Prostate Cancer gov

Prostate Cancer William Dahut, M.D. Chief, Genitourinary CRS MOB, CCR National Cancer Institute Prostate Cancer Importance • Prostate Cancer is the most common non-cutaneous malignancy in men • 218,890 new cases and 27,050 deaths expected in 2007 • Despite some recent advances Androgen Independent Prostate Cancer (AIPC) remains an incurable disease with few effective treatments Prognosis • Prognosis is directly related to stage and grade of the tumor • The Gleason Grade is the most common grading system • Tumors are graded from 1-5 with the higher number indicative of a more aggressive tumor • In practice the two most predominant patterns are added together to give a score from 2-10 Gleason Grade (3) WellDifferentiated Gleason Grade(5) PoorlyDifferentiated Prognosis Related to PSA, Gleason Score, Stage and Positive Biopsies • PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors • Nomograms are now available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Detection • May be detected due to symptoms, physical findings or through PSA screening • Most patients in the US are asymptomatic at the time of diagnosis. Family History • Men with a father or brother affected are twice as likely to develop prostate cancer. • Men with two or three first degree relatives have a five and eleven-fold increased risk of developing prostate cancer. Treatment • Patients with a life expectancy of less then 10 years and/or low grade/ low stage lesions may be candidates for active surveillance • Primary hormone therapy is an option for patients not suitable for definitive local therapy Treatment - continued • Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years • Radical Prostatectomy • External-beam Radiation • Brachytherapy Radical Prostatectomy • Surgical removal of the prostate • May be done with a retropubic, perineal, laproscopic or robotic approach • Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting • 695 men with early stage prostate cancer randomized to radical prostatectomy or watchful waiting • Median of 8.2 years of follow-up 83 deaths in surgery group and 106 in watchful waiting group (P=0.04). • 30 of the 347 men assigned to surgery and 50 of the 348 men assigned to watchful waiting, death was due to prostate cancer • More advanced clinically then current patients External-beam Radiation • Radiation to the prostate from outside the body • Evidence that higher doses are associated with better efficacy • Newer techniques (such as 3-D conformal) hope to increase radiation delivery and to decrease toxicity • Most common side effects are impotence and rectal irritation Brachytherapy • Radiation implants placed directly into the prostate under ultrasound or ct guidance • Very high dose radiation to the prostate with little radiation outside the prostatic bed • Acute urinary symptoms common, some patients with impotence • Procedure completed in one day Treatment of Locally Advanced or Microscopic Nodal Disease • Hormonal therapy plus radiation • Hormonal therapy plus surgery • ? Chemotherapy EORTC Trial • Bolla et al NEJM 1997 – 415 patients with locally advanced prostate cancer were randomized to radiotherapy alone or radiotherapy plus immediate hormone therapy – Therapy continued for 3 years – Median follow-up 45 months – Local control, metastases free and overall survival advantage to the adjuvant hormonal group ECOG ( Messing et al) • Randomized trial of immediate hormonal therapy versus observation in men undergoing radical prostatectomy with evidence of positive lymph nodes • 98 eligible patients were entered onto the study • At 7.1 years 7/47 who received immediate anti-androgen had died compared to 18/51 in the delayed therapy group • Criticisms Biochemical Recurrence • May be occult local or