Castration resistant prostate cancer-what is it? and what do we do about it? Urology Postgraduate Course February 13, 2009

Transcription

1 Castration resistant prostate cancer-what is it? and what do we do about it? Urology Postgraduate Course February 13, 2009 Charles J Ryan, MD Associate Professor of Clinical Medicine Helen Diller Family Comprehensive Cancer Center Department of Medicine University of California, San Francisco Prostate Cancer - A Prolonged Natural History Based of the Use of Androgen Deprivation Therapy Localized Disease Rising PSA (non-castrate) Metastatic Disease Castration Resistant Prostate Cancer N=230,000/yr N=50,000/yr N=30,000/yr Treatment Population = Incidence of 30,000 pts/yr X 4 years Natural History = 120,000 pt prevalence Risk of death from prostate cancer UCSF 2 Survival years Survival months Death The Hypothalmic-Pituitary-Gonadal Axis and Therapeutic Interventions Schematic Model of Castration Resistance DES LHRH agonists (Lupron, Zoladex) HYPOTHALMUS LHRH (pulsatile) PITUITARY 500 ng/ml Testosterone Hypothesis: Low androgen levels + Hypersensitive AR drives Resistance FSH, LH Megace / aminoglutethimide orchiectomy TESTIS Testosterone DHT PROSTATE CANCER CELLS Adrenals Antiandrogens: steroidal (Megace) and non-steroidal (Casodex, Flutamide, Nilutamide) 50 ng/ml PSA Castration Therapy Castration Resistance

2 The Reality of CRPC Treatment Primary Hormonal Therapy why truly Androgen Independent Prostate cancer may not exist Secondary Hormonal Therapy Chemotherapy Persistent AR signaling may be an early event associated with recurrence AR copy number increases with disease progression. Persistent Serum Androgens may stimulate tumor growth despite castration therapy Intratumoral androgens may stimulate tumor growth Novel therapies are in development that exploit these axes. Higher AR levels in HRPC tumors Mechanism 1 Stanbrough et al Cancer Research 2006 Holzberlein et al AR Amplification Figure 2. Range of AR expression and analyses of CKS2 and LRRC15 by quantitative real-time RT-PCR. A, range of AR expression in primary (Pr) and androgen-independent tumors (AIPCa) from Affymetrix data. B, CKS2 and LRRC15 expression assessed by quantitative real-time RT-PCR using unamplified RNA from 5 primary tumors and 10 androgen-independent prostate cancer bone marrow metastases. Expression levels are in arbitrary units based on the lowest level expression being set at 10. Bars, mean expression. (CKS2 associates with cyclin-dependent kinases and enhances their interaction with CDC25 phosphatases, which dephosphorylate them at the G2- M transition LRRC15 is a cell surface glycoprotein major transcriptional target of the Wilms tumor 1 (WT1; +KTS) isoform and is overexpressed due to a WT1 fusion protein in a rare, highly aggressive tumor type, desmoplastic small round cell tumor ) Figure 3. AR expression in human prostate cancers. A: Bar graph representing AR transcript levels based on hybridization of cdna target to oligonucleotide arrays. Two different probe sets for AR are presented. B and C: Immunohistochemical detection of the AR in representative primary untreated prostate cancer with low level of AR transcripts (B) and metastatic AARPC with high levels (C). D and E: Fluorescent in situ hybridization for AR (red) and chromosome X centromere (green) in metastatic AARPC with high levels of AR transcripts and no amplification of the AR gene (D) and metastatic AARPC with high level of AR expression and AR amplification (E).

