapeutic Strategies for Castration Resistant ProstateCancer: Inhibition of Persistent Androgen Production andAndrogen Receptor Mediated SignalingArturo Molina*,† and Arie BelldegrunFrom the OrthoBiotech Oncology Research and Development, A Unit of Cougar Biotechnology and Institute of UrologicOncology, David Geffen School of Medicine at University of California-Los Angeles (AB), Los Angeles, CaliforniaPurpose: Androgen receptor signaling remains essential for many prostate can- Abbreviationscers that have progressed despite androgen deprivation therapy. After medical or and Acronymssurgical castration persistent though not insignificant low levels of androgens are AAWD antiandrogenproduced from nongonadal sources, such as the adrenal glands. Some castration withdrawalresistant prostate cancers acquire the ability to convert adrenal steroids to ACTH adrenocorticotropicandrogens, maintaining levels sufficient to activate androgen receptor. Inhibition hormoneof persistent androgen production and androgen receptor mediated signaling are ADT androgen deprivationrelevant therapeutic strategies for castration resistant prostate cancer. therapyMaterials and Methods: The scientific foundation of and clinical experience with AR androgen receptorsecondary hormonal therapy as well as the development of new investigationalagents for castration resistant prostate cancer, specifically selective cytochrome CRPC castration resistantp450 17 inhibitors and second generation antiandrogens, are discussed. prostate cancerResults: Selective inhibition of cytochrome p450 17 has emerged as an important CYP17 cytochrome p450 17therapeutic pathway for castration resistant prostate cancer. The selective cyto- DES diethylstilbestrolchrome p450 17 inhibitor abiraterone acetate showed promising activity and DHEA dehydroepiandrostenedionetolerability in phase I-II trials. Phase III studies are underway in men with LH luteinizing hormonechemotherapy naïve castration resistant prostate cancer as well as those with PSA prostate specific antigenprogression after docetaxel based chemotherapy. TAK-700 and TOK-001 (for-merly VN124-1) are novel selective cytochrome p450 17 inhibitors that recently TTPP time to PSA progressionentered phase I/II evaluation. MDV3100 is a second generation antiandrogenthat blocks androgen receptor signaling by inhibiting nuclear translocation of the Submitted for publication March 17, 2010. * Correspondence: OrthoBiotech Oncology Re-ligand-receptor complex. Clinical data on MDV3100 are encouraging and support search and Development, A Unit of Cougar Biotech-continued phase III study. nology, 10990 Wilshire Blvd., Suite 1200, Los An-Conclusions: Novel therapies for castration resistant prostate cancer that target geles, California 90024 (telephone: 310-943-8040, extension 124; e-mail: androgen production and androgen receptor mediated signaling have † Financial interest and/or other relationshipdemonstrated promising activity in many men with castration resistant prostate with Ortho Biotech and Cougar Biotechnology.cancer and may redefine the clinical management of these patients. Editor’s Note: This article is the first of 5 published in this issueKey Words: prostate, prostatic neoplasms, androgens, abiraterone, castration for which category 1 CME credits can be earned. Instructions for obtaining credits are given withANDROGEN deprivation therapy is the cor- ADT response duration is limited and the questions on pages 1164 andnerstone of treatment for advanced or most patients experience disease pro- 1165.metastatic prostate cancer. Approxi- gression within 2 to 3 years. Traditionalmately 90% of patients respond to cur- secondary hormonal manipulations, suchrent first line ADT strategies of medical as AAWD, or second line antiandrogens,castration with an LH-releasing hor- glucocorticoids, estrogens or ketocona-mone agonist (with or without an antian- zole, can be of clinical benefit in somedrogen) or surgical castration.1 However, patients after primary ADT failure (see0022-5347/11/1853-0787/0 Vol. 185, 787-794, March 2011THE JOURNAL OF UROLOGY® Printed in U.S.A. 787© 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. DOI:10.1016/j.juro.2010.10.042
  2. 2. 788 NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCERtable).1 However, the response and duration of benefit as well as a brief review of hormonal strategies intend to decrease with each successive hormonal manip- CRPC to date is summarized. To standardize theulation. Chemotherapy may be an option when hormone measurement and reporting of the PSA responsetherapy 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 inas well as in pain and quality of life benefits.2,3 Still, the the Prostate-Specific Antigen Working Group and/orincremental survival benefit with docetaxel is only about Prostate Cancer Clinical Trials Working Group 23 months.2–4 Currently median survival after failed ini- guidelines.7,8tial ADT is approximately 18 months with fewer than20% of patients surviving beyond 3 years.2–4 Prostate TRADITIONAL SECONDARYcancer remains the second leading cause of cancer re- HORMONAL THERAPIES FOR CRPClated death in men in the United States and the need for Cumulative experience with secondary hormonalnew treatment options is critical. therapies provides substantial clinical evidence that Disease progression despite medical or surgical ligand mediated AR signaling remains functional incastration signals the emergence of a prostate can- a large proportion of CRPCs. However, except forcer 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 sincetermed androgen independent or hormone refrac- they suppress pituitary-gonadal axis function ortory, 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 secondarying6 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 therapeuticstrategy. Novel antiandrogens that interfere di- Antiandrogensrectly with AR mediated signaling pathways in The combination of an antiandrogen with gonadalCRPC 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 inhibitorsfor 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 7.0Glucocorticoids: 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 availableEstrogens: Kruit et al20 DES (3) 42 24 3.8 Figg et al21 DES (1) 21 43 Not availableKetoconazole: 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 3.5Aminoglutehimide: 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. 3. NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCER 789pression is often an effective therapeutic maneuver, ticosteroid supplementation.20 Common adversealthough 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 largelywith 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, includinglikely 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 greaterAAWD was associated with a 50% or greater de- decrease in PSA in approximately 30% to 60% ofcrease in PSA in 10% to 15% of patients with pros- CRPC cases with a median response duration oftate cancer with responses lasting a median of about about 7 months.10,21,22 In the largest randomized6 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 casescrease in PSA in about a third of patients, with a compared to 11% for AAWD alone.10 Deferred use ofmedian 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 diseaseportive 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 ofhave 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 nonspecificprednisone 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 thea median of about 2 months.9,14 –16 The mechanisms metabolism of other drugs, including warfarin andunderlying the glucocorticoid activity in CRPC are various statins.not well defined and in the absence of comparativerandomized data no 1 particular agent or regimen isconsidered preferable. INSIGHTS INTO ANDROGEN PRODUCTION AND SIGNALING IN CRPCEstrogensEstrogens have long been known to be active against AR Signalingprostate cancer. The synthetic estrogen DES sup- Prostate cancer gene expression studies revealedpresses 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 uponitary LH production. Also, DES has direct cytotoxic transition to CRPC.23 Up-regulation of the AR geneactivity 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.25of patients with CRPC treated with DES with a The importance of ligand mediated AR signaling inmedian response duration of about 4 months (see CRPC is underscored by findings of frequent ARtable).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, enhanceddial infarction, stroke and pulmonary embolism, is nuclear localization and over expression of nuclearknown to occur with DES and concomitant antico- coactivators.23,25–27 Point mutations may confer ARagulation 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 ofKetoconazole 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 theterol to pregnenolone, aminoglutethimide broadly inhib- recent identification of several constitutively activeits adrenal steroid synthesis and its use necessitates cor- AR splice variants.28
  4. 4. 790 NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCERPersistent Androgen of patients with congenital CYP17 deficiency, a rareProduction in Castrate Environment disorder characterized by adrenal hyperplasia, andWith 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 isthan 2.0 nM). Despite gonadal androgen suppres- not impaired and due to the weak glucocorticoidsion, low levels of circulating androgens persist, activity provided by corticosterone, these patients domainly due to peripheral conversion of adrenal not have adrenocortical insufficiency. However, insteroids, 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 inconvert 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 isandrogen biosynthesis, including CYP17, have effectively managed by low dose glucocorticoids withbeen documented in CRPC tissue23,26,30,31 with or without mineralocorticoid antagonists to suppressevidence of intratumor conversion of upstream ACTH release.precursors of testosterone and dihydrotestoster-one present at concentrations sufficient to activateAR.32,33 These findings have supported the clinical SELECTIVE TARGETINGdevelopment of novel agents that selectively tar- OF CYP17 FOR CRPCget 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 currentlyCytochrome 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 AcetateC17,20 bond of C21 steroids.34 These reactions are key Abiraterone is a highly potent, selective, irreversiblein 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 toThe 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. 5. NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCER 791gen 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, whichvoid 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%). Ofabiraterone was not anticipated to impair mineralo- interest, steroid levels downstream of CYP17 did notcorticoid 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 Ietate in noncastrate men showed that initial an- portion of the second phase I/II study.39 Of 33drogen suppression was soon overcome by a com- phase I patients 19 (58%) had a 50% or greaterpensatory surge in luteinizing hormone and, as decrease in PSA, including 10 of 19 (53%) withsuch, 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 withther decreased castrate testosterone to concentra- prior ketoconazole. The phase II portion of thistions 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 PSAmineralocorticoid precursors (deoxycorticosterone decrease in 29 of 33 patients (88%) with a medianand 