The Role of the Medical Oncologist in the Treatment of Prostate Cancer Alireza saadat hematologist and oncologist
When should you see an oncologist? High risk localized disease Rising PSA after local therapy Hormone sensitive disease Endocrine Resistant Disease
Natural History of Metastatic Prostate Cancer Castration Tumor Volume and Activity Secondary Hormonal Rx Chemo Rx Time
CASTRATE-SENSITIVE, NON- METASTATIC Rising PSA after primary therapy Biochemical recurrence Stage D0 If prostatectomy, consider XRT PSA doubling time predictor of risk for metastasis PSADT < 12 months Androgen ablation therapy standard of care Data supporting intermittent therapy Clinical trials
Side effects of ADT ADT is associated with a wide range of side effects that can significantly impair quality of life. Loss of lean body mass, increased body fat, and decreased muscle strength. Sexual dysfunction Loss of libido in men receiving GnRH agonists usually develops within the first several months and is followed by erectile dysfunction.
Side effects of ADT Loss of bone mineral density, which can result in bone fracture due to osteoporosis. This effect may be compounded by the presence of bone metastases. Vasomotor instability, which is manifested by hot flashes. Gynecomastia, decreased body hair, and smaller penile and/or testicular size. Fatigue or lack of energy. Behavioral and neurologic effects. Cardiovascular and metabolic abnormalities.
CASTRATE-SENSITIVE, METASTATIC Metastasis typically bone and nodes Wide variation in natural history Depends on extent of osseous mets Presence of visceral mets Grade of tumor PSADT Good risk Time to progression 3-5+ years Poor risk Time to progression 1-3 years Standard of care is AAT Evidence supporting intermittent AAT
CASTRATE-RESISTANT, NON- METASTATIC Defined as rising PSA on LHRH therapy Castrate testosterone level Negative scans No symptoms of disease Variable natural history Time to metastasis 1-3+ years PSADT helpful - < 9 months predicts mets within 2 years Treatment is second-line AAT Antiandrogens Ketoconazole/Zytiga
Castrate Resistant, Metastatic (Pre-Taxotere) Good prognosis (asymptomatic, low volume ) Standard Taxotere chemotherapy Antiandrogens, ketoconazole/zytiga Immunotherapy (Provenge, sipuleucel-t) Investigational therapies Poor prognosis (symptomatic, aggressive) Standard Taxotere chemotherapy Investigational chemotherapy combinations
CASTRATE-RESISTANT, METASTATIC (Post-Taxotere) Jevtana (Cabazitaxel) FDA approved Zytiga (Abiraterone) FDA approved MDV3100 Other emerging drugs
Abiraterone Androgens produced in the testis can cause autocrine/paracrine signaling that results in tumor progression Abiraterone is an orally administered small molecule that irreversibly inhibits the products of the CYP17 gene (including both 17,20-lyase and 17-alpha-hydroxylase). doing so, abiraterone blocks the synthesis of androgens in the tumor as well as in the testis and adrenal glands. Patients treated with abiraterone are at risk for adrenal insufficiency and require concurrent steroid replacement therapy.
Abiraterone abiraterone plus prednisone prolonged overall survival compared with prednisone alone in men who had previously been treated with docetaxel and in those who were chemotherapy naïve. Abiraterone is approved for patients who have metastatic castrate resistant prostate cancer. Abiraterone is generally well tolerated, although fluid retention, hypokalemia and hypertension may require treatment.
Enzalutamide Enzalutamide is an orally administered agent that acts at multiple sites in the androgen receptor signaling pathway, including blocking the binding of androgen to the androgen receptor, inhibition of nuclear translocation of the androgen receptor, and inhibition of the association of the androgen receptor with nuclear DNA. Unlike abiraterone, concurrent treatment with steroids is not required. In a phase III trial in men who had received prior docetaxel - based chemotherapy, enzalutamide significantly increased median survival compared with placebo.
Enzalutamide A second phase III trial is evaluating enzalutamide in chemotherapy naïve patients (NCT01212991). Treatment with enzalutamide has rarely been associated with seizures, and its use is contraindicated in patients with a seizure disorder. Enzalutamide is approved for men with metastatic, castration-resistant prostate cancer who have received treatment with docetaxel. There are no data on the efficacy of enzalutamide in men who have previously been treated with abiraterone.
