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Prostate 101

This document summarizes key information about prostate cancer including: 1. Risk factors such as age, ethnicity, family history, and diet. 2. Diagnostic tools like PSA testing which is imperfect but can be improved through measures of density and velocity. 3. Clinical stages from localized to metastatic disease and treatments available at each stage including androgen deprivation therapy and newer agents. 4. Ongoing research into better targeting the androgen receptor pathway which remains important even in advanced "castrate resistant" prostate cancer.

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Dana Rathkopf, MD Genitourinary Oncology Service Memorial Sloan Kettering Cancer Center Prostate Cancer 101 The following material is intended for MSKCC internal medicine housestaff teaching purposes only. The slides are courtesy of Dr. Dana Rathkopf and were updated for the LibGuide in 2012-2013.
Jemal, A. et al. CA Cancer J Clin 2010 Estimated New Cancer Cases and Deaths, US, 2010
ANATOMY
Gleason Grading System CEA, Chromogranin A PSA Image: Chris Pearson
Iyer Cancer 1999 Simone Kaiser: Identification and Characterization of the Ion Channel TRPM8 in Prostate Cancer
Risk Factors for Prostate Cancer • Age – Less than 10% diagnosed in men <54 years – 64% diagnosed between 55-74 years • Ethnicity: – BM 68% higher incidence, 158% higher mortality • Dietary Fat: – Increased relative risk by a factor of 1.6 to 1.9 • Family History: • 5-10% of all patients have family history • Relatives of patients younger than 55 years have greater risk • 1 relative = 2x lifetime risk, >= 2 relatives = 4x lifetime risk • At least 8 candidate susceptibility genes have been reported
Prostate Specific Antigen (PSA): An Imperfect Tool • Glycoprotein secreted by the prostate • ORGAN specific (not cancer-specific) • Sensitivity 70-80% and PPV 30% when PSA is ‘normal’ (< 4) • Does not inform grade , and may lead to detection and treatment of indolent disease • Influenced by biologic variations, age, prostate volume, inflammation, race/ethnicity • NOT influenced by DRE or ejaculation
Improving the use of PSA for Detection • PSA density: >0.15 suggestive of PC CA causes a greater elevation in PSA /volume than BPH • PSA velocity: >0.75 ng/ml/yr suggestive of PC • Percent free PSA: <25% suggestive of PC CA related PSA is bound to α-glycoprotein • Age specific PSA: <2.5 ng/ml 40-49 yo 3.5 ng/ml 50-59 yo 4.5 ng/ml 60-69 yo 6.5 ng/ml 70-79 yo
Scardino and Kelman. Avery Press, 2005. • Average age at diagnosis is 68 years old • PSA screening advances lead time by 5-10 years • Overdiagnosis? Implications of Early Detection in an Aging Population
ERSPC Bottom Line: YES PSA-based screening reduced the rate of death from prostate cancer by 20%; but was associated with a high risk of overdiagnosis. US PLCO Bottom Line: NO The rate of death from prostate cancer was very low and did not differ significantly between the two study groups; but 40% of usual care group had PSA testing. Prostate Cancer Screening: Results of 2 Randomized Controlled Studies
Prostate Cancer Screening Guidelines PSA Screening (life expectancy >10 yrs) PSA Screening (+risk factors) American Cancer Society www.cancer.org Offer at age 50 Offer at age 40-45 American Urologic Association www.auanet.org Baseline 40 years old National Comprehensive Cancer Network www.nccn.org Baseline 40 years old: >1 ng/mL annual follow-up <1 ng/mL rescreen age 45 US Preventive Services Task Force http://www.uspreventiveservicestaskforce.org No screening for patients >75 (No screening ever??) Baseline PSA at age 40 is a stronger independent predictor of PC risk than ethnicity, family history, or DRE. (Loeb et al, AUA 2005)
Prostate Cancer Clinical States FDA-approved Agents for Prostate Cancer Rising PSA Clinical Metastases: Castrate 1st Line Chemo Clinical Metastases: Castrate Pre-Chemo Clinically Localized Disease Clinical Metastases: Non-Castrate Clinical Metastases: Castrate Post-Chemo NON-CASTRATE Diagnosis 241, 740 Androgen Deprivation Therapy CASTRATION -RESISTANT Deaths From Disease 28, 170 Docetaxel 2004 Sipuleucel -T 2010 Cabazitaxel 2010 Abiraterone 2011 Enzalutamide 2012 Abiraterone 2012
Charles B. Huggins, MD Nobel Prize in Physiology or Medicine, 1966 Huggins C, Hodges CV. Studies on prostatic cancer I. The effect of castration, estrogen, and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293–297. William Wallace Scott, Charles B. Huggins, and Clarence V. Hodges
Hormones: Benefits 70 Before After
Hormonal Therapies • Anti-androgens: Casodex, Nilandron, Flutamide Enzalutamide • Adrenal ablation Ketoconazole, Abiraterone
Antiandrogen Withdrawal Response -120-30 0 43 99 136164198 254357 387 417 437527 Time (days) 0 50 100 150 200 250PSA (ng/m l) Flutamide withdrawal Bicalutamide
Anti-Androgen Withdrawal Kelly et al, 1997 Author Scher Dupont Herrada Sartor Figg Small Small Overall 50% PSA Decline 16/57 (28%) 32/40 (80%) 11/39 (28%) 14/29 (48%) 7/21 (33%) 12/82 (15%) 4/8 (50%) 96/276 (35%) Time to Response (weeks) 5.6 NS <6 <4 <6 NS <4 Duration of Response (months) 4 14.5 3.3 8 3.7 3.5 NS
Hormones: Limitations • Hormones are NOT curative • Significant side effect profile: Diminished libido and potency Osteoporosis Weight gain Diminished muscle mass Breast enlargement and breast tenderness Emotional changes Fatigue Anemia
Intermittent ADT Phase III Trials Trial (Year) Patient Population No. of pts randomized Primary Endpoint NCIC PR7 (2011) PSA relapse after RT Non-Metastatic 1386 OS No difference EC 507 (2007) PSA relapse after RP Non-Metastatic 167 TTP AP 17/95 (2007) Locally advanced/ Metastatic (~40%) 335 TTP SEUG (2009) Locally advanced/ Metastatic (~30%) 766 TTP FinnProstate (2012) Locally advanced/ Metastatic (~50%) 554 TTP TULP (2011) Metastatic 193 TTP SWOG 9346 (2012) Metastatic 1535 OS MODIFIED FROM SLIDES by William Oh, M.D.
[TITLE] Overall survival with Intermittent Hormonal Therapy is NOT “NONINFERIOR” to Continuous Therapy (Translation: it is POTENTIALLY inferior) Modified Slide
Conclusions Intermittent is NOT Non-Inferior to Continuous ADT • Continuous ADT remains the standard of care for hormone sensitive metastatic PC • Neither this nor any randomized trial has EVER shown a superior cancer outcome with intermittent ADT • Will more potent reduction of intratumoral androgen (abiraterone) or inhibition of AR signaling (enzalutamide) lead to better outcomes with initial ADT?