3 Pituitary ACTH Mechanism 2: Persistent Serum Androgens Cholesterol Pregnenolone Adrenal Cortex Cholesterol Side Chain Cleavage 18OH- Progesterone DOC Corticosterone Aldosterone Corticosterone 17-hydroxylase 21-hydroxylase 11-hydroxylase 18-hydroxylase 18-oxidase Mineralocorticoids 17OH-pregnenolone 17OH-progesterone 11-DOC Cortisol Glucocorticoids Peripheral Tissues C17-20 lyase DHEA Androstenedione Testosterone DHT Androgens 17-keto-reductase 5-reductase Randomized Phase III Study of vs AAWD->Keto Are Serum Androgens Important in Castration Resistant Disease? CALGB 9583 AAWD AAWD tid plus HC 20/10 CALGB 9583 AAWD AAWD tid plus HC 20/10 Tail of Curve Effect : prolonged PFS / Survival - Tail of Curve Effect : Small et al Journal of Clinical prolonged Oncology 2004 PFS / Survival - Are pretreatment androgen levels a treatment predictive factor for patients receiving secondary hormonal therapy? Small et al Journal of Clinical Oncology 2004

4 Androstendione<=0.49 Androstendione>0.49, P= Time (Months) Number of Patients at Risk Androstendione<= Androstendione> CALGB 9583: Adrenal Androgens During Therapy Do Androgen levels predict outcome? Baseline Androstenedione Levels Baseline Androstenedione Levels Progressive DZ on CAB Small et al JCO 2004 AAWD AAWD plus Baseline N=100 Median (25%, 75%) PD Arm 2 (AAWD + KETO/HC) Month 1 Month 3 N=81 N=43 Median (25%, 75%) Median (25%, 75%) Progression N=57 Median (25%, 75%) DHEA 2.1 (1.6,3.3) 1.0 (0.8,1.3) 1.0 (0.7,1.5) 1.2 (0.8,2.0) DHEAS 317 (144,696) 30 (1,86) 53 (1,173) 119 (30,258) Androstendione 0.63 (0.5,1.1) 0.31 (0.2,0.4) 0.33 (0.2,0.6) 0.45 (0.3,0.6) Testosterone 13 (1,19) 11 (1,17) 10 (1,15) 10 (1,17) Androgen PD Resurgence at at Progression on on Keto P= Androgen Odds Ratio for Response to Keto (95% CI) P value Androstenedione 5.09 ( ) DHEA 2.18 ( ) 0.11 DHEAS 0.87( ) 0.64 Testosterone 4.14 ( ) 0.75 = Androgens have prognostic significance in Androgen Independent disease Ryan, Halabi et al Clinical Cancer Research 2007 Androstenedione in ng/ml Androstenedione in ng/ml p= p= <median (N=89) > median (N=14) <median (N=89) > median (N=14) Duration of Response to Duration of Response to Survival Probability Pts with lowest Androstenedione levels have poorer survival Androgens as Treatment Predictive Factors: Conclusions Mechanism 3 Presence of androgens modestly associates with likelihood of response to ketoconazole. Low levels of androstenedione associates with shortened survival.? Truly hormone refractory Do these androgens represent the only available supply for the AR? Intratumoral Androgen (production and sequestration)