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 forasone 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 andcess, 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 dosethough 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 studystate 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 anaïve CRPC in whom multiple prior hormonal ther- 50% or greater decrease in PSA was seen in 24 of 47apies had failed the pharmacodynamic effects of abi- patients (51%) with a median TTPP of 169 daysraterone acetate appeared to plateau at a dose of 750 (95% CI 130 to 281).42 Objective partial responsesto 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 potentialincluded hypertension, hypokalemia and edema, surrogate indicator of clinical benefit. Consistentwhich 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 fluidlow dose corticosteroids. Spironolactone was specif- retention in 15%, which responded to managementically 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 58iting toxicity was seen with the administration of up patients (41%), including 8 of 27 (30%) who wereto 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 99acetate 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 not90% 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 acetatedays (95% CI 122 to 383) in patients with a 50% or is currently being evaluated in 2 randomized, mul-
  6. 6. 792 NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCERticenter, phase III studies of CRPC and accrual to cantly down-regulated AR protein expression, inthese 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 wasPretreatment 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 CRPCTTPP.44 In patients with a baseline circulating tu-mor cell count of 5/7.5 ml or greater a decrease to Second Generation Antiandrogen MDV3100less than 5/7.5 ml was associated with a 50% or AR over expression is known to be a mechanism ofgreater decrease in PSA.42,43 Correlations between antiandrogen resistance in CRPC. Also, the partialserum 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 inmetastasis 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, potentmor microenvironment (bone marrow) may correlate affinity for AR while being devoid of any agonist ARwith 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 androgensponse. response, leading to the induction of apoptosis. In tumor xenograft models known to over express ARCYP17 Inhibitors TAK-700 and TOK-001 treatment with MDV3100 led to substantial tumorTAK-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/IIsults with TAK-700, an oral selective C17,20-lyase multicenter study in 140 patients with progressiveinhibitor, summarized findings with dose levels of metastatic CRPC with oral dose escalations of 30 to100 through 600 mg twice daily as well as 400 mg 600 mg daily.48 The study population was relativelytwice daily combined with low dose prednisone in 26 heavily pretreated with failure of at least 2 priorpatients 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 leasttreatment related adverse event, as seen in 16 pa- 1 prior chemotherapy in 75 (54%). The most commontients (62%), including 3 with grade 3 or greater treatment related adverse event with MDV3100 wasevents at the 600 mg dose. Other common treatment fatigue, which had an onset of approximately 4related 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 3/4in 30%. Decreases in median testosterone from 4.9 adverse events were seen predominantly at a dose ofto 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 potentialdose and in all 5 at the 600 mg dose. Doses at or concern for seizures a maximum tolerated dose ofabove 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 atued phase II evaluation of TAK-700 at the 400 mg between 150 and 240 mg daily. Overall a 50% ortwice 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%) withing. Also, a phase II study of TAK-700 in men with measurable disease. A similar 50% or greater PSAnonmetastatic 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 patientshibited 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 aprostate cancer xenograft model TOK-001 combined median of 147 (95% CI 140 to 231) and 287 dayswith castration inhibited tumor growth and signifi- (95% CI 203 to 427) in patients with and without
  7. 7. NOVEL THERAPEUTIC STRATEGIES FOR CASTRATION RESISTANT PROSTATE CANCER 793prior 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 tumoralso 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 mayphase 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 promiseAR 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 towas specifically designed based on AR crystal struc- address persistent AR signaling in CRPC. Based onture.49 Compared to bicalutamide BMS-6410988 encouraging clinical results to date it seems likelyshowed higher binding affinity and greater inhibi- that these new classes of agents will substantiallytion of AR mediated signaling in preclinical models. change the treatment and clinical outlook in manyTwo 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 ACKNOWLEDGMENTSA significant proportion of CRPCs continue to rely Christine Gutheil and Karim Chamie assisted withon ligand mediated AR signaling for growth and the manuscript.APPENDIXClinical development status of novel androgen synthesis inhibitors and second generation antiandrogens for CRPC Class/Agent Target Phase StatusAndrogen biosynthesis inhibitors:Abiraterone acetete CYP17 (17- -hydroxylase/C17,20-lyase) IIITOK-001 (formerly VN/124-1) CYP17 (17- -hydroxylase/C17,20-lyase), selective AR modulator I/IITAK-700 CYP17 (C17,20-lyase) I/IIAntiandrogens:MDV3100 AR binding/nuclear translocation I/IIBMS-641988 AR binding IREFERENCES 1. 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