Untreated Primary Metastatic Castration Resistant Scher et al. Endocrine-Related Cancer 11:2004;459 The Androgen Receptor is Often Overexpressed in Castration Resistant Tumors and is a Target for Therapy Increased AR protein AR mRNA overexpression Increased AR DNA copy number o Post-Androgen Depletion
AR HSP90AR degraded AR P AR PARP Transcription of TMPRSS-ETS, etc for growth and survival SRC Androgen precursors Androgens Adrenal synthesis Tumor synthesis DHT AR AR Cell surface ligand/receptor AKT ARP mut AR AR AR ARAmp AR + antiandrogens, progestins glucocorticoids Modified from Chen et al. Curr Opin Pharm, 2008 Therapeutic Targets of the AR Signaling Pathway AGONIST CONVERSION ALTERNATIVE LIGANDS ADRENAL/INTRATUMORAL ANDROGENS LIGAND INDEPENDENT AR PHOSPHORYLATION
FDA Approved Agents with an Overall Survival Benefit in CRPC Agent Year Approved Mechanism Median Overall Survival Hazard Ratio Docetaxel1 vs Mitoxantrone 2004 Anti-microtubule 2.5 18.9 vs 16.5 0.76 Sipuleucel-T2 vs Placebo 2010 Immunomodulatory 4.1 25.8 vs 21.7 0.78 Cabazitaxel3 vs Mitoxantrone 2010 Anti-microtubule 2.4 15.1 vs 12.7 0.70 Abiraterone4 vs Placebo POST-DOCETAXEL* 2011 Androgen synthesis inhibitor 3.7 14.8 vs 10.9 0.65 MDV31005 vs Placebo POST-DOCETAXEL* 2012 AR antagonist 4.8 18.4 vs 13.6 0.63 1Tannock et al., NEJM 2004; 2Kantoff et al., NEJM 2010; 3DeBono et al., NEJM 2010; 4DeBono et al., NEJM 2011; 5Medivation Interim Analysis of the AFFIRM Trial in CRPC post-Docetaxel 11/3/11 *CTC biomarker analysis at MSKCC embedded in the phase 3 trials as a surrogate for survival
Adapted from J E Ang, et al, British Journal of Cancer, 2009 Secondary Mineralicorticoid Syndrome *Low dose steroids minimizes toxicity* Suppression of the Renin- Angiotensin Pathway 4 fold increase due to elevated ACTH partially reverses 17-hydroxylase activity Abiraterone Acetate Selective and Irreversible Inhibition of CYP17
POST-DOCETAXEL ABIRATERONE (Zytiga) FDA APPROVED April 28, 2011 Proof of principle that AR IS STILL RELEVANT IN CRPC!!!
POST-DOCETAXEL: ABIRATERONE MS 15.8m versus 11.2m HR 0.740 (0.63-0.85) De Bono et al., Journ Clin Oncol , 2011.
Overall Study Design of COU-AA-302 CHEMONAIVE CRPC • Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites in 12 countries • Stratification by ECOG performance status 0 vs 1 • No prior novel anti-androgens (MDV3100), ketoconazole or chemotherapy Co-Primary Endpoints: • rPFS by central review • OS Secondary: • Time to opiate use (cancer- related pain) • Time to initiation of chemotherapy • Time to ECOG-PS deterioration • TTPP AA 1000 mg daily Prednisone 5 mg BID (Actual n = 546) Efficacy end points Placebo daily Prednisone 5 mg BID (Actual n = 542) R A N D O M I Z E D 1:1 • Progressive chemo- naïve mCRPC patients (Planned N = 1088) • Asymptomatic or mildly symptomatic Patients
Landmarks of Disease Progression in mCRPC Planned Interim Analysis at 43% of Events 31 Baseline PSA Progression Tumor/Bone Progression Pain Death Adapted from Halabi S. et al, J Clin Oncol. 2009;27:2766-2771. Chemotherapy ECOG PS Decline Secondary Endpoints ECOG PS= Eastern Cooperative Oncology Group Performance Status 24-48 months p < 0.0001 p < 0.0001 p = 0.001 p = 0.0053 rPFS p < 0.0001 OS p = 0.0097
Safety Profile Consistent Despite Longer Duration of Exposure Most Prevalent AE AA + P (n = 542) % Placebo + P (n = 540) % All Grades Grades 3/4 All Grades Grades 3/4 Fatigue 39 2.2 34 1.7 Fluid retention 28 0.7 24 1.7 Hypokalemia 17 2 13 2 Hypertension 22 4 13 3 Cardiac disorders 19 6 16 3 ALT increased 12 5.4 5 0.8 AST increased 11 3.0 5 0.9 32 • Most of the ALT and AST increases occurred during the first 3 months of treatment
Statistically Significant Improvement in rPFS Primary End Point NR, not reached; PL, placebo. 100 80 60 40 20 0 0 ProgressionFree(%) 3 6 9 15 1812 AA + P (median, mos): NR PL + P (median, mos): 8.3 HR (95% CI): 0.43 (0.35-0.52) P value: < 0.0001 546 542 489 400 340 204 164 90 12 3 0 0 AA Placebo 46 30 Time to Progression or Death (Months) AA Placebo
Strong Trend in OS Primary End Point*† *O’Brien-Fleming boundary used; †Data cut off 12/20/2011; ‡Nominal significance level 0.0008. 546 542 538 534 482 465 452 437 27 25 0 0 524 509 503 493 0 2 120 106 258 237 412 387 100 80 60 40 20 0 0 Survival(%) 3 12 15 27 Time to Death (Months) 33 AA Placebo 6 9 30242118 AA Placebo AA + P (median, mos): NR PL + P (median, mos): 27.2 HR (95% CI): 0.75 (0.61-0.93) P value: 0.0097‡
Summary: New Standard of Care? AA and Prednisone for Pre-chemo mCRPC • Delays disease progression • Increases survival* (but not by pre-specified amount) • Extends time with minimal or no symptoms • No new important safety signals * 55% Interim Analysis due at ASCO 2013
Compared to bicalutamide… 20-fold higher affinity for the AR 6/19/06 Rathkopf et al, Clin Cancer Res, 2011 -100% -75% -50% -25% 0% 25% 50% 75% 100% 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 Dose decline post BMS Therapy BY DOSE 5 mg 10 mg 20 mg 40 mg 60 mg 100 mg
WISH LIST Second Generation AR Antagonist Bicalutamide BMS641988 2nd Gen AA Effective in cells with high AR expression X Overcomes agonist activity X X Novel mechanism of action X X
Ligand 1. AR Binding Affinity • DHT ~ 5nM • Bicalutamide ~160 nM • MDV3100 ~35 nM 2. Nuclear Import • DHT: ++++ • Bicalutamide: ++++ • MDV3100: ++ 3. DNA Binding • DHT: ++++ • Bicalutamide: ++ • MDV3100: - 4. Coactivator recruitment: No agonist effects. • DHT: ++++ • Bicalutamide: ++ • MDV3100: - MDV3100: A Novel AR Antagonist 1 2 3 4 DNA POL II HSP90 LBD HD DBD NTD Chen et al. Lancet Oncol 10:981, 2009 Tran et al., Science 324:787, 2010.
