Changes in renal function drive dose adjustments for zoledronic acid
Efficacy analyses are vs. the most potent bisphosphonate used in clinical practice, and the only one approved for use in prostate cancer bone metastasis. This is NOT a comparison vs. placebo, as has been done in Novartis registration trial The primary endpoint is represented on a Kaplan Meier curve. Denosumab was superior to zoledronic acid and reduced the risk of a first on-study SRE by 18% with a confidence interval from 0.71 to 0.95. The P value was equal to 0.0002 for noninferiority and equal to 0.008 for superiority. The median time to first on-study SRE was 20.7 months for denosumab and was 17.1 months for zoledronic acid, a 3.6 mo difference . The 2 most common components of SREs were fractures and radiation to bone. 727 subjects experienced a first on-study SRE; subject incidence was 341 (35.9%) in the denosumab arm and 386 (40.6%) in the zoledronic acid arm.
For the secondary endpoint of time to first and subsequent SRE (multiple event analysis) denosumab was also superior to zoledronic acid and reduced the risk of multiple events by 18% (rate ratio: 0.82; 95% CI: 0.71–0.94; P=0.004). Only events which were at least 21 days apart from each other were counted, matching a similar analysis reported for zoledronic acid in its registration trial (Saad et. al., JNCI 2004)
There was also a significant improvement in PFS with cabazitaxel with an hazard ratio of 0.74. PFS was in this study a composite end-point which takes into account PSA progression, pain progression, tumor progression, symptom deterioration or death. TROPIC slide deck. Slide24
This was a phase III, multinational, multicenter, randomized, double-blind, placebo-controlled study conducted at 147 sites in the United States/Europe/Australia/Canada comparing the efficacy and safety of AA plus prednisone with placebo plus prednisone in men with mCRPC who had failed 1 or 2 chemotherapy regimens, one of which contained docetaxel. Subjects were randomized in a 2:1 ratio to receive AA plus prednisone or placebo plus prednisone, respectively, and were stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (PS; 0-1 vs 2), worst pain over the past 24 hours on the Brief Pain Inventory (BPI)-Short Form (0-3 [absent] vs 4-10 [present]), prior chemotherapy regimens (1 v. 2), and type of progression (PSA only vs radiographic progression with or without PSA progression). Subjects could receive treatment until documented disease progression (of all 3 types including 1) PSA progression, 2) radiographic progression, and 3) symptomatic or clinical progression) or unacceptable toxicity. Efficacy analysis set: ITT (intent-to-treat). Primary efficacy end point: overall survival (OS). Secondary efficacy end points: prostate‑specific antigen (PSA) response rate, time to PSA progression, and radiographic progression-free survival. To determine whether AA, a potent and selective CYP17/lyase inhibitor, is a safe and effective treatment for patients with CRPC post-chemotherapy Specific objectives To determine whether AA plus prednisone is more effective than placebo plus prednisone AA plus prednisone is safe
MCO 2011 - Slide 4 - K. Fizazi - Castration-refractory prostate cancer
Castrate-resistant prostate cancer: chemotherapy, then what? Pr Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France
Advanced prostate cancer Metastatic, hormone-naïve Metastatic CRPC Non-metastatic CRPC Metastases Pre-Doc With Doc Post-Doc Symptoms Zoledronic acid Docetaxel Castration Resistant Prostate Cancer (CRPC): Progression while on Androgen Deprivation Therapy
Phase III trials of Docetaxel in localized prostate cancer Study name PI Local treatment # patients ( enrolled /planned) Status GETUG 12 K. Fizazi (France) XRT 413 / 400 Accrual completed RTOG 0521 H. Sandler (USA) XRT 600 Accrual completed TAX 3501 M. Eisenberger (USA) RP 228 /1700 Early enrolment termination AdPro Ahlgren (Sweden) RP 396 Ongoing DOCET-L-02357 A. D’Amico (USA) XRT 350 Ongoing VA # 553 CAP Montgomery (USA) RP 636 Ongoing CALGB 90203 Eastham (USA) RP 750 Ongoing AdRad Kellokumpu-Lehtinen (Fin) XRT 924 Ongoing
GETUG 12 trial: High-risk localized prostate cancer ADT (3 years) DE x 4 cycles RANDOMI ZE Stratification - Gleason 8 - PSA>20 - T3 - pN+ / pN- ADT (3 years) Local Treatment at 3 months Local Treatment at 3 months n=413 pts Accrual: 2002-2006
Docetaxel Phase III trial in localized CaP PSA response (GETUG 12 trial) PSA 3 months ≤ 0.2 ng/mL: 34% vs 15% p< 0.0001 Fizazi et al., ASCO GU Symposium 2010, Abstr 7 n= 413
Skeletal Related Events (SRE) in men with bone metastases from prostate cancer Pathologic Fracture 25% Pain requiring Radiation to Bone 33% Surgery to Bone 4% Spinal Cord Compression 8% Saad, et al. J Urol 2003;169(Suppl).