Sipuleucel-T Sipuleucel-T is a dendritic cell vaccine that is prepared from peripheral blood mononuclear cells obtained by leukapheresis. These cells are exposed ex vivo to a novel recombinant protein immunogen, which consists of prostatic acid phosphatase (PAP) fused to human granulocyte macrophage colony-stimulating factor. These activated cells are then infused back into the patient approximately three days after the original harvesting. In randomized trials, sipuleucel-t prolonged overall survival compared with placebo in men with minimally symptomatic, metastatic prostate cancer.
Sipuleucel-T There are no data on the effectiveness of sipuleucel-t in men whose only evidence of disease is an elevated PSA or in those with symptomatic metastatic disease. Treatment is contraindicated in patients who are on steroids or opioids for cancer-related pain, and should be used with caution in patients with liver metastases. Although sipuleucel-t prolonged overall survival, it did not significantly increase progression-free survival or affect the serum PSA.
Docetaxel HRPC Trials TAX 327 1 N=1006 Randomize Mitoxantrone 12 mg/m 2 Prednisone 10 mg q day Q 21 days up to 10 cycles Docetaxel 30 mg/m 2 /wk Prednisone 10 mg q day 5 on; 1 off x 6 cycles Docetaxel 75 mg/m 2 Prednisone 10 mg q day Q 21 days up to 10 cycles SWOG 9916 2 N=770 *Warfarin and aspirin Randomize Mitoxantrone 12 mg/m 2 Prednisone 5 mg bid Q 21 days Docetaxel 60 mg/m 2 d 2 Estramustine 280 mg d1-5* Dexamethasone 20 mg, tid d 1 & 2 1. Tannock et al. N Engl J Med 2004:351;1502-1512. 2. Petrylak et al. N Engl J Med 2004;351:1513-1520.
Overall Survival 100% 80% D+E M+P # at Risk 338 336 # of Deaths 217 235 Median in Months 18 16 60% HR: 0.80 (95% CI 0.67, 0.97), p = 0.01 40% 20% 0% 0 12 24 36 48 Months Petrylak et NEJM 2004
Overall Survival TAX 327 Probability of Surviving 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Median survival Hazard (mos) ratio P-value Combined: 18.2 0.83 0.03 D 3 wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone 0 6 12 18 24 30 Months Tannock et al. N Engl J Med 2004:351;1502-1512.
Evidence for Angiongenis as a Target for Prostate Cancersis Microvessel density correlates with prognosis in radical prostatetectomy specimens Elevated levels of VEGF correlate with prognosis in CRPCa bfgf expresse in epithelial and stromal cells
CALGB 9040: Randomized Double Blinded Placebo controlled Phase III Trial Comparing Docetaxel + Prednisone with or without Bevacizumab in men with HRPC Eligibility Metastatic PC T <50 ng/ml No prior chemo Adequate hem, renal & liver function Stratification Halabi nomogram RANDOMIZE Arm A Dexamethasone Docetaxel Prednisone Placebo* Arm B Dexamethasone Docetaxel Prednisone Bevacizumab* 8 mg po x 3 doses 75 mg/m 2 on d1 q21d 10 mg po daily IV on day 1 q 21 days 8 mg po x 3 doses 75 mg/m 2 on d1 q 21d 10 mg po daily 15 mg/kg IV on day 1q 21d N = 1020 patients CALGB, ECOG, NCIC
CALGB Study Primary endpoint of improvement in median survival from 19 in docetaxel arm to 23 months in docetaxel/bevizcuzimab arm not met Press Release Roche 2010
Structure of Thalidomide and the 2nd-Generation IMiDs
MAINSAIL TRIAL Screening Metastatic CRPC Chemo-naïve Disease Progression CRPC Patients N= 1,015 Randomize 1:1 Docetaxel/Prednisone + Lenalidomide Until Progression or Toxicity N ~ 500 Docetaxel/Prednisone + Placebo Until Progression or Toxicity N ~ 500 Follow-Up: For Survival For Other Treatments Up to five years