MDV3100 is active in AR expressing tumor models and inhibits AR nuclear translocation Tran et al., Science 324:787, 2009 LnCAP-AR Cell Lines RD162 is the precursor of the clinical candidate MDV3100
Chemo naïve; N=65 Chemo exposed; N=75 MDV3100: Maximum PSA decrease from baseline Modified from Scher et al., Lancet, 2010 62% 40/65 >50% PSA decline 51% 38/75 >50% PSA decline -100% -75% -50% -25% 0% 25% 1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61 64 67 70 73 76 79 82 85 88 91 94 97 100 103 106 109 112 115 118 121 124 127 130 133 136 139
Pre- and Post-Treatment FDHT PET Imaging On-Target Effect of AR inhibition with MDV3100 18-Fluorodihydrotestosterone (F-DHT) PET Pre -Treatment Post -Treatment Scher HI et al., Lancet, 2010 Dosage
AFFIRM Trial Design Enrollment between September 2009 and November 2010 156 centers from 15 countries and 5 continents. R A N D O M I Z E D 2:1 Primary Endpoint: Overall Survival Enzalutamide 160 mg daily n = 800 Placebo n = 399 Patient Population: 1199 patients with progressive CRPC * Failed docetaxel chemotherapy
Enzalutamide Prolonged Survival, Reducing Risk of Death HR = 0.631 (0.529, 0.752) P <0.0001 37% reduction in risk of death Enzalutamide: 18.4 months (95% CI: 17.3, NYR) Placebo: 13.6 months (95% CI: 11.3, 15.8) Enzalutamide 800 775 701 627 400 211 72 7 0 Placebo 399 376 317 263 167 81 33 3 0
AFFIRM: Clinical Outcomes Variable Enzalutamide (800 pts.) Placebo (399 pts.) Hazard Ratio P -value OS (months) 18.4 13.6 0.631 <0.0001 PSA progression (months) 8.3 3.0 0.218 <0.0001 rPFS (months) 8.3 2.9 0.404 <0.0001 1st SRE (months) 16.7 13.3 0.621 <0.0001 CR + PR 28.9% 3.8% - <0.0001 FACT-P 43.3% 17.8% - <0.0001 Slide modified from presentation by Kevin Kelly, DO
Favorable Adverse Risk Profile All Grades Grades >3* Enzalutamide (n = 800) Placebo (n = 399) Enzalutamide (n = 800) Placebo (n = 399) AEs 98.1% 97.7% 45.3% 53.1% Serious AEs 33.5% 38.6% 28.4% 33.6% Discontinuations due to AEs 7.6% 9.8% 4.6% 7.0% AEs leading to death 2.9% 3.5% 2.9% 3.5% All Grades Grade ≥ 3 Events Enzalutamide (n = 800) Placebo (n = 399) Enzalutamide (n = 800) Placebo (n = 399) Seizure 0.6% 0.0% 0.6% 0.0% Slide modified from presentation by Kevin Kelly, DO and Johann De Bono, MD
• AR antagonist drug class causes convulsions in laboratory animals at high doses by an off-target mechanism • AR antagonist seizure risk increases with brain drug concentrations • AR antagonist drug class inhibits the GABA-A current1 • Seizures have been observed in clinical testing of the next generation AR antagonists BMS-641988 and MDV3100 Seizure potential is an important consideration in the development of AR antagonists* *Slide adapted from discussion by Dr. WK Kelly at 2012 ASCO Annual Meeting 1Foster WR et al. Prostate . 2011
ARN-509 Produces Superior Antitumor Responses than Bicalutamide in Castration Resistant LNCaP/AR-Luc Xenografts. Clegg N et al., Cancer Res 2012 ARN-509: A Novel Anti-Androgen for Prostate Cancer Treatment Exhibits Characteristics Predicting a Higher Therapeutic Index than Current AR Antagonists
Phase II Study of the Novel AR Antagonist ARN-509 in CRPC Activity across the spectrum of CRPC including post-abiraterone Non-Metastatic CRPC Metastatic CRPC Post-Abiraterone CRPC Baseline PSA (ng/mL, range) 9.7 (0.5, 201.7) 14.7 (1.1, 2552.1) 64.1 (12.0, 1315.2) 12-Week PSA Response* 91% 88% 29% %ChangeinPSAfrombaseline Individual Patients * Per PCWG2, the % of patients that reach ≥ 50% decline from baseline at week 12 (3 months) on study n=45 n=25 n=14 Rathkopf et al. Poster Presentation, 2012 Prostate Cancer Foundation Annual Meeting -100 -75 -50 -25 0 25 50 75 100
Beyond Hormones: Chemotherapy Historically regarded as inactive for prostate cancer: new trial designs and new drugs have changed this view.
Chemotherapy for CRPC Background • 1985: No evidence for palliative benefit from chemotherapy. Chemotherapy recommended only for clinical trials. • 1996: Mitoxantrone + prednisone vs prednisone alone establishes a palliative benefit for mitoxantrone in 30% of symptomatic patients. Studies are too small to detect a survival benefit. FDA approval. • 2004: The larger TAX327 and SWOG 99-16 trials show a 3 month improvement in survival (1619 months) for Docetaxel compared to Mitoxantrone. FDA approval.
Relief of Pain (Palliation): Mitoxantrone, the gold standard Tannock et al: J Clin Oncol. 1996 Response Mito. + Pred. (n = 80) Pred. (n = 81) P-Value Primary Endpoint (decreased pain) 23 (29%) 10 (12%) .011 Secondary Endpoint (decreased analgesics) 7 7 Total Palliative Response 30 (38%) 17 (21%) .025
TAX 327 Established Docetaxel as the First-Line Standard of Care for Castration-Resistant Prostate Cancer: Benefit Was Restricted to Every 3 Week Dosing Months Median survival Hazard (mos) ratio P-value Docetaxel every 3 weeks: 18.9 0.76 0.009 Docetaxel weekly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – ProbabilityofSurviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Tannock et al., NEJM, 351:1502, 2004
53 Cabazitaxel Primary Endpoint: Overall Survival—Updated ITT Analysis* 28% reduction in risk of death Time (months) ProportionofOS(%) 377 378 299 321 195 241 94 137 31 60 9 19 100 80 60 40 20 0 0 6 12 18 24 30 MP CBZP Median OS (months) 12.7 15.1 Hazard ratio 0.72 95% CI 0.61–0.84 P-value <.0001 Number at Risk MP CBZP Censored MP CBZP Combined median follow-up: 13.7 months * Data cut-off 3/10/2010
Why do we need clinical trials? • Hormones and chemotherapy are not curative • Durability of effects is limited • Despite the proven benefits, both have significant side effects • There are patients who will not respond to standard treatments
RADIUM-223 T1/2 Range in tissue Average particle energy per decay Bone surface to red bone marrow dose ratio Strontium 89 50.5 d 2.4 mm 0.58 MeV 1.6 Samarium 153-EDTMP 1.9 d 0.55 mm 0.22 MeV 4.4 Radium 223 11.4 d < 0.1 mm 27.4 MeV 10.3 Adapted from Bruland et al, Clin Cancer Res, 2006
Radium-223 Targets Bone Metastases • Radium-223 acts as a calcium mimic • Naturally targets new bone growth in and around bone metastases • Radium-223 is excreted by the small intestine Ra Ca
ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design TREATMENT 6 injections at 4-week intervals Radium-223 (50 kBq/kg) + Best standard of care (IV q 4 weeks up to 6 treatments) Placebo (saline) + Best standard of care R A N D OM I S E D 2:1 N = 921 PATIENTS • Confirmed symptomatic CRPC • ≥ 2 bone metastases • No known visceral metastases • Post-docetaxel or unfit for docetaxel Primary Endpoint: Overall Survival • Total ALP: < 220 U/L vs ≥ 220 U/L • Bisphosphonate use: Yes vs No • Prior docetaxel: Yes vs No STRATIFICATION Clinicaltrials.gov identifier: NCT00699751
ALSYMPCA Updated Analysis Overall Survival Radium-223, n = 614 Median OS: 14.9 months Placebo, n = 307 Median OS: 11.3 months HR = 0.695 95% CI, 0.581, 0.832 P = 0.00007 Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Radium-223 614 578 504 369 274 178 105 60 41 18 7 1 0 0 Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 0 0 10 20 30 40 50 60 70 80 90 100 %