Zoledronate: Time to Skeletal Related Event in CRPC <ul><ul><li>Median, days P value </li></ul></ul><ul><li>ZOMETA ® 4 mg 488 .009 </li></ul><ul><li>Placebo 321 </li></ul>Zol 4 mg 214 149 97 70 47 35 3 Placebo 298 128 78 44 32 20 3 over 5 Months delay Saad et al. JNCI 2004; 96:879 488 321 Zoledronate Placebo 0.009
Proportion (%) of Patients With Each SRE Saad et al. JNCI 2004; 96:879
Standard of care in advanced prostate cancer before 2010 Clinical setting Sub-setting Standard treatment Options Non-metastatic CRPC None (ADT) Endocrine manipulations Metastases, hormone-naive ADT CAB Metastatic CRPC Bone metastases Zoledronic acid Asymptomatic CRPC None Docetaxel, Endocrine manipulations Symptomatic CRPC Docetaxel Doc + estramustine CRPC progressing after docetaxel None Docetaxel re-challenge
A decade of research in prostate cancer 2004-2009: No significant result <ul><li>2010: </li></ul><ul><li>- Sipuleucel-T </li></ul><ul><li>Cabazitaxel </li></ul><ul><li>Denosumab </li></ul><ul><li>Abiraterone </li></ul>
Denosumab may interrupt the “vicious cycle” of bone metastases PDGF, BMPs TGF-β, IGFs FGFs Osteoblasts RANKL RANK Denosumab Tumor Cell Formation Inhibited Apoptotic Osteoclast PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT Adapted from Roodman D. N Engl J Med . 2004;350:1655.
Prostate SRE Phase III Study Design *IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine (per Zometa ® label) <ul><li>Time to first on-study SRE (non-inferiority) </li></ul>Primary Endpoint <ul><li>Time to first on-study SRE (superiority) </li></ul><ul><li>Time to first and subsequent on-study SRE (superiority) </li></ul>Supplemental Calcium and Vitamin D Secondary Endpoints n= 1901 patients Denosumab 120 mg SC and Placebo IV* every 4 weeks (N = 1912) Zoledronic acid 4 mg IV* and Placebo SC every 4 weeks (N = 1910) <ul><li>Castration resistant prostate cancer and bone metastases </li></ul>Key Inclusion <ul><li>Current or prior intravenous bisphosphonate administration </li></ul>Key Exclusion
Time to First SRE Subjects at risk: 0 1.00 Proportion of Subjects Without SRE 0 3 6 9 12 15 18 21 24 27 0.25 0.50 0.75 KM Estimate of Median Months Denosumab Zoledronic acid 20.7 17.1 HR 0.82 (95% CI: 0.71, 0.95) P = 0.0002 (Non-inferiority) P = 0.008 (Superiority) Study Month Risk Reduction Fizazi et al., Lancet 2011 Zoledronic Acid 951 733 544 407 299 207 140 93 64 47 Denosumab 950 758 582 472 361 259 168 115 70 39 18%
Time to First and Subsequent SRE *Events occurring at least 21 days apart Rate Ratio = 0.82 (95% CI: 0.71, 0.94) Study Month 0.0 2.0 0 3 6 9 12 15 18 21 24 27 Cumulative Mean Number of SREs per Patient 30 33 36 0.2 0.6 1.0 1.4 1.8 0.4 0.8 1.2 1.6 Denosumab Zoledronic acid 584 494 Events P = 0.008 Risk Reduction Fizazi et al., Lancet 2011 18%
Placebo Median time to first SRE (months) Zoledronic acid Zoledronic acid Denosumab 10.7 16.0 17.1 20.7 10 20 Saad, et al. J Natl Cancer Inst 2004;96:879-82; Fizazi, et al. J Clin Oncol 2010;28 (suppl 18) LBA4507. Denosumab (120 mg Q4W) is not approved for use in patients with advanced cancer to delay SREs. Denosumab is investigational in that setting. 2000-2010: A decade of progress in preventing SRE in men with prostate cancer
