The role of chemotherapy in prostate cancer has evolved considerably over the last 30 years. In 1981, estramustime was FDA-approved for palliation of metastatic prostate cancer symptoms. In 1996, the FDA approved mitoxantrone and corticosteriods in men with symptomatic androgen-independent prostate cancer for significant reduction in pain. On May 19, 2004, the FDA approved Taxotere® (docetaxel) for injection for use in combination with prednisone for the treatment of patients with androgen-independent (hormone-refractory) metastatic prostate cancer.
TAX 327, was a randomized, multicenter global clinical trial designed to evaluate chemotherapy with docetaxel and prednisone in the treatment of men with metastatic, hormone-refractory prostate cancer. 1006 patients were randomized to one of three treatment arms: mitoxantrone (12 mg/m 2 q3w) + prednisone (5 mg bid) weekly docetaxel (30 mg/m 2 ) + prednisone (5 mg bid) docetaxel once every three weeks (75 mg/m 2 ) + prednisone (5 mg bid) The primary efficacy endpoint was overall survival.
The initial analysis at 2 years showed that patients in the Taxotere ® q3w arm had a 24% reduced risk of mortality compared to patients in the mitoxantrone arm. Patients in the Taxotere ® q3w arm had a 14.5% median survival advantage and a 27.6% survival advantage at 2 years compared to patients in the mitoxantrone arm.
PSA normalization among patients in the TAX 327 study also had independent prognostic significance, but was a weaker surrogate for overall survival. Thus, PSA declines represent a continuum of prognosis and cut-offs are not fully predictive of the survival benefits with chemotherapy.
02/23/13 ISCT FINAL v.2A-- 5-5-09
Explain difference between traditional chemo regimens (i.e. 3 weeks per cycle for “x” number of cycles) and the “ipi” format of induction followed by maintenance Emphasize importance of timing between pre-Tx XRT and dose 1, implications for scheduling, need to work closely with RT
New Developments for Relapsed Prostate Cancer April 1st 2003 Richard Lam M.D. Prostate Oncology Specialists, Marina del Rey, California
New Developments for Relapsed Prostate Cancer April 1st 2003 Richard Lam M.D. Prostate Oncology Specialists, Marina del Rey, California Change from baseline in AUPC-VAS is the primary efficacy of the study. Values shown are mean plus or minus one standard error for each of the first four weeks after administration. Differences are statistically significant at weeks 2, 3 and 4.
Module12 Dr Lam-AdvancedPC
XII. Advanced Disease Richard Lam, MD Research DirectorProstate Oncology Specialists Marina del Rey, CA
Methods to Achieve CastrationSurgicalMedical Lupron, Trelstar, Eligard, Viadur, ZoladexTime
Androgen Deprivation Therapy for Advanced DiseaseDuration of effectiveness: average 18 months (sometimes up to 10 years though)Prognostic indicators PSA PSA doubling time Gleason score Small cell histology Extent of disease Addition of anti-androgens, such as bicalutamide PSA nadir
FDA-Approved Chemotherapy Agents until 2010 1980s 1990s 2000s Taxotere® (docetaxel) Estramustine Mitoxantrone with injection concentratephosphate (EMP) corticosteroids with prednisone
TAXOTERE: Study Design R Taxotere every 3 Primary endpoint A weeks (n=335) • Overall survival (OS) N D Secondary endpoints O • Pain response • 50% PSA decline M • Response rates I • Quality of life Z Mitoxantrone every 3 weeks E (n=337)
PSA response does not matter to the FDA (even though itpredicts survival). However, for guiding individual treatment decisions, PSA response is extremely useful. 1.00 PSA normalized (n=115) Proportion surviving PSA not normalized (n=743) 0.75 0.50 (%) 0.25 p<0.0001 0 0 5 10 15 20 25 30 35 40 45 50 Survival time (months)
Taxotere: Side EffectsEffects on Blood Red blood count can be lowered (Anemia). Fatigue Shortness of Breath Transfusions White blood count. Fever Infection
Taxotere: Side Effects (Cont.)Effects on Gastrointestinal Tract Upper Tract Impaired taste Mild, if any, nausea Loss of appetite Lower Tract Diarrhea Liver Inflammation
Taxotere: Side Effects (Cont.)Other systems Hair loss Numbness in fingers and toes Tear duct stenosis Finger nail discoloration, pain, discharge
Promising Taxotere Combinations How Can We Improve on Taxotere?ThalidomideAvastinXelodaCarboplatinSamarium (Quadramet)Custersin
Taxotere Combined with Platinum DerivativesPrevious Response ReferenceChemo/ Combination Rate # Pts. 2/34 Carboplatin 18% ASCO 2007 Abst. # 238 1/40 Carboplatin 95% Eur Urol Emcyt 51:1252 1/40 Carboplatin 68% Cancer Emcyt 98:2592 2/34 Oxaliplatin 64% GUCS 2008 Abst. # 155 Obtaining good results in men previously treated with chemotherapy indicates a more powerful and active regimen
Inhibitors of Angiogenesis Vascular Endothelial Growth Factor (VEGF)1. Over expression of the COX-2 enzyme stimulates production of VEGF. COX-2 inhibitors (Celebrex ®) reduce VEGF (Fujita et al. The Prostate 2002).2. Thalidomide blocks VEGF and basic fibroblastic growth factor (D’Amato Proc Natl Acad Sci 1994).3. Avastin® is a synthetic monoclonal antibody that blocks VEGF directly (FDA approved for colon, lung, kidney and brain cancer).