ALYSMPCA Updated Analysis Conclusions • Significantly improved OS (3.6m), SRE (5.5m) • Favorable safety profile • Has activity and safety profile compatible for use with patients who are not good candidates for docetaxel Radium-223, a novel alpha-pharmaceutical, may provide a new standard of care for the treatment of CRPC patients with bone metastases
Cabozantinib (XL184) in Chemotherapy-pretreated Metastatic Castration Resistant Prostate Cancer (mCRPC): Results from a Phase 2 Nonrandomized Expansion Cohort (abstract #4513) M.R. Smith, C. Sweeney, D. Rathkopf, H.I. Scher, C. Logothetis, D.J. George, C.S. Higano, E.Y. Yu, A.L. Harzstark, E.J. Small, O.A. Sartor, M.S. Gordon, N.J. Vogelzang, D.C. Smith, M. Hussain, J.S. de Bono, N.B. Haas, C. Scheffold, Y. Lee, P.G. Corn Massachusetts General Hospital Cancer Center, Boston, MA; Dana-Farber Cancer Institute, Boston, MA; Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY; The University of Texas MD Anderson Cancer Center, Houston, TX; Duke University Medical Center, Durham, NC; Fred Hutchinson Cancer Research Center, Seattle, WA; University of California, San Francisco, San Francisco, CA; Tulane Cancer Center, New Orleans, LA; Pinnacle Oncology Hematology, Scottsdale, AZ; US Oncology Research/ Comprehensive Cancer Centers NV, Las Vegas, NV; University of Michigan, Ann Arbor, MI; Royal Marsden Hospital & Institute of Cancer Research, Sutton, United Kingdom; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Exelixis, South San Francisco, CA; University of Texas M. D. Anderson Cancer Center, Houston, TX
Cabozantinib (XL-184) Oral TKI that Inhibits MET and VEGFR • Randomized discontinuation trial in CRPC – High rates of bone scan improvement – Reduction in bone markers – Regression of soft tissue disease – PFS improvement – Pain improvement and narcotics reduction – PSA changes discordant with other measures of antitumor activity M. Hussain et al. ASCO 2011 (Abstract #4516) Bone scan Baseline Follow-up
Subject 1316-2127 (Taxotere-pretreated) Partial Response; Bone Scan and Pain Improvement; ↓PSA; ↓tALP Screening Week 12 CT scan: confirmed PR with 41% tumor decrease at Week 12 -2 0 2 4 6 8 10 12 14 0 100 200 300 400 500 600 700 800 900 tALP PSA 0 100 200 300 400 500 Screening Weeks On Study tALP PSA Baseline Week 6 Target lesions: -33% Week 12 Target lesions: -41%
Most Frequently Reported Adverse Events (N = 93) Adverse Event All Grades, n (%) Grade 3, n (%) Grade 4, n (%) Fatigue 77 (83) 24 (26) 2 ( 2) Decreased appetite 68 (73) 6 ( 6) - Diarrhea 65 (70) 10 (11) - Nausea 62 (67) 9 (10) - Vomiting 35 (38) 4 (4) - Dysgeusia 35 (38) - - Weight decreased 34 (37) 3 (3) - Dysphonia 33 (35) - - Back pain 32 (34) 5 (5) 2 (2) Dyspnea 30 (32) 4 (4) 1 (1) Hypothyroidism 29 (31) - - Adverse Events of Interest Hand-foot syndrome 23 (25) 5 (5) - Hypertension 22 (24) 8 (9) - Thrombosis venous 12 (13) 1(1) 5 (5) One patient with extensive liver disease experienced a related Grade 3 portal vein thrombosis with Grade 5 liver failure 84% of patients experienced at least one dose reduction due to AE
SUMMARY Exciting Time in Treatment for CRPC • The Androgen Receptor remains a relevant target. • New technology to evaluate response and progression: circulating tumor cells, FDHT PET. • Collaborative efforts to increase accrual and share concepts and ideas. • 4 new drugs approved …More to come!!!

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Prostate 101

  • 1.
    Dana Rathkopf, MD GenitourinaryOncology Service Memorial Sloan Kettering Cancer Center Prostate Cancer 101 The following material is intended for MSKCC internal medicine housestaff teaching purposes only. The slides are courtesy of Dr. Dana Rathkopf and were updated for the LibGuide in 2012-2013.
  • 2.
    Jemal, A. etal. CA Cancer J Clin 2010 Estimated New Cancer Cases and Deaths, US, 2010
  • 4.
  • 5.
    Gleason Grading System CEA, ChromograninA PSA Image: Chris Pearson
  • 6.
    Iyer Cancer 1999 SimoneKaiser: Identification and Characterization of the Ion Channel TRPM8 in Prostate Cancer
  • 7.
    Risk Factors forProstate Cancer • Age – Less than 10% diagnosed in men <54 years – 64% diagnosed between 55-74 years • Ethnicity: – BM 68% higher incidence, 158% higher mortality • Dietary Fat: – Increased relative risk by a factor of 1.6 to 1.9 • Family History: • 5-10% of all patients have family history • Relatives of patients younger than 55 years have greater risk • 1 relative = 2x lifetime risk, >= 2 relatives = 4x lifetime risk • At least 8 candidate susceptibility genes have been reported
  • 8.
    Prostate Specific Antigen(PSA): An Imperfect Tool • Glycoprotein secreted by the prostate • ORGAN specific (not cancer-specific) • Sensitivity 70-80% and PPV 30% when PSA is ‘normal’ (< 4) • Does not inform grade , and may lead to detection and treatment of indolent disease • Influenced by biologic variations, age, prostate volume, inflammation, race/ethnicity • NOT influenced by DRE or ejaculation
  • 9.
    Improving the useof PSA for Detection • PSA density: >0.15 suggestive of PC CA causes a greater elevation in PSA /volume than BPH • PSA velocity: >0.75 ng/ml/yr suggestive of PC • Percent free PSA: <25% suggestive of PC CA related PSA is bound to α-glycoprotein • Age specific PSA: <2.5 ng/ml 40-49 yo 3.5 ng/ml 50-59 yo 4.5 ng/ml 60-69 yo 6.5 ng/ml 70-79 yo
  • 10.
    Scardino and Kelman.Avery Press, 2005. • Average age at diagnosis is 68 years old • PSA screening advances lead time by 5-10 years • Overdiagnosis? Implications of Early Detection in an Aging Population
  • 11.
    ERSPC Bottom Line:YES PSA-based screening reduced the rate of death from prostate cancer by 20%; but was associated with a high risk of overdiagnosis. US PLCO Bottom Line: NO The rate of death from prostate cancer was very low and did not differ significantly between the two study groups; but 40% of usual care group had PSA testing. Prostate Cancer Screening: Results of 2 Randomized Controlled Studies
  • 12.
    Prostate Cancer ScreeningGuidelines PSA Screening (life expectancy >10 yrs) PSA Screening (+risk factors) American Cancer Society www.cancer.org Offer at age 50 Offer at age 40-45 American Urologic Association www.auanet.org Baseline 40 years old National Comprehensive Cancer Network www.nccn.org Baseline 40 years old: >1 ng/mL annual follow-up <1 ng/mL rescreen age 45 US Preventive Services Task Force http://www.uspreventiveservicestaskforce.org No screening for patients >75 (No screening ever??) Baseline PSA at age 40 is a stronger independent predictor of PC risk than ethnicity, family history, or DRE. (Loeb et al, AUA 2005)
  • 13.
    Prostate Cancer ClinicalStates FDA-approved Agents for Prostate Cancer Rising PSA Clinical Metastases: Castrate 1st Line Chemo Clinical Metastases: Castrate Pre-Chemo Clinically Localized Disease Clinical Metastases: Non-Castrate Clinical Metastases: Castrate Post-Chemo NON-CASTRATE Diagnosis 241, 740 Androgen Deprivation Therapy CASTRATION -RESISTANT Deaths From Disease 28, 170 Docetaxel 2004 Sipuleucel -T 2010 Cabazitaxel 2010 Abiraterone 2011 Enzalutamide 2012 Abiraterone 2012
  • 14.