TROPIC: Phase III Registration Study 146 Sites in 26 Countries mcrpc patients who progressed during and after treatment with a docetaxel based regimen (N=755) Stratification factors ECOG PS (0, 1 vs. 2) Measurable vs. non measurable disease cabazitaxel 25 mg/m² q 3 wk + prednisone* for 10 cycles (n=378) *Oral prednisone/prednisolone: 10 mg daily. Primary endpoint: OS Secondary endpoints: Progression free survival (PFS), response rate, and safety mitoxantrone 12 mg/m² q 3 wk + prednisone* for 10 cycles (n=377) Inclusion: Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression 2
Primary Endpoint: Overall Survival Proportion of OS (%) 100 (ITT Analysis) 80 60 40 Median OS (months) Hazard Ratio 95% CI P value MP CBZP 12.7 15.1 0.70 0.59 0.83 <.0001 20 Number at risk 0 0 months 6 months 12 months 18 months 24 months 30 months MP 377 300 188 67 11 1 CBZP 378 321 231 90 28 4 2
On-Study Laboratory Abnormalities Safety Population MP (n=371) CBZP (n=371) All Grades (%) Grade 3 (%) All Grades (%) Grade 3 (%) Hematology Anemia 81.4 4.9 97.3 10.5 Leukopenia 92.5 42.3 95.7 68.2 Neutropenia 87.6 58.0 93.5 81.7 Thrombocytopenia 43.1 1.6 47.4 4.0 Biochemistry Alkaline Phosphatase 57.7 9.7 53.6 7.3 ALAT 18.9 0.3 25.9 1.1 ASAT 28.0 0.5 27.8 0.8 Hyperbilirubinemia 4.6 0.8 3.8 0.5 Creatinine 11.6 0.5 15.6 1.3 2
Total Deaths During Study Safety Population MP (n=371) CBZP (n=371) Total deaths during study 275 (74.1%) 227 (61.2%) Due to progression 253 (68.2%) 197 (53.1%) Due to AEs 7 (1.9%) 18 (4.9%) Due to other reasons 15 (4.0%) 12 (3.2%) 3
APPENDICULAR AND AXIAL METASTASIS
Skeletal-Related Events Pathologic fracture Spinal cord compression/vertebral body collapse Radiation or surgery to bone Change in antineoplastic therapy
Bone Metastases Can Have Serious Consequences
The Cycle of Bone Destruction: Osteoblastic Effects
SKELETAL RELATED EVENTS SRE Fracture, need for XRT, cord compression, pain, hypercalcemia Zometa (Zoledronic acid) Potent bisphosphonate given IV every 3-4 weeks Inhibits osteoclasts 35% reduction in SREs, postponement to time to first SRE Side-effects (nephrotoxicity, ONJ, flu-like symptoms) Xgeva (Denosumab) Rank ligand inhibitor (osteoclast inhibitor) given SQ every 3-4 weeks Slightly better reduction in SREs and time to first SRE than zometa Side-effects (hypocalcemia, ONJ) Both FDA-approved for castrate-resistant, bone mets ASCO no superiority of either drug
Zometa 039: Skeletal-Related Event (SRE) Prevention Study Bone metastases with progressive disease after ADT (N=639) Randomize Standard Care + ZOMETA Standard Care + Placebo Endpoint: SRE
Proportion of Patients With SRE (-HCM) at Month 15 by Treatment (Intent-to-Treat Patients) 0.8 0.7 0.6 Proportion of Patients With SRE 0.5 0.4 0.3 38% * 34% 45% 0.2 0.1 0 ZOMETA 8/4 mg ZOMETA 4 mg Placebo *P<.05 vs placebo
Time to First SRE ( HCM) by Treatment % Patients Without the Event ZOMETA 4 mg Median Time, Days* NR 110 100 90 80 70 60 50 40 30 20 10 0 Placebo 321 0 50 100 150 200 250 300 350 400 450 500 550 Time After the Start of Study Drug (Days) *P=.011 ZOMETA 4 mg vs placebo
Study Design: International, Randomized, Double- Blind, Active-Controlled Study Key Inclusion Hormone-refractory (castration resistant) prostate cancer and bone metastases Key Exclusion Current or prior IV bisphosphonate treatment Denosumab 120 mg SC and Placebo IV* every 4 weeks (N = 950) Zoledronic acid 4 mg IV* and Placebo SC every 4 weeks (N = 951) Calcium and Vitamin D supplemented in both treatment groups Accrual period from May 2006 to December 2008 Analysis cut-off date October 2009 *Per protocol and Zometa label, IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine. No SC dose adjustments made due to increased serum creatinine.
