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Thursday, October 11, 2012 7:30 PM – 8:30 PM ET Prostate Cancer: New Agents and Emerging Clinical Algorithms
Christopher J Logothetis, MD Chairman/Professor Genitourinary Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas A Oliver Sartor, MD Medical Director Tulane Cancer Center Laborde Professor of Cancer Research Professor of Medicine and Urology Tulane Medical School New Orleans, Louisiana Neil Love, MD Research To Practice Miami, Florida
Agenda — Emerging Systemic Treatments for Prostate Cancer Optimal Sequencing of Endocrine Therapy –Case from Dr Sartor: 75-year-old retired attorney –Continuous vs intermittent ADT –COU-AA-301, COU-AA-302: Abiraterone –AFFIRM: Enzalutamide –Early data with TAK-700 (Orteronel) Bone-Targeted Treatment –ALSYMPCA: Radium-223 Tolerability of Next-Generation Hormonal Agents –Faculty cases Other New Agents of Interest –Cabozantinib, dasatinib
Current Controversies, Recent Developments and Emerging Strategies in the Management of Prostate Cancer A Clinical Investigator Think Tank Moderator Neil Love, MD Daniel P Petrylak, MD A Oliver Sartor, MD Susan F Slovin, MD, PhD Matthew R Smith, MD, PhD Tomasz M Beer, MD Robert Dreicer, MD, MS Mario A Eisenberger, MD William K Oh, MD Faculty
Faculty Case: Dr Sartor A 75-year-old retired attorney with an active lifestyle Underwent radical prostatectomy 5 years prior –Recurrence followed by salvage radiation therapy PSA-only recurrence: –PSADT = 8 months –PSA 4.6 ng/mL Patient experiencing “PSA anxiety”
A 75-year-old underwent radical prostatectomy 5 years ago recurrence salvage radiation PSA recurrence. Workup shows no metastases. PSADT = 8 months, PSA currently 4.6 ng/mL. What systemic treatment, if any, would you likely recommend?
Current Controversies, Recent Developments and Emerging Strategies in the Management of Prostate Cancer — A Clinical Investigator Think Tank September 7, 2012 75-year-old with PSA-only disease Robert Dreicer, MD, MS: “There’s no right answer; I would not have initiated therapy.” Mario A Eisenberger, MD: “No, I don’t think we would start treatment. We would wait” Susan F Slovin, MD, PhD: “I would not initiate therapy.”
A 55-year-old underwent radical prostatectomy 5 years ago recurrence salvage radiation PSA recurrence. Workup shows no metastases. PSADT = 8 months, PSA currently 4.6 ng/mL. What systemic treatment, if any, would you likely recommend?
Intermittent (IAD) versus Continuous Androgen Deprivation (CAD) in Hormone Sensitive Metastatic Prostate Cancer (HSM1PC) Patients (pts): Results of S9346 (INT-0162), an International Phase III Trial Hussain M et al. Proc ASCO 2012;Abstract 4.
Induction Registration Newly diagnosed metastatic prostate cancer & a PSA ≥5 ng/mL If PSA ≤4 ng/mL on months 6 & 7 (PSA normalization criteria) STEP 2 Randomly Assign Continuous AD Intermittent AD STEP 1 Induction AD = Goserelin + Bicalutamide X 7 months Discontinue AD, monthly PSAs. Resume AD based on pre-specified criteria Hussain M et al. Proc ASCO 2012;Abstract 4. Study Design
Overall Survival (OS): Intermittent Therapy Is Inferior Compared to Continuous Therapy Hussain M et al. Proc ASCO 2012;Abstract 4. * OS for intermittent therapy was deemed inferior based on the prespecified statistical design requirement that the 95% CI for the hazard ratio should include 1.2. Continuous therapy (n = 765) Intermittent therapy (n = 770) Median overall survival5.8 years5.1 years Hazard ratio (95% CI)* 1.09 (0.95-1.24) 7-year survival42%38%
The 75-year-old retired attorney with PSA-only relapse receives intermittent ADT but 2 years later is found to have multiple bone metastases on routine follow-up. Patient is asymptomatic. PSA = 30, PS = 0. What systemic treatment would you likely recommend?
The 75-year-old retired attorney with PSA-only relapse receives intermittent ADT but 2 years later is found to have 3 small liver metastases and is experiencing pain from several sites of bone metastasis along with anorexia and fatigue. What systemic treatment would you likely recommend?
What percentage of your patients with late-line metastatic prostate cancer receiving abiraterone have discernible corticosteroid- associated side effects?
The mechanism of action of enzalutamide (MDV3100) is identical to that of bicalutamide, but enzalutamide is much more potent.