    Charles B. Huggins,MD Nobel Prize in Physiology or Medicine, 1966 Huggins C, Hodges CV. Studies on prostatic cancer I. The effect of castration, estrogen, and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293–297. William Wallace Scott, Charles B. Huggins, and Clarence V. Hodges
  • 16.
  • 17.
    Hormonal Therapies • Anti-androgens: Casodex,Nilandron, Flutamide Enzalutamide • Adrenal ablation Ketoconazole, Abiraterone
  • 18.
    Antiandrogen Withdrawal Response -120-300 43 99 136164198 254357 387 417 437527 Time (days) 0 50 100 150 200 250PSA (ng/m l) Flutamide withdrawal Bicalutamide
  • 19.
    Anti-Androgen Withdrawal Kelly etal, 1997 Author Scher Dupont Herrada Sartor Figg Small Small Overall 50% PSA Decline 16/57 (28%) 32/40 (80%) 11/39 (28%) 14/29 (48%) 7/21 (33%) 12/82 (15%) 4/8 (50%) 96/276 (35%) Time to Response (weeks) 5.6 NS <6 <4 <6 NS <4 Duration of Response (months) 4 14.5 3.3 8 3.7 3.5 NS
  • 20.
    Hormones: Limitations • Hormonesare NOT curative • Significant side effect profile: Diminished libido and potency Osteoporosis Weight gain Diminished muscle mass Breast enlargement and breast tenderness Emotional changes Fatigue Anemia
  • 21.
    Intermittent ADT PhaseIII Trials Trial (Year) Patient Population No. of pts randomized Primary Endpoint NCIC PR7 (2011) PSA relapse after RT Non-Metastatic 1386 OS No difference EC 507 (2007) PSA relapse after RP Non-Metastatic 167 TTP AP 17/95 (2007) Locally advanced/ Metastatic (~40%) 335 TTP SEUG (2009) Locally advanced/ Metastatic (~30%) 766 TTP FinnProstate (2012) Locally advanced/ Metastatic (~50%) 554 TTP TULP (2011) Metastatic 193 TTP SWOG 9346 (2012) Metastatic 1535 OS MODIFIED FROM SLIDES by William Oh, M.D.
  • 22.
    [TITLE] Overall survival withIntermittent Hormonal Therapy is NOT “NONINFERIOR” to Continuous Therapy (Translation: it is POTENTIALLY inferior) Modified Slide
  • 23.
    Conclusions Intermittent is NOTNon-Inferior to Continuous ADT • Continuous ADT remains the standard of care for hormone sensitive metastatic PC • Neither this nor any randomized trial has EVER shown a superior cancer outcome with intermittent ADT • Will more potent reduction of intratumoral androgen (abiraterone) or inhibition of AR signaling (enzalutamide) lead to better outcomes with initial ADT?
  • 24.
    Untreated Primary Metastatic Castration Resistant Scher etal. Endocrine-Related Cancer 11:2004;459 The Androgen Receptor is Often Overexpressed in Castration Resistant Tumors and is a Target for Therapy Increased AR protein AR mRNA overexpression Increased AR DNA copy number o Post-Androgen Depletion
  • 25.
    AR HSP90AR degraded AR P ARPARP Transcription of TMPRSS-ETS, etc for growth and survival SRC Androgen precursors Androgens Adrenal synthesis Tumor synthesis DHT AR AR Cell surface ligand/receptor AKT ARP mut AR AR AR ARAmp AR + antiandrogens, progestins glucocorticoids Modified from Chen et al. Curr Opin Pharm, 2008 Therapeutic Targets of the AR Signaling Pathway AGONIST CONVERSION ALTERNATIVE LIGANDS ADRENAL/INTRATUMORAL ANDROGENS LIGAND INDEPENDENT AR PHOSPHORYLATION
  • 26.
    FDA Approved Agents withan Overall Survival Benefit in CRPC Agent Year Approved Mechanism Median Overall Survival Hazard Ratio Docetaxel1 vs Mitoxantrone 2004 Anti-microtubule 2.5 18.9 vs 16.5 0.76 Sipuleucel-T2 vs Placebo 2010 Immunomodulatory 4.1 25.8 vs 21.7 0.78 Cabazitaxel3 vs Mitoxantrone 2010 Anti-microtubule 2.4 15.1 vs 12.7 0.70 Abiraterone4 vs Placebo POST-DOCETAXEL* 2011 Androgen synthesis inhibitor 3.7 14.8 vs 10.9 0.65 MDV31005 vs Placebo POST-DOCETAXEL* 2012 AR antagonist 4.8 18.4 vs 13.6 0.63 1Tannock et al., NEJM 2004; 2Kantoff et al., NEJM 2010; 3DeBono et al., NEJM 2010; 4DeBono et al., NEJM 2011; 5Medivation Interim Analysis of the AFFIRM Trial in CRPC post-Docetaxel 11/3/11 *CTC biomarker analysis at MSKCC embedded in the phase 3 trials as a surrogate for survival
  • 27.
    Adapted from JE Ang, et al, British Journal of Cancer, 2009 Secondary Mineralicorticoid Syndrome *Low dose steroids minimizes toxicity* Suppression of the Renin- Angiotensin Pathway 4 fold increase due to elevated ACTH partially reverses 17-hydroxylase activity Abiraterone Acetate Selective and Irreversible Inhibition of CYP17
  • 28.
    POST-DOCETAXEL ABIRATERONE (Zytiga) FDAAPPROVED April 28, 2011 Proof of principle that AR IS STILL RELEVANT IN CRPC!!!
  • 29.
    POST-DOCETAXEL: ABIRATERONE MS 15.8mversus 11.2m HR 0.740 (0.63-0.85) De Bono et al., Journ Clin Oncol , 2011.
  • 30.
    Overall Study Designof COU-AA-302 CHEMONAIVE CRPC • Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites in 12 countries • Stratification by ECOG performance status 0 vs 1 • No prior novel anti-androgens (MDV3100), ketoconazole or chemotherapy Co-Primary Endpoints: • rPFS by central review • OS Secondary: • Time to opiate use (cancer- related pain) • Time to initiation of chemotherapy • Time to ECOG-PS deterioration • TTPP AA 1000 mg daily Prednisone 5 mg BID (Actual n = 546) Efficacy end points Placebo daily Prednisone 5 mg BID (Actual n = 542) R A N D O M I Z E D 1:1 • Progressive chemo- naïve mCRPC patients (Planned N = 1088) • Asymptomatic or mildly symptomatic Patients
  • 31.
    Landmarks of DiseaseProgression in mCRPC Planned Interim Analysis at 43% of Events 31 Baseline PSA Progression Tumor/Bone Progression Pain Death Adapted from Halabi S. et al, J Clin Oncol. 2009;27:2766-2771. Chemotherapy ECOG PS Decline Secondary Endpoints ECOG PS= Eastern Cooperative Oncology Group Performance Status 24-48 months p < 0.0001 p < 0.0001 p = 0.001 p = 0.0053 rPFS p < 0.0001 OS p = 0.0097
  • 32.
    Safety Profile ConsistentDespite Longer Duration of Exposure Most Prevalent AE AA + P (n = 542) % Placebo + P (n = 540) % All Grades Grades 3/4 All Grades Grades 3/4 Fatigue 39 2.2 34 1.7 Fluid retention 28 0.7 24 1.7 Hypokalemia 17 2 13 2 Hypertension 22 4 13 3 Cardiac disorders 19 6 16 3 ALT increased 12 5.4 5 0.8 AST increased 11 3.0 5 0.9 32 • Most of the ALT and AST increases occurred during the first 3 months of treatment
  • 33.