Time to First On-Study SRE Proportion of Subjects Without SRE 1.00 0.75 0.50 0.25 0 HR 0.82 (95% CI: 0.71, 0.95) P = 0.0002 (Non-inferiority) P = 0.008 (Superiority) Denosumab Zoledronic acid KM Estimate of Median Months 20.7 17.1 18% Risk Reduction 0 3 6 9 12 15 18 21 24 27 Study Month Subjects at risk: Zoledronic Acid 951 733 544 407 299 207 140 93 64 47 Denosumab 950 758 582 472 361 259 168 115 70 39
Ligand activated androgen receptor signaling remains a driver in CRPC Hypothesis: Hormone-refractory prostate cancer (HRPC) frequently remains driven by a ligand-activated androgen receptor (AR). This disease is not truly hormone refractory
Biological evidence for a continued hormone driver in CRPC High intratumoral androgens despite castration Castration resistance: AR amplification/ mutations in CRPC increase AR activity AR mrna expression alone resistance in isogenic lines Aberrant activation of the androgen receptor
Abiraterone Clinical Trials Abiraterone vs placbo in patients with CRPC prior to docetaxel Abiraterone/prednisone vs placebo/prednisone in CPRC patients post chemotherapy. Close to accrual
AFFIRM Phase 3 Registration Trial of MDV3100 in Post-Chemotherapy CRPC Patients 2 MDV3100 240 mg QD R 1 Placebo QD Primary Endpoint: 25% survival increase (12 to 15 months) Sample size: ~1170 (780 and 390) Statistics: 85% Power; p=0.05, two-sided Biomarkers: CTC enumeration and profiling with outcome Scher, H. (North America) and De Bono, J. Co-PI, Medivation
Conclusions Standard of care for CRPCA is docetaxel/prednisone Novel phase IIII studies are combining docetaxel with novel targeted agents Carbazitaxel is approved as a second line therapy for castration resistant prostate cancer New biological approaches are being evaluated in the second line setting
Prostate Cancer The Future Immunotherapy or Vaccine therapy Provenge GVAX Others in development Satraplatin-an oral chemotherapy agent Targeted agents such as erlotinib, bevacizumab
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PATIENT CASE A 68 yo man had T3, PSA 15, grade 8 cancer and underwent XRT and 2 years ADT with PSA going to undetectable. One year after completing ADT, his PSA begins to rise and reaches 2.5 ng/dl in 12 months. He is anxious but asymptomatic. What term is used to describe his prostate cancer? What assessment should be done? a) Serum testosterone level b) Calculate PSA doubling time C) Bone scan d) CT ab/pelvis/cxr e) All the above (correct answer)
Testosterone level is normal at 190. PSADT is ~6 months. Bone scan and CT scans do not show obvious mets. What are the correct treatment options? a) Continued monitoring with PSA q 3 months b) Repeat XRT to prostate c) LHRH agonist given continuously or intermittently d) Taxotere chemotherapy e) Casodex alone
Lupron is started every 3 months. PSA falls to 0.4 after 6 months but then rises to 5.5 over next 9 months. Repeat bone scan shows 4 new osseous lesions in the pelvis and spine c/w mets. CT shows enlarged pelvic nodes. He remains asymptomatic other than hot flashes. What term is used to describe his prostate cancer? What are the correct treatment options? a) Taxotere chemotherapy b) Add casodex 50 mg/d c)zytiga d)provenge e) Start zometa or xgeva f) b and e (correct)
Casodex is added to Lupron. Zometa is started monthly. PSA continues to rise. He reports mild low back pain relieved with advil. What are the correct treatment options? a) Another antiandrogen b) Ketoconazole c) Provenge d) Taxotere chemotherapy e)zytiga f) b or c (correct)
The pt undergoes treatment with Provenge which is well-tolerated. His PSA continues to rise rapidly. His back pain worsens and is requiring hydrocodone for relief. Scans show 4 new osseous lesions and larger nodes. CT shows new left hydronephrosis. What are the correct treatment options? a) Referral to Urologist for management of hydro b) XRT to L-spine c)taxotere d)all the above (correct)
Urologist stents left ureter. He receives XRT to L- spine with good palliation of pain. He is then treated with Taxotere for 8 cycles with a 50% drop in his PSA. Treatment stopped due to worsening fatigue. His PSA begins to increase within the next 6-7 months. Repeat scans show 3 new bone lesions. What are the correct treatment options? a) Repeat Taxotere b) Jevtana (Cabazitaxel) c)zytiga (Abiraterone) d)investigational drug e)all the above (correct answer)
Questions Prostate cancer after hormone ablation is A) Still hormone responsive B) Does not respond to chemotherapy C) Spreads to the bone in 90% of pateints D) A and C
Question 2 A significant complication of treatments targeting bone (bisphosphophonates and denosamab) is A) Osteonecrosis of the jaw B) Hand foot syndrome C) Rash D) Diarrhea