Enzalutamide Mechanism of Action Oral drug rationally designed to target AR signaling, impacting multiple steps in AR signaling pathway No demonstrated agonist effects in preclinical models Tran et al. Science 2009;324:787-90. Inhibits binding of androgens to AR Inhibits nuclear translocation of AR Inhibits association of AR with DNA
Enzalutamide Inhibits Multiple Steps in the AR Signaling Pathway Mukherji D et al. Expert Opin Investig Drugs 2012;21:227-33. Carson C et al. Urology 2003;61:2-7. Testosterone/DHT Enzalutamide
Abiraterone Mechanism of Action Attard G et al. J Clin Oncol 2008;26:4563-71. Abiraterone inhibits 17α-hydroxylase (crossed out in red)
Current Controversies, Recent Developments and Emerging Strategies in the Management of Prostate Cancer — A Clinical Investigator Think Tank September 7, 2012 Sequence of enzalutamide and abiraterone in metastatic disease Tomasz M Beer, MD: “Given no data, go with enzalutamide first.” Robert Dreicer, MD, MS: “With all the caveats, enzalutamide.” Mario A Eisenberger, MD: “Enzalutamide. It’s easier to use. It’s less toxic. No need for steroids.” William K Oh, MD: “Probably enzalutamide…less toxicity” Daniel P Petrylak, MD: “Since we’re trying to sequence these drugs, if you believe that corticosteroids may have an abrogating effect on sipuleucel-T, I would tend to go with enzalutamide first.” Susan F Slovin, MD, PhD: “Enzalutamide, with one caveat…in patients where I want to go to a completely different category of drugs I would use abiraterone” Matthew R Smith, MD, PhD: “Prefer to use abiraterone first for now in the prechemotherapy setting, since I have longer experience with it. It’s a very transient answer, and we await the results of the PREVAIL trial.”
Interim Analysis (IA) Results of COU- AA-302, a Randomized, Phase III Study of Abiraterone Acetate (AA) in Chemotherapy-Naïve Patients (pts) with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Ryan CJ et al. Proc ASCO 2012;Abstract LBA4518.
Overall Study Design of COU-AA-302 Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites in 12 countries; USA, Europe, Australia, Canada Stratification by ECOG performance status 0 vs 1 Ryan CJ et al. Proc ASCO 2012;Abstract LBA4518. R Patients Progressive chemo- naïve mCRPC patients (Planned N = 1,088) Asymptomatic or mildly symptomatic 1:1 Co-Primary: rPFS by central review OS Secondary: Time to opiate use (cancer-related pain) Time to initiation of chemotherapy Time to ECOG-PS deterioration TTPP Efficacy endpoints AA 1,000 mg daily Prednisone 5 mg BID (Actual n = 546) AA 1,000 mg daily Prednisone 5 mg BID (Actual n = 546) Placebo daily Prednisone 5 mg BID (Actual n = 542) Placebo daily Prednisone 5 mg BID (Actual n = 542)
Statistically Significant Improvement in rPFS Not OS Data cutoff 12/20/2011 100 80 60 40 20 0 0 Progression-Free (%) 369151812 Time to Progression or Death (Months) AA + P PL + P AA + P (median, mos):NR PL + P (median, mos):8.3 HR0.43 P value:< 0.0001 AA + P (median, mos):NR PL + P (median, mos):27.2 HR:0.75 P value:0.0097 100 80 60 40 20 0 0 Survival (%) 3121527 Time to Death (Months) 33 AA + P PL + P 6930242118 With permission from Ryan CJ et al. Proc ASCO 2012;Abstract LBA4518. Data cutoff 12/20/2010 NR = not reached PL = placebo Prespecified significant p-value by O'Brien- Fleming Boundary for overall survival = 0.0008
AA + P (n = 542) % Placebo + P (n = 540) % All gradesGrades 3/4All gradesGrades 3/4 Fatigue392342 Fluid retention280.7241.7 Hypokalemia172132 Hypertension224133 Cardiac disorders196163 Atrial fibrillation41.350.9 ALT increased125.450.8 AST increased113.050.9 Most ALT and AST increases occurred during the first 3 months of treatment Ryan CJ et al. Proc ASCO 2012;Abstract LBA4518. Side Effects of Abiraterone
Increased Survival with Enzalutamide in Prostate Cancer After Chemotherapy Scher HI et al. N Engl J Med 2012;367:1187-97.