Taxotere & Thalidomide Taxotere & Thalidomide 50 men 75 Men Metastatic Disease Taxotere Alone 25 menJournal of Clinical Oncology Vol. 22:2532
Taxotere + or (-) Avastin: Overall Survival Data Median OS, 1.0 Mos (Range) Bevacizumab + CT 22.6 (21.1-24.5) 0.8 Placebo + CT 21.5 (20.0-23.0) HR: 0.91 (95% CI: 0.78-1.05) Probability 0.6 Log rank P = .181 0.4 0.2 0 0 6 12 18 24 30 36 42 Mos Patients at Risk, n Placebo + CT 526 480 390 305 199 100 44 22 Bev + CT 524 484 417 327 217 117 52 23Kelly WK, et al. ASCO 2010. Abstract LBA4511.
Rate of Cancer Progression Median PFS, 1.0 Mos (Range) Bevacizumab + CT 9.9 (9.1-10.6) 0.8 Placebo + CT 7.5 (6.7-8.0) HR: 0.77 (95% CI: 0.68-0.88) Probability 0.6 Log rank P < .0001 0.4 0.2 0 0 6 12 18 24 30 36 42 Mos Patients at Risk, n Placebo + CT 526 303 134 75 34 8 4 0 Bev + CT 524 381 194 97 44 15 5 1Kelly WK, et al. ASCO 2010. Abstract LBA4511.
Avastin Significantly Improved Other Clinical EndpointsOutcome, % Bevacizumab Arm Placebo Arm P Value (n = 524) (n = 526)≥ 50% decline in PSA 69.5% 57.9% .0002Scan response rate 53.2% 42.1% .0113 The Marginal Advantages Seen with Avastin & Taxotere in this Study May Possibly Be Explained by the Failure to Incorporate Thalidomide (or Revlimid) in the RegimenKelly WK, et al. ASCO 2010. Abstract LBA4511.
Taxotere and CurstersinCurstersin blocks Clusterin, a cell protein secreted by cancer cells that inhibits the killing effect of chemotherapyCurstersin is anti-sense oligonucleotide that reduces Clusterin production Chi, Kim. Proc. ASCO 2009, abs #5012.
The Cancer Cell Makes Clusterin From RNA Clusterin Protein RNA
Curstersin No Translation, this step fails Clusterin not Created RNA of ClusterinRNA Exploded view: Transcription
Taxotere vs. Taxotere & Curstersin: Overall Survival Further Information on a Clinical Trial of Taxotere & Curstersin Is Available by Calling Jennifer at (310) 827-7707 Ext #32
Taxotere Combined with ? Effective Ineffective or Too Toxic CisplatinCarboplatin with Mitoxantrone Emcyt AdriamycinCapecitabine Vinorelbine (Velban)Avastin and Revlimid Vitamin D (Calcitriol)Curstersin * ?Avastin/Revlimid? *Available on trial and final results are still pending
Cabazitaxel (Jevtana) Mitoxantrone & 755 patients Prednisone whose cancer (n = 377) is Progressing Cabazitaxel & on Taxotere Prednisone 10 (n = 378) Obtaining Results in Taxotere Resistant Patients Would Constitute a Notable AccomplishmentDe Bono JS, et al. ASCO 2010. Abstract 4508.
Cabazitaxel: Side Effects Toxicity manageable and similar between treatment arms Higher incidence of: grade 3 low blood counts (82% vs 58%) fevers from low blood counts (7.5% vs 1.3%) diarrhea (46.6% vs. 10.5%)De Bono JS, et al. ASCO 2010. Abstract 4508.
Immune Approaches to Combat Advanced Prostate CancerSipuleucel-T (Provenge)Ipilimumab (Yervoy)
Immune SystemMade of cells and antibodies.Underactive: allows cancer to progress (post- transplant, HIV)Overactive: leads to autoimmune illness. Control cancer?
Round #2: Larger Provenge Study Sipuleucel-T Control (N = 341) (N = 171) Serum PSA median, ng/mL 51.7 47.2 Serum PAP median, U/L 2.7 3.2Kantoff, IMPACT manuscript, submitted, 2010
Round #2: Overall Survival HR = 0.759 (95% CI: 0.606, 0.951) p = 0.017 (Cox model) Median Survival Benefit = 4.1 months Sipuleucel-T (n = 341) Median Survival: 25.8 mo. 36 mo. survival: 32.1% Control (n = 171) Median Survival: 21.7 mo. 36 mo. survival: 23.0% No. at Risk Sipuleucel-T 341 274 142 56 18 3 Control 171 123 59 22 5 2Kantoff, ASCO-GU March 2010
The Regulatory T-Cells (T-Regs): SuppressImmune Activity, and can Enhance Cancer Activity
“The T-Regs”Treg cells are a subset of T cells that suppresses other T cells “The Police”Cancer patients have been demonstrated to have an increased levels of Treg cells in the bloodStudies show that higher levels of Treg cells in the blood predict shorter survivalCTLA is an important receptor on the surface.