Sipuleucel-T: Autologous APCs cultured with antigen fusion protein (PAP)
Sipuleucel-T autologous vaccine: Overall Survival p = 0.032 ( Cox model ) HR = 0.7 8 [95% CI: 0.61, 0.9 8 ] Kantoff PW, NEJM 2010, 363: 411-22 Small EJ, J Clin Oncol 2009; 24: 3089-94 Sipuleucel-T (n = 341) vs Placebo (n=171) Median OS: 25.8 vs 21.7 months
Cabazitaxel in Second-line CRPC TROPIC Study R A N D O M I Z E Mitoxantrone 12mg/m2 q3w Prednisone 10mg qd mHRPC Progression after TXT Cabazitaxel 25mg/m2 q3w Prednisone 10mg qd 360 pts 360 pts R A N D O M I Z E <ul><li>Stratification factor : </li></ul><ul><ul><li>ECOG PS (0,1 vs 2) </li></ul></ul><ul><ul><li>Mesurable/non_mesurable </li></ul></ul><ul><li>Primary Endpoint: </li></ul><ul><ul><li>Overall survival </li></ul></ul><ul><li>Secondary Endpoint: </li></ul><ul><ul><li>PSA response, PSA progression, PFS, RR, Pain progression, Safety, PK of cabazitaxel </li></ul></ul>Enrollment closed: 745/720 pts Hypothesis: Reduction of 25% in the risk of death or median OS=10.67 months for cabazitaxel vs 8 months 511 events, duration 36 months
Progression-free survival Number at risk PFS (%) 80 60 40 20 0 100 0 months 3 months 9 mont h s 15 mont h s 18 mont h s 21 mont h s 6 mont h s 12 mont h s PFS endpoint composite: progression du PSA, progression de la douleur, progression tumorale, deterioration des symptômes, ou mort. 2.8 1.4 Median PFS (mo) 0.65–0.87 95% CI <.0002 P -value 0.75 Hazard Ratio CBZP MP De Bono et al. Lancet In Press 2010 26% risk reduction MP 377 115 52 27 9 6 4 2 CBZP 378 168 90 52 15 4 0 0
Cabazitaxel vs Mitoxantrone: Overall Survival Median FU: 13.7 mo MTX+PRED CBZ+PRED Proportion of Overall Survival 0 10 20 30 40 50 60 70 80 90 100 0 6 12 18 24 30 377 378 300 321 188 231 67 90 11 28 1 4 Number at Risk MTX + PRED CBZ + PRED 28% risk of death reduction Time (months) De Bono et al. Lancet 2010 MP CBZP Median OS (months) 12.7 15.1 Hazard ratio 0.72 95% CI 0.61–0.84 P -value <.0001
Is prostate cancer chemo-sensitive? <ul><li>High response rate (>50%) in first-line </li></ul><ul><li>Benefit in OS in first-line </li></ul><ul><li>Second-line chemotherapy with demonstrated activity </li></ul><ul><li>Chemotherapy improves PFS/OS when used in the localized setting to prevent relapse </li></ul>YES YES YES: OS improved First answer in 2011
Androgen Biosynthesis Inhibitors <ul><li>Androgens are produced at 3 critical sites: </li></ul><ul><ul><li>Testes </li></ul></ul><ul><ul><li>Adrenal gland </li></ul></ul><ul><ul><li>Prostate cancer cells </li></ul></ul>1. Attard G et al, J Clin Oncol, 2008; 2. Attard G et al. J Clin Oncol. 2009; 3. Reid AH et al. J Clin Oncol. 2010; 4. Ryan C et al, J Clin Oncol, 2009; 5. Danila D et al, J Clin Oncol, 2010.
Androgen Receptor, the Target, is Still Expressed in CRPC Prostate cancer in intact animal After castration Castration-resistant Xenograft model of MDA PCa 2b prostate cancer Navone and Fizazi, unpublished data Androgen Receptor
Clinical benefit of abiraterone October 2008 January 2010 Images courtesy of Dr Fizazi.
