PROSTATE CANCER Beyond Chemotherapy

PROSTATE CANCER Beyond Chemotherapy Chadi Nabhan, M. D. Oncology Specialists, S. C. Lutheran General Hospital Clinical Assistant Professor Park Ridge, IL 60068 cnabhan@oncmed.net BACKGROUND • The most common diagnosed malignancy in men • 40,000 men die of this disease annually • Detection is increased with widespread use of PSA screening • Treatment is dependent on the stage, comorbidities, and patient preference CHRONIC DISEASE…..?? • Median time from PSA rise following local therapy with curative intent until bone mets is 8 years Pound CR et al. JAMA, 1999 • Median survival following establishment of metastatic disease is 5 years. Ward JF et al. J Urol, 2003 Localized disease is potentially curable METASTATIC DISEASE • Shift in the focus of care • Cure is no longer possible • Goals are to delay mets, preserve QOL, and potentially improve survival • PSA rise is usually the first sign of recurrence METASTATIC DISEASE • Androgen ablation has been the mainstay of therapy for over 50 years. Huggins et al. Cancer Research, 1941, 1: 293-297 • Endocrine manipulation is achieved by either orchiectomy or medical hormonal therapy • The premise is that the growth of most prostate cancer cells are androgen dependent ANTI-ANDROGENS • Blocks DHT activity at the cellular level • Use of nonsteroidal antiandrogens (Casodex, Flutamide) interferes with binding of Testosterone and DHT to the receptor HORMONAL QUESTIONS?? • Delayed versus Immediate • CAB versus Monotherapy • High dose anti-androgens • Managing complications SIDE EFFECTS OF AD • • • • • • Osteoporosis Vasomotor flushing Anemia Loss of libido Fatigue Obesity and its related diseases NEED for TREATMENT...? • Identify patients with potential rapid progressive disease • Sometimes patients have no measurable disease and have no symptoms • Rising PSA with no metastases and no symptoms represent a “TRUE” challenge!!!! PSA-DT & V • D’Amico et al. JNCI, 2003: 8669 patients, PSA-DT < 3 months was associated with worse survival and increased prostate cancer-specific mortality, regardless of what was the primary therapy PSA rise by < 2 per year before surgery and have a Gleason >7 have the highest possibility for post-op PSA-DT < 3 months • D’Amico et al.. JCO, 2005: PSA-DT • Ward JF et al. J Urol, 2003: 3903 patients who had undergone prostatectomy: PSA-DT < 12 months was associated with higher risk of mets 718 patients who had undergone XRT: PSA-DT < 13 months was associated with higher risk of dying from prostate cancer • Sandler HM et al. Int J Radiat Oncol Biol Phys: PSA-DT Freedland SJ et al. JAMA, 2005: Review of 379 patients who demonstrated PSA-only progression after RP: 5, 10, and 15-year survival was lowest in those with PSA-DT < 3 months despite other factors………… 5-year OS was 98% for PSA-DT > 15 months versus 51% for PSA-DT < 3 months despite similar Gleason (4+4), and biochemical-free period of 3 years How do Prostate cancer cells survive after androgen deprivation?? • Androgen receptor related pathways • Non-androgen receptor pathways AIPC • ALL men will eventually become androgen-independent despite initial response to castration • Some have elevated PSA without radiographic evidence of disease • Differentiation between rising PSA with metastases and that without metastases Treating AIPC: An Unmet Need Diagnosis Androgen Dependent PCa Primary Therapy • Radical Prostatectomy • Brachytherapy Androgen Deprivation • Lupron • Zoladex • Casodex Androgen Independent PCa (asymptomatic) (symptomatic) Death Palliative Interventions • Bisphosphonates • Taxanes • Novantrone • Radiation Therapy • Cryotherapy • Watchful Waiting • Eulexin • Ketoconazole • DES No approved therapies • Emcyt TREATMENT GOALS IN AIPC • Delay objective disease progression (nodal/bony mets) • Delay onset of disease related pain and symptoms • Preserve or improve quality of life • Improve survival • Minimize toxicity CHEMOTHERAPY • Petrylak et al. NEJM, 2004: randomized 770 men to: Taxotere/Estramustine vs Mitoxantrone/Prednisone OS: 17.5 