    Statistically Significant Improvementin rPFS Primary End Point NR, not reached; PL, placebo. 100 80 60 40 20 0 0 ProgressionFree(%) 3 6 9 15 1812 AA + P (median, mos): NR PL + P (median, mos): 8.3 HR (95% CI): 0.43 (0.35-0.52) P value: < 0.0001 546 542 489 400 340 204 164 90 12 3 0 0 AA Placebo 46 30 Time to Progression or Death (Months) AA Placebo
  • 34.
    Strong Trend inOS Primary End Point*† *O’Brien-Fleming boundary used; †Data cut off 12/20/2011; ‡Nominal significance level 0.0008. 546 542 538 534 482 465 452 437 27 25 0 0 524 509 503 493 0 2 120 106 258 237 412 387 100 80 60 40 20 0 0 Survival(%) 3 12 15 27 Time to Death (Months) 33 AA Placebo 6 9 30242118 AA Placebo AA + P (median, mos): NR PL + P (median, mos): 27.2 HR (95% CI): 0.75 (0.61-0.93) P value: 0.0097‡
  • 35.
    Summary: New Standardof Care? AA and Prednisone for Pre-chemo mCRPC • Delays disease progression • Increases survival* (but not by pre-specified amount) • Extends time with minimal or no symptoms • No new important safety signals * 55% Interim Analysis due at ASCO 2013
  • 36.
    Compared to bicalutamide…20-fold higher affinity for the AR 6/19/06 Rathkopf et al, Clin Cancer Res, 2011 -100% -75% -50% -25% 0% 25% 50% 75% 100% 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 Dose decline post BMS Therapy BY DOSE 5 mg 10 mg 20 mg 40 mg 60 mg 100 mg
  • 37.
    WISH LIST Second GenerationAR Antagonist Bicalutamide BMS641988 2nd Gen AA Effective in cells with high AR expression X Overcomes agonist activity X X Novel mechanism of action X X
  • 38.
    Ligand 1. AR BindingAffinity • DHT ~ 5nM • Bicalutamide ~160 nM • MDV3100 ~35 nM 2. Nuclear Import • DHT: ++++ • Bicalutamide: ++++ • MDV3100: ++ 3. DNA Binding • DHT: ++++ • Bicalutamide: ++ • MDV3100: - 4. Coactivator recruitment: No agonist effects. • DHT: ++++ • Bicalutamide: ++ • MDV3100: - MDV3100: A Novel AR Antagonist 1 2 3 4 DNA POL II HSP90 LBD HD DBD NTD Chen et al. Lancet Oncol 10:981, 2009 Tran et al., Science 324:787, 2010.
  • 39.
    MDV3100 is activein AR expressing tumor models and inhibits AR nuclear translocation Tran et al., Science 324:787, 2009 LnCAP-AR Cell Lines RD162 is the precursor of the clinical candidate MDV3100
  • 40.
    Chemo naïve; N=65Chemo exposed; N=75 MDV3100: Maximum PSA decrease from baseline Modified from Scher et al., Lancet, 2010 62% 40/65 >50% PSA decline 51% 38/75 >50% PSA decline -100% -75% -50% -25% 0% 25% 1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61 64 67 70 73 76 79 82 85 88 91 94 97 100 103 106 109 112 115 118 121 124 127 130 133 136 139
  • 41.
    Pre- and Post-TreatmentFDHT PET Imaging On-Target Effect of AR inhibition with MDV3100 18-Fluorodihydrotestosterone (F-DHT) PET Pre -Treatment Post -Treatment Scher HI et al., Lancet, 2010 Dosage
  • 42.
    AFFIRM Trial Design Enrollmentbetween September 2009 and November 2010 156 centers from 15 countries and 5 continents. R A N D O M I Z E D 2:1 Primary Endpoint: Overall Survival Enzalutamide 160 mg daily n = 800 Placebo n = 399 Patient Population: 1199 patients with progressive CRPC * Failed docetaxel chemotherapy
  • 43.
    Enzalutamide Prolonged Survival,Reducing Risk of Death HR = 0.631 (0.529, 0.752) P <0.0001 37% reduction in risk of death Enzalutamide: 18.4 months (95% CI: 17.3, NYR) Placebo: 13.6 months (95% CI: 11.3, 15.8) Enzalutamide 800 775 701 627 400 211 72 7 0 Placebo 399 376 317 263 167 81 33 3 0
  • 44.
    AFFIRM: Clinical Outcomes VariableEnzalutamide (800 pts.) Placebo (399 pts.) Hazard Ratio P -value OS (months) 18.4 13.6 0.631 <0.0001 PSA progression (months) 8.3 3.0 0.218 <0.0001 rPFS (months) 8.3 2.9 0.404 <0.0001 1st SRE (months) 16.7 13.3 0.621 <0.0001 CR + PR 28.9% 3.8% - <0.0001 FACT-P 43.3% 17.8% - <0.0001 Slide modified from presentation by Kevin Kelly, DO
  • 45.
    Favorable Adverse RiskProfile All Grades Grades >3* Enzalutamide (n = 800) Placebo (n = 399) Enzalutamide (n = 800) Placebo (n = 399) AEs 98.1% 97.7% 45.3% 53.1% Serious AEs 33.5% 38.6% 28.4% 33.6% Discontinuations due to AEs 7.6% 9.8% 4.6% 7.0% AEs leading to death 2.9% 3.5% 2.9% 3.5% All Grades Grade ≥ 3 Events Enzalutamide (n = 800) Placebo (n = 399) Enzalutamide (n = 800) Placebo (n = 399) Seizure 0.6% 0.0% 0.6% 0.0% Slide modified from presentation by Kevin Kelly, DO and Johann De Bono, MD
  • 46.
    • AR antagonistdrug class causes convulsions in laboratory animals at high doses by an off-target mechanism • AR antagonist seizure risk increases with brain drug concentrations • AR antagonist drug class inhibits the GABA-A current1 • Seizures have been observed in clinical testing of the next generation AR antagonists BMS-641988 and MDV3100 Seizure potential is an important consideration in the development of AR antagonists* *Slide adapted from discussion by Dr. WK Kelly at 2012 ASCO Annual Meeting 1Foster WR et al. Prostate . 2011
  • 47.
    ARN-509 Produces Superior AntitumorResponses than Bicalutamide in Castration Resistant LNCaP/AR-Luc Xenografts. Clegg N et al., Cancer Res 2012 ARN-509: A Novel Anti-Androgen for Prostate Cancer Treatment Exhibits Characteristics Predicting a Higher Therapeutic Index than Current AR Antagonists
  • 48.
    Phase II Studyof the Novel AR Antagonist ARN-509 in CRPC Activity across the spectrum of CRPC including post-abiraterone Non-Metastatic CRPC Metastatic CRPC Post-Abiraterone CRPC Baseline PSA (ng/mL, range) 9.7 (0.5, 201.7) 14.7 (1.1, 2552.1) 64.1 (12.0, 1315.2) 12-Week PSA Response* 91% 88% 29% %ChangeinPSAfrombaseline Individual Patients * Per PCWG2, the % of patients that reach ≥ 50% decline from baseline at week 12 (3 months) on study n=45 n=25 n=14 Rathkopf et al. Poster Presentation, 2012 Prostate Cancer Foundation Annual Meeting -100 -75 -50 -25 0 25 50 75 100
  • 49.
    Beyond Hormones: Chemotherapy Historically regardedas inactive for prostate cancer: new trial designs and new drugs have changed this view.
