Treatment Options for Docetaxel refractory patients Winston W

Treatment Options for Docetaxel refractory patients Winston W Tan MD FACP Senior Consultant Hematology/Oncology Genitourinary Oncology Mayo Clinic College of Medicine

Learning Objectives • Describe the mechanisms by which androgen receptor signaling affects prostate cancer growth despite castrate levels of testosterone • Summarize therapeutic options for castration-resistant prostate cancer (CRPC), including the role of chemotherapy, and emerging therapies • Apply clinical evidence for best treatment strategies in CRPC to improve patient care

S 9364: Nadir PSA Level Predicts Survival in Patients With Metastatic Disease Treated With Primary ADT Hussain M, et al. J Clin Oncol. 2006; 24: 3984 -3990; with permission.

CRPC: Evolving Paradigm • Androgen receptor (AR) signaling is a key factor in prostate cancer growth despite castrate serum levels of testosterone – Caused by a number of different factors: • • • Receptor overexpression/amplification AR mutations Increased AR ligand expression AR coactivators Ligand-independent AR activation • AR signaling leads to tumor growth and proliferation despite castrate androgen levels Gelmann EP. J Clin Oncol. 2002; 20: 3001 -3015.

CRPC: Evolving Paradigm • CRPC: A working definition – Evidence of PSA and/or radiographic disease progression in the setting of castrate levels of testosterone (≤ 50 ng/d. L)

Chemotherapy for AIPC • Mitoxantrone combined with prednisone is palliative with a median survival of 10 -12 months • Phase I/II studies show a trend towards improved median survival with the combination of Estramustine/Docetaxel >Time to progression 5 -6 months >Median survival 20 -23 months Petrylak et al. Semin Onc. 1999; 26(Suppl 17): 28 -33. Savarese et al. JCO. 2001; 19: 2509 -2516. Petrylak et al. Eur Urol Suppl. 2002; 1: 15 -23.

Management of Metastatic CRPC: Chemotherapy • The standard of care for CRPC changed from mitoxantrone/prednisone to docetaxel/prednisone based on SWOG 99 -16 and TAX-327 studies 1, 2 SWOG 99 -161 N=770 - Mitoxantrone 12 mg/m 2; Day 1 - Prednisone 5 mg BID; 21 -day cycles Randomized - Prednisone 10 mg QD - Mitoxantrone 12 mg/m 2 every 3 wks; every 21 days up to 10 cycles TAX-3272 N=1006 - Docetaxel 60 mg/m 2 ; Day 2 + dexamethasone 20 mg TID; Days 1– 2 - Estramustine 280 mg TID; Days 1– 5 of 21 -day cycles Randomized 1. Petrylak DP, et al. N Engl J Med. 2004; 351: 1513 -1520. 2. Tannock TF, et al. N Engl J Med. 2004; 351: 1502 -1512. - Prednisone 10 mg QD - Docetaxel 30 mg/m 2 weekly; 5 wks on, 1 wk off × 6 cycles - Prednisone 10 mg QD - Docetaxel 75 mg/m 2 every 3 wks

Management of Metastatic CRPC: Chemotherapy • SWOG 99 -16 – Docetaxel/estramustine improved median survival by 2 months compared with mitoxantrone/prednisone HR: 0. 80 Petrylak DP, et al. N Engl J Med. 2004; 351: 1513 -1520; with permission.

Management of Metastatic CRPC: Chemotherapy (TAX-327) • Docetaxel therapy led to improved survival and rates of response in terms of pain, PSA level, and quality of life compared with mitoxantrone/prednisone HR: 0. 83, P=0. 03 Tannock TF, et al. N Engl J Med. 2004; 351: 1502 -1512; with permission.

Management of Metastatic CRPC: Chemotherapy • Long-term follow-up of TAX-327: – 310 additional deaths at 5 years Median survival Difference in survival Patient survival >3 years D 3 P D 1 P M+P 19. 2 months 17. 8 months 16. 3 months P=0. 004 18. 6% P=0. 004 16. 8% 13. 5% D 3 P=docetaxel every 3 weeks; D 1 P=weekly docetaxel; M+P=mitoxantrone/prednisone therapy. Berthold DR, et al. J Clin Oncol. 2008; 26: 242 -245.

AR-Targeting Therapies: Abiraterone Acetate • • Inhibits the CYP 17 (17α-hydroxylase and C 17, 20 -lyase) dual enzyme complex, which is principally responsible for androgen synthesis Results in PSA decline, tumor response, and improvements in ECOG performance scores Tumor Response: Partial Response Tumor Response: Stable Disease ECOG PS Improvement ≥ 1 level Patient Population N PSA Decline ≥ 50% CRPC, chemotherapy naive 1 33 24 (73%) 9 (27%) 19 (58%) 8 (61. 5%) CRPC, prior docetaxel 2 47 24 (51%) 6 (13%) 25 (53%) 11 (35%) CRPC, prior docetaxel 3 58 45% 39 (64%) – 16 (50%), n=32 ECOG PS, Eastern Cooperative Oncology Group Performance Status 1. Ryan C, et al. J Clin Oncol. 2009; 27(suppl): 245 s (abstract 5046). 2. Reid AH, et al. J Clin Oncol. 2009; 27(suppl): 246 s (abstract 5047). 3. Danila DC, et al. J Clin Oncol. 2009; 27(suppl): 246 s (abstract 5048).