Ipilimumab: Antibody against the CTLA-4 receptor on the T-Reg Cell SurfaceCTLA-4 CTLA-4 Cell Surface
Antibody against CTLA-4 (ipilimumab) Beer et al. ASCO Abstract # 5004, 200826 patients with hormone refractory, end stage, metastatic prostate cancer treated with escalating doses (phase I) with or without radiation to a metastatic site.6 men had greater than 50% decline in PSA.2 men had PSA drop to zero.Side effects were diarrhea, liver inflammation and rash
PSA Control is Observed 100 Best PSA Change From Baseline (%) 50 100 aBest PSA Change From Baseline (%) 50 0 0 a a -50 -50 11/43 responses (26%) 25/43 PSA control (58%) -100 -100 a 10 mg/kg +XRT Chemotherapy- +XRT Prior a Prior Chemotherapy Naïve Chemotherapy
Abiraterone: Brief ReviewEvidence is accumulating that castration-resistant prostate cancer frequently remains hormone-driven by using adrenal hormones or through intracrine synthesis.CYP17A1 (or 17-a-hydroxylase or 17,20-lyase) is a cytochrome P450 enzyme responsible for androgen and estrogen synthesis from adrenal hormones.Abiraterone is a potent, selective, and irreversible inhibitor of CYP17A1
Abiraterone suppresses steroids 6 2 Testosterone Androstenedione 5 4 nmol/l ng/dl Lower limit of 3 sensitivity 1 No rise at 2 progression No rise at progression 1 0.07 0 01 Start of 10 20 60 70 At Start of 28 56 At treatment Days progression Days progression treatment 12.5 12.5 DHEA Estradiol 10.0 10.0 ρmol/lnmol/l 7.5 7.5 No rise at 5.0 progression 5.0 2.5 2.5 0 0 28 56 At 10 20 30 40 50 60 Start of treatment Days progression Days post treatment
Abiraterone: Brief ReviewAntitumor demonstrates activity pre-docetaxel and post-docetaxel•PSA, RECIST, bone scans ••Confirmed in Multiple phase II studies •Pre-docetaxel: 60-80% PSA response rate •Post-docetaxel: 40-50% PSA response rate•Phase III studies •Post-docetaxel: Completed accrual first quarter ’09 •Pre-docetaxel: Completed accrual first quarter ‘10
Abiraterone-CB-301 Results (deBono, ASCO June 2011) PSA Time to PSA Overall response progression SurvivalAbiraterone 38% 11 months 15.8 months Placebo 10% 6.6 months 11.2 months
•Binds AR more potently than bicalutamide.•Does not stimulate the AR•Engineered for activity in prostate cancer cells with acommon and specific molecular defect: OverexpressedAR•Inhibits movement of the androgen receptor to thenucleus where it binds to DNA and triggers a signallingcascade leading to tumor growth
MDV3100MDV3100 attacks the androgen receptor at multiple levels.Appears effective In chemo-naïve men (62% likelihood of 50% PSA decline). Post-chemotherapy disease (50% PSA response rate). Scher, H. PASCO 2009, abs 5011.Preliminary Phase III results 2012
Waterfall Plot of Percent PSA Change from Baseline at12 Weeks for Chemotherapy-Naive Patients Treated at 60, 150, and 240 mg/day of MDV3100 7 pt off N=42 Chemo-naïve study <12 weeks >50% Decline: 23/42 (55%)
MDV3100 Affirm Study Results (deBono, ASCO June 2012) PSA Time to PSA Overall Response Progression SurvivalMDV- 54% 8.3mo 18.43100 monthsPlacebo 1.5% 2.9mo 13.6 months
Symptoms Commonly Seen in Advanced DiseaseSkeletal Complications Bone pain Spinal cord compression Low blood counts Fatigue Infections
Quadramet Samarium Sm 153 Lexidronam Injection Indicated for relief of pain in patients with confirmed osteoblastic metastatic bone lesions. Controlled studies included patients with prostate cancer, breast cancer, and others. Administered intravenously, usually as an outpatient procedure. Repeat administrations are safe and effective.1Quadramet (samarium Sm 153 lexidronam injection) prescribing information. September 2003.2Resche I, et al. Eur J Cancer. 1997;33:1583–1591.3Serafini AN, et al. J Clin Oncol. 1998;16:1574–1581.
Pain Reduction Change in AUPC-VAS in Prostate Cancer Change from Baseline 2 Placebo 0 1.0 mCi/kg -2 -4 -6 * * * -8 -10 0 1 2 3 4AUPC: area under the pain curve.VAS: visual analog scale; Week NumberPDS: pain descriptor scale.*P≤0.05 vs placebo.Sartor O, et al. Urology. 2004;63:940-945.