5 Persistent Intraprostatic Androgen Concentrations after Medical Castration in Healthy Men Stephanie T. Page, Daniel W. Lin, Elahe A. Mostaghel, David L. Hess, Lawrence D. True, John K. Amory, Peter S. Nelson, Alvin M. Matsumoto and William J. Bremner Intraprostatic Androgens in Recurrent PC Androgen Stimulated Prostate Testosterone Androgenstimulated benign prostate N= pmol/g tissue Recurrent Wilcoxon twosided, prostate cancer N=18 (TUR) 3.75 pmol/g P=0.30 DHT 13.7 pmol/g tissue 1.25 pmol/g tissue P < Male volunteers N=13 (4 per group) Page, S. T. et al. J Clin Endocrinol Metab 2006;91: ages 35ミ55 yr (prostate-specific antigen < 2.0 ng/ml; normal transrectal ultrasound) randomly assigned to: 1) a long-acting GnRH-antagonist, acyline, every 2 wk; 2) acyline plus testosterone (T) gel (10 mg/d); 3) placebo for 28 d. Serum hormones were assessed weekly. Prostate biopsies were obtained on d 28. Extracted androgens were measured by RIA, and immunohistochemistry for androgen-regulated proteins was performed. Prostate sequesters DHT, T to a lesser extent Titus, Mohler et al Clin Cancer Res Jul 1;11(13): Fig. 1. LC/MS/MS multiple reaction monitoring profile of representative samples of AS-BP (A) and recurrent prostate cancer (B); cps, counts per second. The parent/product ion pairs for testosterone (blue), internal standard testosterone-d3 (red), dihydrotestosterone (green), and internal standard dihydrotestosterone-d4 (black) were monitored and product ion used for androgen quantitation. UCSF 5 Alpha Reductase in Recurrent prostate Cancer 5 alpha reductase converts: T to DHT in Tumor Androstenedione to Androstanedione Results: Type 1 5 alpha reductase increases relative to Type 2 in recurrent CaP Titus et al Clinical Cancer Research Vol. 11, , June 15, 2005 N=23 N=23 N=22 Genes Expressed at Higher Levels in AIPC BM Biopsies (Compared to primaries - among others) Symbol Fold (AIPC:Primary) Gene Name AR 5.84 Androgen Receptor AR AKR1C Aldo-keto reductase family 1, member C3 Stanbrough et al Cancer Research March 1, 2006 Significance Converts androstenedione to testosterone SRD5A alpha reductase type 1 Converts T to DHT Converts Androstenedione to Androstanedione HSD3B Beta -hydroxysteroid dehydrogenase type 2 Converts DHEA to Androstenedione AKR1C2 3.4 Aldo-keto reductase 2 Catabolizes DHT Can convert Androstanedione to Androstenedione AKR1C1 3.1 Aldo-keto reductase 1 Catabolizes DHT U C S F

6 Net Increase in Androgen Synthesis Enzymes The Persistent Relevance of Androgens The Biological Foundation of Secondary Hormonal Therapy HD Casodex, Novel AAs AR Amplification (30%) CRPC Intratumor Androgen Production/conversion Dutasteride,? Abiraterone? Figure 3. Increased expression of enzymes mediating androgen synthesis and catabolism in androgen-independent prostate cancer. Androgen synthesis (from adrenal DHEA and androstenedione) and catabolism are outlined, and fold increase for each enzyme is indicated. The indicated metabolites are 5- androstane-3,17 ァ -diol (3-diol), and 5-androstane-3 ァ,17 ァ -diol (3 ァ - diol). Stanbrough et al Cancer Research March 1, 2006 Persistent Serum Androgens (e.g. adrenals), Abiraterone Steroids Pituitary ACTH Cholesterol Adrenal Cortex Secondary Hormonal Therapy: Adrenal Androgen Inhibition Does it Validate Mechanism? Cholesterol Side Chain Cleavage Pregnenolone 18OH- Progesterone DOC Corticosterone Aldosterone Corticosterone 21-hydroxylase 11-hydroxylase 18-hydroxylase 18-oxidase Mineralocorticoids Abiraterone 17-hydroxylase 17OH-pregnenolone 17OH-progesterone 11-DOC Cortisol Glucocorticoids Abiraterone C17-20 lyase Peripheral Tissues DHEA Androstenedione Testosterone DHT Androgens 17-keto-reductase 5-reductase

7 Activity of Abiraterone in Patients Previously Treated with Baseline Post Cycle 6 Resp to abiraterone in patients with prior ketoconazole therapy 10/19 (53%) Resp to abiraterone in patients with NO prior ketoconazole therapy 6/11 (55%) Time to Progression in post-ketoconazole patients 21 weeks Ryan et al Proc ASCO GU Symposium 2008 Conclusions Androgen / AR interactions persist in Castration Resistant Prostate Cancer. Intratumor steroid production suggests that these effects are not Endocrine or even Hormonal at all. Abiraterone acetate, demonstrates considerable activity Responses in prior ketoconazole responders suggest that Pathway addiction can be identified by these therapies.