metastatic disease • Options include additional local therapy, hormonal treatment or watchful waiting • Little data to predict the impact of treatment on survival Pound Data • Probably the most important report on this population because of the limited use of radiation and hormonal therapy • Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. • Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) • No patients received hormonal therapy without clinically evident metastatic disease. • Median time from PSA elevation to metastatic disease was 8 years • Median time to death after metastatic disease was 5 years. • Prognostic factors predictive of outcome included the Gleason score on the surgical specimen, time to PSA recurrence and PSA doubling time. Disseminated Disease (Hormone responsive) • Prostate Cancer tends to spread to bone and lymph nodes • However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. • Many patients do not have measurable lesions thus traditional response criteria (RECIST) is difficult to use. Bone Scan in Metastatic Prostate Cancer Treatment of Metastatic Disease • Leuprolide and Goserelin are most common GnRh-agonists • Both agents may cause a decrease in libido, hot flashes, bone loss and increased risks of DM and CVD. • May initially result in an increase in testosterone • Orchiectomy- side effects include hot flashes , decreased libido and sexual potency Osteoporosis Risk Factors for men • Hormonal changes associated with aging correlate with bone loss – Lower testosterone levels – Leads to less aromatization (conversion) of testosterone to estradiol – Estradiol protects / strengthens bone E2 • Therefore lower levels = less protection Hormonal Therapy • BMD loss with hormonal therapy – Decrease T by >95% – Decrease E2 by >80% 1 yr Orchiectomy 2 yr 2.4% 10% GnRH Agonist 3.4% 6.5% Hormonal Therapy • This decrease in BMD is associated with an increase in fractures • Men without prostate cancer over the age of 65 who are not on hormonal therapy have a fracture rate of 0.5% per year • With hormone therapy there was a 5% incidence of osteoporotic fractures seen in a median of 22 months • In one series, within 7 years 28% of prostate cancer patients treated with orchiectomy had a fracture vs. 1% of patients who did not undergo orchiectomy Androgen-Dependent and Androgen-Independent Progression of Prostate Cancer Chemotherapy • Initial studies disappointing • Quality-of-life measurements • Difficulty in evaluating response PSA Endpoints • Conflicting data on the importance of the magnitude of the PSA decline • Differentiating agents may paradoxically increase PSA secretion • Primary use may be to select which drugs should proceed to phase III trials. • Endpoints (other than survival) remain a major problem in this population Bone Scan Before And After 12 weeks of BAY43-9006 Treatment (Case 1) Before After Before After TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer RANDOMIZE Taxotere 75mg/m2 Q3 + Prednisone 10mg orally given daily Taxotere 30mg/m2 Wkly + Prednisone 10mg orally given daily Hormone Refractory Prostate Cancer Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily Eligibility • Progressive prostate cancer despite primary androgen deprivation – Karnofsky performance status >=60% – No previous therapy with cytotoxic agents except estramustine – No other major medical conditions • Pts were evaluated for PSA, pain and baseline and 3 weekly during treatment QOL at Main Results of Study • TAX327 study showed significantly longer survival for the 3 weekly docetaxel (D3P) arm compared to mitoxantrone No significant survival benefit with weekly docetaxel D3P arm showed better palliation, as recorded by pain and quality of life responses Greater number of patients had significant PSA declines • • • P