  • 50.
    Chemotherapy for CRPC Background •1985: No evidence for palliative benefit from chemotherapy. Chemotherapy recommended only for clinical trials. • 1996: Mitoxantrone + prednisone vs prednisone alone establishes a palliative benefit for mitoxantrone in 30% of symptomatic patients. Studies are too small to detect a survival benefit. FDA approval. • 2004: The larger TAX327 and SWOG 99-16 trials show a 3 month improvement in survival (1619 months) for Docetaxel compared to Mitoxantrone. FDA approval.
  • 51.
    Relief of Pain(Palliation): Mitoxantrone, the gold standard Tannock et al: J Clin Oncol. 1996 Response Mito. + Pred. (n = 80) Pred. (n = 81) P-Value Primary Endpoint (decreased pain) 23 (29%) 10 (12%) .011 Secondary Endpoint (decreased analgesics) 7 7 Total Palliative Response 30 (38%) 17 (21%) .025
  • 52.
    TAX 327 EstablishedDocetaxel as the First-Line Standard of Care for Castration-Resistant Prostate Cancer: Benefit Was Restricted to Every 3 Week Dosing Months Median survival Hazard (mos) ratio P-value Docetaxel every 3 weeks: 18.9 0.76 0.009 Docetaxel weekly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – ProbabilityofSurviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Tannock et al., NEJM, 351:1502, 2004
  • 53.
    53 Cabazitaxel Primary Endpoint: OverallSurvival—Updated ITT Analysis* 28% reduction in risk of death Time (months) ProportionofOS(%) 377 378 299 321 195 241 94 137 31 60 9 19 100 80 60 40 20 0 0 6 12 18 24 30 MP CBZP Median OS (months) 12.7 15.1 Hazard ratio 0.72 95% CI 0.61–0.84 P-value <.0001 Number at Risk MP CBZP Censored MP CBZP Combined median follow-up: 13.7 months * Data cut-off 3/10/2010
  • 54.
    Why do weneed clinical trials? • Hormones and chemotherapy are not curative • Durability of effects is limited • Despite the proven benefits, both have significant side effects • There are patients who will not respond to standard treatments
  • 55.
    RADIUM-223 T1/2 Range intissue Average particle energy per decay Bone surface to red bone marrow dose ratio Strontium 89 50.5 d 2.4 mm 0.58 MeV 1.6 Samarium 153-EDTMP 1.9 d 0.55 mm 0.22 MeV 4.4 Radium 223 11.4 d < 0.1 mm 27.4 MeV 10.3 Adapted from Bruland et al, Clin Cancer Res, 2006
  • 56.
    Radium-223 Targets BoneMetastases • Radium-223 acts as a calcium mimic • Naturally targets new bone growth in and around bone metastases • Radium-223 is excreted by the small intestine Ra Ca
  • 57.
    ALSYMPCA (ALpharadin inSYMptomatic Prostate CAncer) Phase III Study Design TREATMENT 6 injections at 4-week intervals Radium-223 (50 kBq/kg) + Best standard of care (IV q 4 weeks up to 6 treatments) Placebo (saline) + Best standard of care R A N D OM I S E D 2:1 N = 921 PATIENTS • Confirmed symptomatic CRPC • ≥ 2 bone metastases • No known visceral metastases • Post-docetaxel or unfit for docetaxel Primary Endpoint: Overall Survival • Total ALP: < 220 U/L vs ≥ 220 U/L • Bisphosphonate use: Yes vs No • Prior docetaxel: Yes vs No STRATIFICATION Clinicaltrials.gov identifier: NCT00699751
  • 58.
    ALSYMPCA Updated Analysis OverallSurvival Radium-223, n = 614 Median OS: 14.9 months Placebo, n = 307 Median OS: 11.3 months HR = 0.695 95% CI, 0.581, 0.832 P = 0.00007 Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Radium-223 614 578 504 369 274 178 105 60 41 18 7 1 0 0 Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 0 0 10 20 30 40 50 60 70 80 90 100 %
  • 60.
    ALYSMPCA Updated AnalysisConclusions • Significantly improved OS (3.6m), SRE (5.5m) • Favorable safety profile • Has activity and safety profile compatible for use with patients who are not good candidates for docetaxel Radium-223, a novel alpha-pharmaceutical, may provide a new standard of care for the treatment of CRPC patients with bone metastases
  • 61.
    Cabozantinib (XL184) in Chemotherapy-pretreatedMetastatic Castration Resistant Prostate Cancer (mCRPC): Results from a Phase 2 Nonrandomized Expansion Cohort (abstract #4513) M.R. Smith, C. Sweeney, D. Rathkopf, H.I. Scher, C. Logothetis, D.J. George, C.S. Higano, E.Y. Yu, A.L. Harzstark, E.J. Small, O.A. Sartor, M.S. Gordon, N.J. Vogelzang, D.C. Smith, M. Hussain, J.S. de Bono, N.B. Haas, C. Scheffold, Y. Lee, P.G. Corn Massachusetts General Hospital Cancer Center, Boston, MA; Dana-Farber Cancer Institute, Boston, MA; Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY; The University of Texas MD Anderson Cancer Center, Houston, TX; Duke University Medical Center, Durham, NC; Fred Hutchinson Cancer Research Center, Seattle, WA; University of California, San Francisco, San Francisco, CA; Tulane Cancer Center, New Orleans, LA; Pinnacle Oncology Hematology, Scottsdale, AZ; US Oncology Research/ Comprehensive Cancer Centers NV, Las Vegas, NV; University of Michigan, Ann Arbor, MI; Royal Marsden Hospital & Institute of Cancer Research, Sutton, United Kingdom; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Exelixis, South San Francisco, CA; University of Texas M. D. Anderson Cancer Center, Houston, TX
  • 62.
    Cabozantinib (XL-184) Oral TKIthat Inhibits MET and VEGFR • Randomized discontinuation trial in CRPC – High rates of bone scan improvement – Reduction in bone markers – Regression of soft tissue disease – PFS improvement – Pain improvement and narcotics reduction – PSA changes discordant with other measures of antitumor activity M. Hussain et al. ASCO 2011 (Abstract #4516) Bone scan Baseline Follow-up
  • 63.
    Subject 1316-2127 (Taxotere-pretreated) PartialResponse; Bone Scan and Pain Improvement; ↓PSA; ↓tALP Screening Week 12 CT scan: confirmed PR with 41% tumor decrease at Week 12 -2 0 2 4 6 8 10 12 14 0 100 200 300 400 500 600 700 800 900 tALP PSA 0 100 200 300 400 500 Screening Weeks On Study tALP PSA Baseline Week 6 Target lesions: -33% Week 12 Target lesions: -41%
  • 64.
    Most Frequently ReportedAdverse Events (N = 93) Adverse Event All Grades, n (%) Grade 3, n (%) Grade 4, n (%) Fatigue 77 (83) 24 (26) 2 ( 2) Decreased appetite 68 (73) 6 ( 6) - Diarrhea 65 (70) 10 (11) - Nausea 62 (67) 9 (10) - Vomiting 35 (38) 4 (4) - Dysgeusia 35 (38) - - Weight decreased 34 (37) 3 (3) - Dysphonia 33 (35) - - Back pain 32 (34) 5 (5) 2 (2) Dyspnea 30 (32) 4 (4) 1 (1) Hypothyroidism 29 (31) - - Adverse Events of Interest Hand-foot syndrome 23 (25) 5 (5) - Hypertension 22 (24) 8 (9) - Thrombosis venous 12 (13) 1(1) 5 (5) One patient with extensive liver disease experienced a related Grade 3 portal vein thrombosis with Grade 5 liver failure 84% of patients experienced at least one dose reduction due to AE
  • 65.