AFFIRM: Interim Analysis of Enzalutamide versus Placebo in Patients with CRPC Scher HI et al. N Engl J Med 2012;367:1187-97. Enzalutamide (n = 800) Placebo (n = 399) Hazard ratiop-value Overall survival18.4 mo13.6 mo0.63< 0.001 Progression- free survival*8.3 mo2.9 mo0.40< 0.001 Time to PSA progression8.3 mo3.0 mo0.25 < 0.001 PSA response rate54%2%— < 0.001 * According to radiographic evidence
AFFIRM: Frequent Adverse Events More Common with Enzalutamide Scher HI et al. N Engl J Med 2012;367:1187-97. Adverse event Enzalutamide (n = 800) Placebo (n = 399) Any gradeGrade ≥3Any gradeGrade ≥3 Fatigue34%6%29%7% Diarrhea21%1%18%< 1% Hot flash20%0%10%0% Musculoskeletal pain14%1%10%< 1% Headache12%< 1%6%0% Seizures were reported in 5 patients (0.6%) receiving enzalutamide.
Safety and Activity of the Investigational Agent Orteronel without Prednisone in Men with Nonmetastatic Castration-Resistant Prostate Cancer and Rising Prostate-Specific Antigen: Updated Results of a Phase II Study George DJ et al. Proc ASCO 2012;Abstract 4549.
Orteronel (TAK-700) in Nonmetastatic CRPC 39 patients with non-mCRCP and rising PSA received orteronel 300 mg BID Drug-related Grade ≥3 AEs: 36% –Dyspnea: 8% –Hypertension: 13% –Fatigue, hypokalemia, pneumonitis: 5% each At 3 months, –PSA ≤0.2 ng/mL: 16% –PSA 50: 76% –PSA 90: 32% At 6 months, –PSA 50: 45% –PSA 90: 21% Median time to PSA progression: 14.8 months George DJ et al. Proc ASCO 2012;Abstract 4549.
Ongoing Phase III Studies of Orteronel Study ID No. of patientsRandomizationSetting NCT011932441,454 Orteronel/prednisone Placebo/prednisone Chemo-naïve mCRPC NCT011932571,083 Orteronel/prednisone Placebo/prednisone mCRCP progressing on/after docetaxel NCT01546987900 LHRH + oral anti-androgen/RT LHRH + oral anti-androgen/RT + orteronel BID x 2 years High-risk PC www.clinicaltrials.gov, September 2012
A Phase III, Randomized, Double-Blind, Multicenter Trial Comparing the Investigational Agent Orteronel (TAK- 700) plus Prednisone (P) with Placebo plus P in Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) That Has Progressed During or Following Docetaxel-Based Therapy Dreicer R et al. Proc ASCO 2012;Abstract TPS4693.
Radium Targets Osteoblastic Bone Metastases by Acting as a Calcium Mimetic Radium-223 acts as a calcium mimetic Naturally self-targets to bone metastases Cheetham PJ et al. Oncology 2012;26(4):330-7.
Lethality of Alpha-Particles Is a Consequence of DNA Double-Strand Breaks Beta and gamma radiation → single-strand DNA breaks, more repairable Alpha radiation → double-strand DNA breaks, which are lethal and more difficult to repair Bruland OS et al. Clin Cancer Res 2006;12:6250s-7s.
Radium-223 Targets Bone Metastases Alpha-particles induce double-strand DNA breaks in adjacent tumor cells Short penetration of alpha emitters (2-10 cell diameters) = highly localized tumor cell killing and minimal damage to surrounding normal tissue Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007:103.
Updated Analysis of the Phase III, Double- Blind, Randomized, Multinational Study of Radium-223 Chloride in Castration- Resistant Prostate Cancer (CRPC) Patients with Bone Metastases (ALSYMPCA) Parker C et al. Proc ASCO 2012;Abstract LBA4512.
TREATMENT 6 injections at 4-week intervals Radium-223 (50 kBq/kg) + best standard of care Placebo (saline) + best standard of care N = 921 PATIENTS Confirmed symptomatic CRPC ≥ 2 bone metastases No known visceral metastases Post-docetaxel or unfit for docetaxel Confirmed symptomatic CRPC ≥ 2 bone metastases No known visceral metastases Post-docetaxel or unfit for docetaxel ALSYMPCA (Radium-223 Dichloride in Symptomatic Prostate Cancer) Phase III Study Design www.clinicaltrials.gov, September 2012 Total ALP: < 220 vs ≥ 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No Total ALP: < 220 vs ≥ 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No STRATIFICATION Planned follow-up is 3 years Primary endpoint: OS Secondary: Time to first SRE, safety, etc. R 2:1
ALSYMPCA Updated Analysis: Overall Survival Parker C et al. Proc ASCO 2012;Abstract LBA4512. Radium-223 (n = 614) Placebo (n = 307) Median OS14.9 mo11.3 mo Hazard ratio0.695 p-value0.00007
ALSYMPCA Updated Analysis: Time to First SRE* * Provisional data Parker C et al. Proc ASCO 2012;Abstract LBA4512. Radium-223 (n = 614) Placebo (n = 307) Time to first SRE12.2 mo6.7 mo Hazard ratio0.64 p-value<0.0001
Radium-223 Chloride Impact on Skeletal-Related Events and ECOG Performance Status in Patients with Castration-Resistant Prostate Cancer with Bone Metastases: Interim Results of a Phase III Trial (ALSYMPCA) Sartor AO et al. Proc ASCO 2012;Abstract 4551.