ro p o ti o n A l i v e 0 .0 0 1 2 3 Years 4 5 6 7 Docetaxel 3-Weekly 0 .2 0 .4 0 .6 0 .8 1 .0 P ro p o ti o n A l i v e 0 .0 0 1 2 3 Years 4 5 6 7 Docetaxel 3-Weekly Mitoxantrone 0 .2 0 .4 0 .6 0 .8 1 .0 1 .0 Docetaxel 3-Weekly Docetaxel Weekly Mitoxantrone P ro p o ti o n A l i v e 0 .0 0 0 .2 0 .4 0 .6 0 .8 1 2 3 Years 4 5 6 7 Survival > 3 years Docetaxel Q3W (n=335) 3-yr survival rate 17.9% Docetaxel Weekly (n=334) 16.7% Mitoxantrone (n=337) 13.7% Survival by Age Docetaxel Docetaxel Q3W (n=335) n Median Survival Hazard Ratio p-value n Median Survival Hazard Ratio p-value 176 19.5 0.81 0.071 >=69 years 159 18.9 0.77 0.036 176 18.6 0.82 0.091 Weekly (n=334) 158 17.2 0.93 0.55 <=68 years Mitoxantrone (n=337) 170 16.4 167 15.7 Conclusions • The updated survival analysis confirms the previously reported results. • Similar hazard ratios among the analyzed subgroups are evidence for robust data. Implications • Three weekly docetaxel and prednisone remains the preferred treatment option for most patients with mHRPC. Importance of Angiogenesis in Prostate Cancer • VEGF, PDGF and bFGF higher in prostate cancer than in normal tissue • Progressive increase in angiogenesis factors as prostate cancers move through the various pathologic states • Siegal et al (Cancer 1995 May 15;75(10):2545-51) demonstrated that microvessel density was higher in prostate cancer tissue than the adjacent hypoplastic or benign tissue Thalidomide Inhibits Angiogenesis in the Rabbit Cornea Model D’Amato et al., PNAS 91:4082-4085, 1994 PC3 xenograft Treatment with Docetaxel and Thalidomide Randomized Phase II Trial of Docetaxel Plus Thalidomide in Metastatic AndrogenIndependent Prostate Cancer Trial Design: Thalidomide and Docetaxel • 75 patients with metastatic AIPC – Docetaxel 30 mg/m2 for three out of every four weeks – Docetaxel at the same dose plus thalidomide 200 mg daily • 2:1 randomization in favor of the combination arm • Patients were not permitted to have received prior chemotherapy Clinical Results: Thalidomide and Docetaxel Docetaxel No. of Patients 25 Docetaxel + Thalidomide 50 50% decline in PSA Response in soft tissue disease Median PFS (months) 37% 3/11 (27%) 3.7 50% 7/20 (35%) 5.9 Dahut et al J Clin Oncol 2004 Improved Survival with Docetaxel and Thalidomide P=0.0407 Thalidomide + Docetaxel median 26.9 months Docetaxel Median 14 months Median follow up = 46.7 mo Dahut et al J Clin Oncol, (2005) Phase II Study of Docetaxel, Bevacizumab, Thalidomide, and Prednisone in AIPC INTRODUCTION Td and Bv: different antiangiogenic mechanisms  Td on bFGF, endothelial cells, and TNF  Bv on VEGF Tumor angiogenesis, a complex interplay of multiple angiogenic factors Activated various pathways may easily override angiogenic restriction of one inhibitor Clinical Trial Design • Phase II trial of up to 60 patients – Docetaxel 75mg/m2 IV on cycle 1 day 1, repeated every 21 days – Bevacizumab 15mg/kg cycle 1 day 1, repeated every 21 days – Thalidomide 200 mg daily – Prednisone » 10 mg daily RESULTS Efficacy  39 pts have had >2 Cs and 23 pts active •Median treatment cycles: 15 [2-29] •PSA response and duration: 34 of 39 pts (87%): PSA declines of >50% Median duration of >50% PSA decline: 13 cycles [0~27] 28 of 39 pts (72%) had PSA declines of >80% 12/17 (71%) alive @ 18 months 50 40 30 20 10 Best Response in PSA RESULTS % of PSA at Enrollment 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 Patients RESULTS Measurable Disease • 19 pts evaluable: 1 CR, 10 PR, & 8 SD • The overall response rate is 58% • Improvement (disappearance of lesions) seen on multiple bone scans Bone scan RESULTS Safety profile Generally well tolerated Significant toxicities observed:  Febrile neutropenia (5/39)  Syncope (4/39)  Colonic perforation or fistula (2/39)  Grade 3 bleeding (2/39)  Thrombosis (2/39, both asymptomatic pulmonary embolism)  Grade 2 epiphora (3/39), Grade 2 neuropathy (3/39), Grade 2 osteonecrosis of the jaw (6/39) Conclusion • The combination of two mechanistically different antiangiogenic agents thalidomide and bevacizumab with docetaxel result in a high durable response in PSA (87%) with acceptable toxicities. This may represent a novel strategy of improving conventional treatment of metastatic AIPC. • A Phase III, Randomized, Placebo Controlled Trial of Satraplatin and Prednisone vs. Placebo and Prednisone for Patients with Hormone Refractory Prostate Cancer (HRPC) SPARC Satraplatin and Prednisone Against Refractory Cancer Daniel Petrylak, Oliver Sartor, Fred Witjes, Jean-Marc Ferrero, William R. Berry, Alan Koletsky, Silvia Falcon, Faith E. Nathan, Michael E. Petrone, and Cora Sternberg Columbia Presbyterian Medical Center, Dana Farber Cancer institute, Centre Antoine Lacassagne, Boca Ratton Center for Hematology-Oncology, ESSALUD, Radboud University Neijmegen Medical Center, San Camillo Forlanini Hospital, US Oncology And GPC Biotech Satraplatin • Novel oral platinum compound • Acceptable safety profile in >500 patients treated in Phase I and II studies • No cross resistance in taxane or anthracycline resistant cell lines • Satraplatin significantly prolonged PFS for patients with chemotherapy-naïve HRPC in the EORTC trial* *Sternberg CN, Oncology 2005;68:2-9 SPARC: Endpoints Primary • Progression Free Survival (PFS) - 694 PFS events needed to detect HR of 1.3 with 90% power • Overall Survival (OS) - 700 deaths needed to detect HR of 1.3 with 90% power Secondary - Time to Pain Progression (TTP) SPARC: Definition of PFS PFS = Composite endpoint based on first occurrence of • Tumor Progression (RECIST for soft tissue lesions,  2 new lesions on bone scan) • Skeletal Event (fracture, RT, bone surgery, initiation of bisphosphonates) • Symptomatic Progression (increase in PPI* score or analgesic consumption, worsening of ECOG PS, weight loss >10%) • Death SPARC: Study Schema Arm A: Satraplatin 80 mg/m2 d1-5 q 35d Antiemetic 1 mg BID d1-5 q 35d Prednisone 5 mg BID 2:1 Randomization No cross-over to satraplatin Arm B: Placebo 80 mg/m2 d1-5 q 35d Placebo* 1 mg BID d1-5 q 35d Prednisone 5 mg BID • All patients treated until progression, intolerable toxicity or death * Placebo antiemetic SPARC: Progression Free Survival ITT (Per IRC) 100 90 HR: 0.67 (95% CI: 0.57 - 0.77) P = 0.0000003 S+P Median (wks) Satraplatin + Prednisone 80 Survival Probability (%) 70 P 9.7 60 50 40 30 20 10 Placebo + Prednisone 11.1 0 0 10 20 30 40 Weeks 50 60 70 80 90 No. at Risk S 635 363 140 229 63 143 37 90 24 63 11 43 5 24 5 18 12 P 315 1 SPARC: ODAC • • Concerns that much of the Composite PFS was driven by changes in narcotic use Concerns that in a drug with known toxicities that it was not truly blinded • • Concerns that the TTP was not clinically meaningful (although strongly statistically positive) Approval deferred pending final survival data Immunotherapy for Prostate Cancer: What we have learned from Pox Viral vectors Generation of a clinically relevant T-cell anti-tumor immune response • Must overcome tolerance to TAA • Must generate sufficient quantity and quality of tumor specific T-cells Heterologous Prime and Boost Median time to PSA progression: Arm A (FFFF) 9.2 months Arm B (FFFV) 9.1 months Arm C (VFFF) 18.2 months C B A E7897Kaufman et. al., J. Clin Onc 2004, ASCO 2005 T-cell Activation and Costimulatory Molecules Antigen Presenting Cell MHC + Peptide Costimulatory Costimulatory Molecule Molecule T-Cell TCR Ligand Ligand CD28 B7-1 (CD80) ICAM-1 (CD54) LFA-1 LFA-3 (CD58) CD2 (Region 1) None LFA-3 ICAM-1 B7-1 TRICOM T-cell Activation (CPM x 105) Costimulatory Molecule Patient #14 (cohort 1) Pre-Vaccine