    SUMMARY Exciting Time inTreatment for CRPC • The Androgen Receptor remains a relevant target. • New technology to evaluate response and progression: circulating tumor cells, FDHT PET. • Collaborative efforts to increase accrual and share concepts and ideas. • 4 new drugs approved …More to come!!!

Editor's Notes

  • #6 Dr. Gleason: Pathologist from Minnesota who pulblished a morphometric scale of PC grading
  • #7 T1a incidental TURPT1c indicental PSAT2 palpableT3 ECE/SVIT4 Adjacent organs*Not everyone does LND*T score imperfect measure of dz: ie T1C Gleason 9 6 cores versus Gl 6 1 core
  • #9 Enzyme liquifies semenInitially described in the forensic literatureMay have a role in local activation of GF at metastatic sitesPre and post DRE bx: change in value 0.04
  • #10 • PSA density is used to help differentiate between cancer and BPH in men with moderately high PSA levels (4 to 10 ng/mL) and normal DRE results. Cancer causes a greater elevation in PSA per prostate volume than BPH -- which means PSA density should be higher in men with cancer. To find PSA density, doctors divide the PSA results by prostate volume (as estimated by transrectal ultrasound). This method is imperfect, but studies showing that PSA density levels over 0.15 indicate a high risk of cancer have led doctors to use PSA density tests for men with PSA levels between 4 and 10 ng/mL.• PSA velocity monitors changes in PSA over time. PSA levels rise more rapidly in men with prostate cancer than in other men. To be most effective, PSA should be measured at least three times over a two-year period to calculate PSA velocity. Research has found that about 70% of men with a PSA velocity of 0.75 ng/mL or greater have cancer when PSA is 4 to 10 ng/mL. But only about 50% of men with a PSA velocity below 0.75 ng/mL per year have cancer. The test is used primarily to determine the need for a repeat biopsy in those with PSA levels between 4 to 10 ng/mL and a prior negative biopsy.• Age-specific PSA levels have been suggested for younger men, because PSA levels usually rise with age. Thus, while 2 ng/mL may be normal in a 60-year old, this level is more likely to signify cancer in men between ages 40 and 49. Since research has yet to show that using age-specific PSA values will increase the detection of curable cancers, for now the standard cut-off of 4 ng/mL is still considered preferable for men between age 50 and 70.• Percent free PSA is the ratio of free (unbound) PSA to bound (attached to proteins) PSA in the blood. Men with prostate cancer have a lower percent free PSA than men without cancer. Measuring the ratio of free to total PSA appears to be particularly promising for eliminating unnecessary biopsies in men with PSA levels between 4 and 10 ng/mL.
  • #11 60-70% of all PC diagnosed &gt;70 yoIn an aging population, the implications of detecting and diagnosing all prostate cancers is clear68 life expectancy 14.5-16.3 yrs; may die of other causes
  • #15 The use of HT in PC was pioneered by Huggins et al in 1941 when they:he proved that administration of the female hormone estrogen slowed the growth of prostate cancer in males.&quot;the Huggins operation&quot; -- castration -- for particularly advanced cases. Dr. Huggins, in collaboration with his students Clarence V. Hodges and William Wallace Scott, published three papers in 1941 that demonstrated the relationship between the endocrine system and the normal functioning of the prostate gland. The regression and the consequent relief of pain was often spectacular and occurred within days or sometimes even hours after treatment. Four of Dr. Huggins&apos; original 21 hormone-therapy patients lived for more than 12 years after treatmentPalliation, relief of urinary symptoms, concomitant decline in acid phosphatase.
  • #23 9 % relative risk of death with intermittent therapyHowever upper limit of 95% CI was &gt; 1.24 (more than the prespecified threshold of 1.2). SO OS with IT was NOT NON-INFERIOR to CONTINUOUSSurvival much better than 3 yrs expected so it took longer to observe the number of deaths required for the final analysis hence the longer duration
  • #26 (1) AR is bound to the molecular chaparone HSP90 which prevents its degradation. HSP90 inhibitors, such as 17-AAG, cause AR degradation and decrease AR levels. (Dave Solit)(2) In men treated with GnRH agonists to shut down testicular androgen synthesis, residual serum androgens are synthesized by the adrenal glands. In additional, evidence suggests intratumoral androgen synthesis. Both can be inhibited by the nonspecific p450 inhibitor ketoconazole and the 17-lyase inhibitor abiraterone.(3) Testosterone is converted to the more potent dihydrotestosterone (DHT) by 5α-reductase, which is inhibited by finasteride and dutasteride. (Morris)(4) Ligands, such as DHT bind to AR and this is inhibited by antiandrogens such as bicalutamide and novel agents MDV-3100 and BMS641988. Mutation of AR as well as AR overexpression can convert endogenous steroids (e.g. progestins, estrogens, and corticosteroids) and some antiandrogens into agonists. MDV-3100 was designed to suppress AR function even when AR is overexpressed. (5) Activation of receptor tyrosine kinases, can lead to downstream AR activation. Two downstream kinases that directly phosphorylate AR on tyrosine are Ack1 and SRC. Other downstream pathways of receptor tyrosine kinases, including the AKT and MAP kinase pathways, are also implicated. Antibodies such as trastuzamab and pertuzumab and small molecular TKI inhibitors such as erlotinib and lapatinib target HER2. Dasatinib targets SRC. (6) Proper transcription mediated by AR requires the proper chromatin state. HDAC inhibitors inhibit transcription of AR target genes by the disruption of chromatin structure and inhibition of recruitment of coactivators and RNA polymerase II.
  • #29 First time a hormone used post-chemo with a survival benefit. AR STILL RELEVANT.
  • #34 The Kaplan Meier curve for the co-Primary endpoint of rPFS is shown here. The radiographic Progression Free Survival (rPFS), as assessed by independent radiologic review in the AA/Prednisone arm had not yet been reached and was 8.3 months in the Placebo/Prednisone arm, associated with a Hazard ratio of 0.43 (95% Confidence Interval 0.35-0.52) P&lt;0.0001.
  • #35 The Kaplan Meier plot for the Co-Primary endpoint of Overall Survival is shown here.the Median survival in the Prednisone control arm is 27.2 months while the median survival has not yet been reached in the Abiraterone arm., This conforms to a Hazard ratio of 0.75 and a p value of 0.0097 -A strong statistical trend in favor of AAThe prespecified p value for significance of OS at 43% of events is 0.0008 by the O’Brien-Fleming boundary (as implemented in the LanDemets alpha-spending method).
  • #36 Taken in aggregate,AA proved favorable across a broad spectrum of clinical outcomes including: delay progression, improve survival, maintain QOLAs clinical oncologists charged with providing safe and effective treatment to our patients, these findings merit consideration of providing a new approach to a population in need of treatment with less toxicity.
  • #40 Confocal microscopy
  • #41 KETO: PRE 55/77 (71%) VS POST 23/63 (37%) This set the stage not just for using MDV3100 in CRPC post-chemo pts previously assumed tobe refractory, but also abiraterone.
  • #57 &gt;90% bone metsCurrently approved radiopharmaceuticalsdealy SRE but do not effect survivalAlkaline earth metals- taken up in bone
  • #58 Sx= any analgesic or palliative RT within 12 weeks (even if rendered pain free)
  • #59 Consistent across all subgroups: Doc, Bisphos,
  • #60 Heme: Modest increase grade ¾ thrombocytopeniaExcretion: GI
  • #63 Potent oral TKIInhibits MET and VEGFR2Randomized discontinuation trial of cabo inmCRPC
  • #65 Majority tox grade 1 or 2