Abiraterone COU 301 Phase III Study AA 1000 mg daily Prednisone 5 mg BID n = 797 Placebo daily Prednisone 5 mg BID n = 398 Randomize 2:1 Progressing mCRPC patients Failed 1 or 2 chemotherapy regimens, 1 of which contained docetaxel (N=1195) Clinicaltrials.gov identifier: NCT00638690. BPI, Brief Pain Inventory; ECOG, Eastern Cooperative Oncology Group; ITT, intent to treat; PS, performance status. Stratification factors ECOG PS; worse pain over previous 24 hrs; prior chemotherapy; type of progression Primary end point (ITT): OS (25% improvement; HR 0.8) Secondary end points (ITT): PSA; TTPP; rPFS
Overall Survival <ul><li>Median OS, days (95%CI): </li></ul><ul><li>Abiraterone: 450 (430-470) </li></ul><ul><li>Placebo: 332 (310-366) </li></ul><ul><li>P < 0.0001 </li></ul><ul><li>HR = 0.646 (0.54-0.77) </li></ul>% S u r v i v a l Placebo A A A A C e n s o r e d 7 9 7 0 0 2 0 4 0 6 0 8 0 1 0 0 1 0 0 4 0 0 3 0 0 2 0 0 5 0 0 6 0 0 7 0 0 3 9 8 7 2 8 3 5 2 6 3 1 2 9 6 4 7 5 1 8 0 2 0 4 6 9 2 5 8 0 1 D a y s F r o m R a n d o m i z a t i o n Placebo Abiraterone: 14.8 months (95%CI: 14.1, 15.4) Placebo: 10.9 months (95%CI: 10.2, 12.0) De Bono, ESMO 2010
Standard of care in advanced prostate cancer (2011) Clinical setting Sub-setting Standard treatment Options Non-metastatic CRPC None (ADT) Endocrine manipulations Metastases, hormone-naive ADT CAB Metastatic CRPC Bone metastases Denosumab Zoledronic acid Asymptomatic CRPC Sipuleucel-T Docetaxel Symptomatic CRPC Docetaxel Doc + estramustine CRPC progressing after docetaxel Cabazitaxel Abiraterone Docetaxel rechallenge CRPC progressing after caba/abi None (ADT) Clinical trial
The effects of MDV3100 on the Androgen Receptor are distinct from Bicalutamide Ligand 1 2 Chen, et al. 3 4 DNA POL II HSP 90 LBD HD DBD NTD <ul><li>AR Binding Affinity </li></ul><ul><ul><li>DHT ~ 5nM </li></ul></ul><ul><ul><li>Bicalutamide ~160 nM </li></ul></ul><ul><ul><li>MDV3100 ~35 nM </li></ul></ul><ul><li>Nuclear Import </li></ul><ul><ul><li>DHT: ++++ </li></ul></ul><ul><ul><li>Bicalutamide: ++++ </li></ul></ul><ul><ul><li>MDV3100: ++ </li></ul></ul><ul><li>DNA Binding </li></ul><ul><ul><li>DHT: ++++ </li></ul></ul><ul><ul><li>Bicalutamide: ++ </li></ul></ul><ul><ul><li>MDV3100: - </li></ul></ul><ul><li>Coactivator recruitment </li></ul><ul><ul><li>DHT: ++++ </li></ul></ul><ul><ul><li>Bicalutamide: ++ </li></ul></ul><ul><ul><li>MDV3100: - </li></ul></ul>
MDV 3100: PSA response Chemotherapy-Naïve (n=65) Post-Chemotherapy (n=75) 62% (40/65) > 50% Decline 51% (38/75) > 50% Decline PSA Change from Baseline Scher HI et al., Lancet Oncol 2010
What about the (near) future? Clinical setting Sub-setting Standard treatment Options Non-metastatic CRPC None (ADT) Denosumab? Endocrine manipulation Metastases, hormone-naive ADT Docetaxel? CAB Metastatic CRPC Bone metastases Denosumab Alpharadin? Zoledronic acid Asymptomatic CRPC Sipuleucel-T Abiraterone? Docetaxel Symptomatic CRPC Docetaxel + VEGF-Trap? + Zibotentan? + Dasatinib? Doc +estramustine CRPC progressing after docetaxel Cabazitaxel Abiraterone MDV? TAK 700? Ipi? Docetaxel CRPC progressing after caba/abi None (ADT) Clinical trial
There Is Not Just One Prostate Cancer Move toward personalized, biologically-oriented medicine in prostate cancer? About 50% of CaP Do gene fusion-positive prostate cancers react differently to hormone manipulations than gene fusion-negative prostate cancers?
PTEN loss AR amplif. mutation MYC amplification Molecular classification and Target-oriented therapy BRACness ERG transl ? Early metastatic prostate cancer Prostate Tumor (PR, biopsy, metastases) Circulating Tumor Cells VERIDEX: CellSearch™ System ISET TM System (Isolation by Size of Epithelial Tumor cell) Personalized Medicine +other biomarkers
Conclusion: Advanced prostate cancer is now a chronic disease <ul><li>After 5 years without significant progress, 4 drugs have shown phase III positive results in 2010! </li></ul><ul><ul><ul><li>Cabazitaxel (overall survival) </li></ul></ul></ul><ul><ul><ul><li>Denosumab (SRE) </li></ul></ul></ul><ul><ul><ul><li>Abiraterone (overall survival) </li></ul></ul></ul><ul><ul><ul><li>Sipuleucel-T (overall survival) </li></ul></ul></ul><ul><li>More to come! </li></ul><ul><ul><li>TAK 700, MDV 3100 </li></ul></ul><ul><ul><li>Ipilimumab </li></ul></ul><ul><ul><li>Cabozantinib… </li></ul></ul>