months vs 15.6 months (P=0.02) TTP: 6.3 months vs 3.2 months (P<0.001) Pain relief was similar More side effects with taxotere CHEMOTHERAPY Tannock et al. NEJM, 2004: randomized 1006 men to: Taxotere Q 3 weeks/Prednisone Taxotere Q week/Prednisone Mitoxantrone/Prednisone OS: 18.9 vs 17.4 vs 16.5 months More PSA decrease in taxotere arms, better QOL, but more adverse events CHEMO SWOG 9916 TAX 327 PSA (taxotere) 50% 45.4% 32% 18.9 months 2.5 months PSA (mitoxantrone) 27% OS (Tax) Improvement 18 months 2 months SATRAPLATIN • • • • • Structurally similar to cisplatin Orally bioavailable 80-120 mg/m2 for 5 days every 4-5 weeks Phase II study suggested 39% response EORTC (phase III study) compared Satraplatin/Pred versus Prednisone • SPARC study is accruing IXABEPILONE • Epitholone: induces microtubule bundling and mitotic arrest • 40 mg/m2 IV every 3 weeks • Phase II suggested 39% RR in chemonaïve • Oh et al, JCO, 2005: with/without estramustine • The drug is being compared with mitoxantrone in taxane failure patients NOVEL THERAPIES & CONCEPTS • • • • • • Differentiating agents Immunotherapy Angiogenesis Signal transduction Monoclonal antibodies Gene expression Vitamin D analogues • Mechanisms are not entirely known • Vit D analogs have differentiation, antiproliferation, and chemosensitizing properties • Calcitriol induces differentiation and apoptosis of prostate cancer cells • Combined with taxotere Calcitriol + Taxotere • Phase II study with taxotere at 36 mg/m2 weekly for 6 weeks every 8 weeks (day 2) • Calcitriol at 0.5 mcg/kg weekly (day 1) • PSA responses in 30/37 (80%) • Measurable responses in 53% • Median TTP 11.4 months • Median survival 19.4 months ASCENT • 250 patients randomized to 45 mcg of high-dose calcitriol (DN-101) or placebo with taxotere weekly • Beer TM et al. JCO, 2005: Synergy between taxotere and Calcitriol • Beer TM et al, JCO, 2003: Phase II with calcitriol + Taxotere: good responses and a suggestion of survival ASCENT-2 • Taxotere/Prednisone versus • Taxotere/DN-101 Why Immunotherapy? • Malignancy results, in part, from resistance to or escape from host defenses • Active immunotherapy – Seeks to induce tumor-specific immunity – Generally well tolerated • Does not preclude using cytotoxic or other palliative therapies later Provenge Manufacturing Provenge® Antigen Loading Antigen Processing Antigen Precursor APC Antigen-loaded precursor APC Maturing antigenloaded APC Infuse patient T cells attack tumor cells In vivo T cell activation Provenge Administration 3 Leukaphereses, 3 Infusions • Three doses prepared from the patient’s own cells • Cells for each dose collected by leukapheresis • Each dose administered via a single intravenous infusion at Weeks 0, 2, and 4. Infused at Weeks 0 2 4 PHASE III STUDY IN AIPC P R O G R E S S I O N Provenge Q 2 weeks x 3 (n=82) Treated at MD Discretion Asymptomatic Metastatic Androgen Independent Prostate Cancer (n=127) 2:1 Placebo Q 2 weeks x 3 (n=45) Long-term follow up D9903 (Salvage) Q 2 weeks x 3 Time to Disease Progression Approached Statistical Significance Probability of non-progression 1.00 Time to Disease Progression (ITT) Provenge (n=82) Placebo (n=45) Phase 3 Trial #D9901 0.75 p = 0.061 (log rank) HR = 1.43 (95% CI: 0.98 - 2.09) 0.50 0.25 0.00 0 10 20 30 40 50 60 70 80 Time to progression, weeks Statistically Significant Delay in TTP in Gleason Sum ≤7 Patients Time to Disease Progression Probability of non-progression 1.00 Gleason < 7 subgroup (n=75) Phase 3 Trial #D9901 Provenge (n=50) Placebo (n=25) p = 0.001 (log rank) HR = 2.23 (95% CI: 1.34 - 3.73) 0.75 0.50 0.25 0.00 0 10 20 30 40 50 60 70 80 Time to progression, weeks Significant Delay in Pain Onset Gleason ≤7 Time to Onset of Disease-Related Pain: Gleason  7 Subgroup Phase 3 Trial #D9901 1.00 Probability of No Pain Provenge (n=48) Placebo (n=23) 0.75 p = 0.016 (log rank) HR = 2.67 (95% CI: 1.16 - 6.13) 0.50 0.25 0.00 0 10 20 30 40 50 60 70 80 Time to Onset of Disease-Related Pain (weeks) Significant Survival Benefit Gleason ≤7 1.00 Phase 3 Trial #D9901 Provenge (n=50) Placebo (n=25) p = 0.047 (log-rank) HR = 1.89 Cumulative Survival 0.75 0.50 0.25 0.00 0 10 20 30 40 Survival Time (months) PROVENGE • Burch PA et al. Prostate 2004: Phase II study with promising results • Smith EJ et al. JCO 2006: Phase III study with provenge versus placebo in 127 patients OS 25.9 months versus 21.4 months in favor of provenge D9902 B is accruing patients. D9902B Provenge Q 2 weeks x 3 P R O G R E S S I O N Treated at MD discretion Asymptomatic Metastatic Androgen Independent Prostate Cancer (n=275) 2:1 Placebo Q 2 weeks x 3 P A I N Followed for survival PB01 (Salvage) Q 2 weeks x 3 GVAX • Uses irradiated allogeneic cultured prostate cancer cells modified to secrete high levels of GM-CSF Simons et al. Proc SCAO, 2002 Small EJ. et al. Proc ASCO, 2004 VTAL-1: Asymptomatic patients to GVAX versus chemo VTAL-2: Symptomatic patients to chemo versus chemo plus GVAX ANGIOGENESIS • Prostate cancer patients have higher levels of VEGF • CALGB 90040: Taxotere/Prednisone/Estramustine/Avastin: Good results but high toxicity • CALGB 90401: Taxotere/Pred versus same plus avastin THALIDOMIDE • Randomized phase II study of thalidomide at 200 mg/daily plus taxotere versus taxotere alone • Trend towards thalidomide arm • PFS: 5.9 months versus 3.7 months • OS 25.9 months versus 14.7 months in favor of combination (P=0.04). Median follow-up of 46 months • Retter A et al. ASCO Symposium Orlando, 2005 Signal Transduction • Cell surface receptors are activated by specific signals from the environment that stimulate specific response within the cell • Signal transduction is the process of sending signals or activating pathways in the cell to stimulate a cell response such as growth and proliferation, differentiation and apoptosis • Altered signal transduction may lead to deregulated cell growth and potentially CANCER EGFR • Expressed in 40-80% of prostate cancers • Associated with cancer cells dedifferentiation • Increased in metastatses as opposed to the primary tumor • EGFR expression is increased in AIPC IRESSA • Over 100 patients were treated with single agent (Schroder et al, 2004 and Syed et al, 2003 and Moore et al, 2002) • Few PSA declines and symptomatic relief • Maybe, mutations of the receptor do not exist in AIPC • Being combined with other agents Tarceva in AIPC • 19 Patients enrolled • Primary end point is the overall clinical benefit (SD+CR+PR) • Skin rash and diarrhea are most common side effects • Data suggest a 28% clinical benefit. Nabhan et al. ASCO Prostate Symposium, Orlando, February 2007 PDGFR • High levels of PDGFR are expressed in AIPC…Enhances survival • Gleevec is an inhibitor to PDFR • Gleevec is being studied in combination with Docetaxel • Nausea and fatigue are the major side effects Gleevec + Taxotere • 600 mg of Gleevec with 30 mg/m2 of taxotere weekly for 4 weeks every 6 weeks • 8 out of 21 patients (38%) with more than 50% reduction in PSA and several lasting more than 18 months • A study comparing the combination to single agent taxotere is being conducted GM-CSF • Small EJ et al. Clin Cancer Res, 1999: GM-CSF induces immune responses against experimental and human tumors • Toxicity is mild • Responses were seen • Maintenance study is currently open!! CONCLUSIONS • Prostate cancer is a chronic disease with much comorbidity • ALL patients will become hormone refractory and androgen-independent • Chemotherapy is active but is not the only answer • There are many new agents under development CONCLUSIONS • Maintenance therapies • Immunotherapy • New non-toxic approaches in chemothearpy-failures CLINICAL TRIALS ARE ENCOURAGED Available Studies • Chemotherapy Naïve: Provenge Vaccine study Traceva (one daily tablet) Chemotherapy responders Maintennace study with GM-CSF (Usually patients, receive no treatments and wait until PSA or the disease start to cause symptoms) Available Studies • Chemotherapy non-responders Continue chemotherapy and add Sorafenib (tablet twice daily) Chemotherapy failures or refractory Trial with Gleevec and Sorafenib combination