Faculty Case: Dr Sartor An 85-year-old man Metastatic CRPC unsuitable for docetaxel due to frailty –Increasing pain –Prior treatments: LHRH/nilutamide, then abiraterone/prednisone, denosumab, low-dose dexamethasone Expanded access protocol: Radium-223 –4 doses with diminished pain and no side effects –PSA rising but more slowly
Cabozantinib has resulted in bone scan improvements and pain relief in chemotherapy- pretreated metastatic CRPC.
Smith MR et al. Proc ASCO 2012;Abstract 4513. Cabozantinib (XL184) in Chemotherapy- Pretreated Metastatic Castration Resistant Prostate Cancer (mCRPC): Results from a Phase II Nonrandomized Expansion Cohort (NRE)
Cabozantinib: Dual Inhibitor of MET and VEGFR MET and its ligand HGF drive tumor cell invasion and metastasis MET and VEGFR2 synergize to promote angiogenesis Bone metastases associated with high levels of MET expression –HGF and VEGF direct crosstalk between tumor cells, osteoblasts and osteoclasts In Prostate Cancer: Preclinically, androgen deprivation increases MET expression MET increases with progression and metastases in bone and lymph nodes With permission from Hussain M et al. Proc ASCO 2011;Abstract 4516.
Smith MR et al. Proc ASCO 2012;Abstract 4513. Computer-assisted evaluation of BSLA Bone scan evaluable (n = 93) a n (%) Bone scan response Complete (100% reduction of BSLA) Partial (≥30% reduction of BSLA) 62 (67) 4 (4) 58 (62) Stable15 (16) Progressive disease7 (8) Median duration of response, months (range)5.4 (5.0 – 6.9) BSLA = bone scan lesion area a Bone metastases at baseline and ≥1 post-baseline scan available for 84 patients Bone Scan Response to Cabozantinib by Independent Radiology Review
Src-dependent bone resorption Pivotal role in survival, apoptosis, growth and resistance pathways Potential Effects of Dasatinib in Prostate Cancer Saad F. Medscape Oncology 2012. Invasive growth of primary tumors and metastases Potential role in early and advanced disease Invasive growth of primary tumors and metastases Potential role in early and advanced disease Dasatinib Invasion and tumor spread Chemomodulation Malignant bone disease Potential effects
Araujo JC et al. Cancer 2012;118(1):63-71. Dasatinib Combined with Docetaxel for Castration-Resistant Prostate Cancer: Results from a Phase 1-2 Study
Dasatinib 100 mg QD plus Docetaxel Araujo JC et al. Cancer 2012;118(1):63-71. Best response by RECIST (N = 30) Partial response60% Stable disease (≥18 wk)17% Overall disease control rate77%
Primary endpoint: OS Secondary endpoints: Change in uNTX, time to first SRE, change in pain intensity, time to PSA progression, objective tumor response rate, PFS, safety/tolerability www.clinicaltrials.gov, September 2012 READY: Phase III Study of Docetaxel ± Dasatinib Docetaxel + prednisone + placebo Docetaxel + prednisone + placebo Docetaxel + prednisone + dasatinib 100 mg PO QD R Metastatic CRPC (N = 1,500)
Araujo JC et al. Cancer 2012;118(1):63-71. Best response by RECIST (N = 30) Partial response60% Stable disease (≥18 wk)17% Overall disease control rate77% Dasatinib 100 mg QD plus Docetaxel
Potential Predictive Biomarkers in CRPC BiomarkerContext of use in CRPC Androgen precursor levels (DHEA, etc) Abiraterone sensitivity AR splice variantsEnzalutamide sensitivity PTEN loss or PI3K pathway activationPI3 kinase inhibitor sensitivity Microtubule mutationsTaxane sensitivity High bone turnover biomarkers (TRAP, urine NTx, BAP, etc) Bone-targeted agent benefit (denosumab, zoledronic acid, radium- 223) Ras/Raf mutations B-raf inhibitor sensitivity (sorafenib, vemurafenib) DNA repair defectsPARP inhibition sensitivity Myc amplificationCytotoxic chemo, cell cycle inhibitors C-MET activityCabozantinib sensitivity Pain intensity Value of immediate immunotherapy (sipuleucel-T) Armstrong AJ. ASCO 2012 Education Session. Armstrong AJ et al. Eur Urol 2012;61(3):549-59.