Post-3 Vaccine (Day 85) Reduction of 2.2 cm R. hilar lymph node to 0.7cm post 3 vaccinations Corresponding with a decrease in PSA from 85  56 Correlation of Immune Response with Clinical Response All 5 patients who had an increase in PSA specific T-cell response of at least 6 fold (range 6.7 to 7.7 fold) had some evidence of clinical benefit. There is a significant difference in the T-cell response of those with evidence of clinical benefit vs. those without evidence of clinical benefit (two-tailed p=0.003, exact Wilcoxon rank sum test). Pt Number Gleason Time on trial 12 mos PSA response None OR 1 3+3 N/A 3 14 15 23 4+3 4+5 3+4 4+4 12 mos 8 mos 34+ mos 24 mos 30-50% 30-50% >50% None 29% >50% N/A N/A Conclusions • Vaccine alone appears to be associated with clinical benefit (PSA declines, disease stabilization and OR) in some patients. • Immune response appears to correlate with evidence of clinical benefit. Conclusions • Perhaps a vaccine alone in advanced disease is not optimal • Can we combine vaccine with other modalities to improve the proportion of patients with clinical benefit? Combination Therapy • Vaccine + EBRT (Gulley et al., Clin Ca Res, 2005) – Can generate immune response – Evidence of immune mediated prostate cell killing – Led to ongoing trial with 153Sm EDTMP +/- vaccine • Vaccine + Docetaxel (Arlen et al., Clin Ca Res, 2006) – No blunting of immune response – Hypothesis generating finding that giving vaccine first may improve outcomes on chemotherapy • Vaccine and ipilimumab Increased Avidity with anti-CTLA-4 Vaccine Modality Precursor Frequency Absolute (/105 cells) rV-CEA 321 Relative ↑ 1X Peptide Concentration (Avidity) Absolute (nM) 510 Relative ↑ 1X rV-CEA TRICOM 769 2.4X 5 102X rV-CEA TRICOM + GM-CSF 1,289 4X 0.6 850X rV-CEA TRICOM + GM-CSF+ Anti-CTLA-4 1,890 5.3X 0.02 25,501X CEA Tg mice Hodge, JI, 2005 Vaccine + anti-CTLA-4 • Eligibility – Patients with metastatic CRPC – No bone pain requiring narcotics – No prior chemotherapy • Design – Phase I safety trial with fixed dose of vaccine with dose escalation of anti-CTLA-4 antibody ipilimumab (1, 3, 5 and 10 mg/kg) NCI# 05-C-0167 PI Gulley Pt DL Max PSA (≥50%) none none none none none none 50%* none 90% (?steroid) 59%* 75%* 93% none none none (stable) none (stable) none too early Not sustained Prior Chemo On Study irSAE PSA Declines • Patient 12 (5 mg/kg dose level) – PSA 383.9  21.6 (94.4% ) 1 2 3 4 5 7 6 10 11 8 9 12 13 14 15 16 17 18 1 mg/kg 1 mg/kg 1 mg/kg 3 mg/kg 3 mg/kg 3 mg/kg 3 mg/kg 3 mg/kg 3 mg/kg 5 mg/kg 5 mg/kg 5 mg/kg 5 mg/kg 5 mg/kg 5 mg/kg 10mg/kg 10mg/kg 10mg/kg * none none Diarrhea Gr 1 none none Diarrhea Gr 2 none none Rash, Colitis, ANC Diarrhea Gr 3 Panhypopit Gr 3 none Panhypopit Gr2 Panhypopit Gr2 Colitis Gr2 none Colitis Gr2 none # of MDX010 Doses 3 3 3 1 3 2 3 3 2 2 2 6 3 2 1 2 1 1 Length on study (mos) 3.7 3.6 3.2 1.6 3.2 1.7 2.9 4 8.8+ 6 6.7 7+ 3.1 3.2 4.3+ 3.2 3+ 1+ 450 400 PSA (ng/mL) 350 300 250 200 150 100 50 0 -2 -1 0 2 6 10 14 18 22 26 30 Weeks on Trial Conclusions • • • • • Pox viral vaccines appear to be very safe Can induce immune responses Can induce clinical responses This vaccine alone for patients with metastatic CRPC may not be optimal Novel Strategies – – – Promising phase I data from giving vaccine combined with anti-CTLA-4 Can be safely combined with cytotoxic therapies (radiation or chemotherapy) and still generate immune responses Clinical endpoint trials of vaccine with other therapies are ongoing or planned General Conclusions • • • • Docetaxel and Prednisone (q3w) remains the standard in patients who have PD after hormonal treatment Several promising combinations are under investigation in an attempt to improve on this regimen Satraplatin awaits final survival data Vaccine strategies appear to have potential