AR-Targeting Therapies: MDV 3100 • Novel small-molecule AR antagonist • Binds the AR with greater relative affinity than the clinically used antiandrogen bicalutamide • Reduces the efficiency of its nuclear translocation and impairs both DNA binding to androgen response elements and recruitment of coactivators • Results of recent phase I/II study: – PSA declines of >50% observed in 43% of CRPC patients • Phase III trial in the post-docetaxel setting ongoing Scher HI, et al. Lancet Oncology. 2010; 375: 1437 -1446.

AR-Targeting Therapies: BMS-641988 • Hypothesized to slow growth of prostate cancer by blocking action of androgens • Found to have superior potency and efficacy compared with bicalutamide 1 • Found to promote an expression profile more similar to castration than bicalutamide 1 • Awaiting data from 2 completed Phase I trials for CRPC – Randomized multicenter dose-escalation study (United States)2 – Nonrandomized multicenter, open-label study (Japan)3 1. Attar RM, et al. Proc Amer Assoc Cancer Res. 2006; 47: Abstract 5345. 2. Clinical Trials. gov. www. clinicaltrials. gov/ct 2/show/NCT 00326586. 3. Clinical Trials. gov. www. clinicaltrials. gov/ct 2/show/NCT 00644488.

Management of Metastatic CRPC: Docetaxel-Refractory Patients • No standard of care • Salvage chemotherapeutic regimens include: – Mitoxantrone and/or ixabepilone plus prednisone 1 -3 – Carboplatin plus docetaxel 4, 5 1. Thomas C, et al. Urologe A. 2009; 48: 1070 -1074. 2. Rosenberg JE, et al. Cancer. 2007; 110: 566 -563. 3. Rosenberg JE, et al. J Clin Oncol. 2009; 27: 2772 -2778. 4. Reuter CW, et al. World J Urol. 2010; Mar 14 [Epub ahead of print] 5. Ross RW, et al. Cancer. 2008; 112: 521 -526.

Management of Metastatic CRPC: Docetaxel-Refractory Patients • Mitoxantrone or ixabepilone plus prednisone MP=mitoxantrone/prednisone. Rosenberg JE, et al. Cancer. 2007; 110: 566 -563; with permission.

Management of Metastatic CRPC: Docetaxel-Refractory Patients • Carboplatin/docetaxel therapy – Recent data suggest that platinum salts may be effective when combined with taxanes (docetaxel) Progression-free survival Ross RW, et al. Cancer. 2008; 112: 521 -526; with permission. Overall survival

Management of Metastatic CRPC: Docetaxel-Refractory Patients • Cabazitaxel – Novel taxane that appears to be active in docetaxelresistant tumor cell lines – Evaluated in the phase III TROPIC study • Median survival cabazitaxel treatment group vs mitoxantrone treatment group • Improved progression-free survival and tumor response rates Sartor AO, et al. [Abstract No. 9]. 2010 Genitourinary Cancers Symposium; San Francisco, CA.

TROPIC: Phase III Registration Study m. CRPC 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) mitoxantrone 12 mg/m² q 3 wk + prednisone* for 10 cycles (n=377) *Oral prednisone/prednisolone: 10 mg daily. Inclusion: Patients with measurable Primary endpoint: OS Secondary endpoints: Progression-free disease must have progressed by survival (PFS), response rate, and safety RECIST; otherwise must have had new lesions or PSA progression Sartor AO, et al. Presented at the 2010 Genitourinary Cancers Symposium. March 5 -7, 2010; San Francisco, CA.

TROPIC Primary Endpoint: Overall Survival (Intent-to-Treat Analysis) Proportion of OS (%) MP 12. 7 Median OS (months) Hazard Ratio 95% CI P Value Number at risk MP CBZP 15. 1 0. 70 0. 59– 0. 83 <. 0001 377 300 188 67 11 1 CBZP 378 321 231 90 28 4 Approved by FDA: June 2010 Sartor AO, et al. Presented at the 2010 Genitourinary Cancers Symposium. March 5 -7, 2010; San Francisco, CA.

Management of CRPC: Docetaxel-Refractory Patients • Conclusions from the TROPIC trial – Cabazitaxel demonstrated a statistically and clinically significant overall survival improvement compared with mitoxantrone • 30% risk reduction of death (HR = 0. 70, P<. 0001) • Median overall survival improvement in favor of cabazitaxel – Benefit was consistent across subgroups – Progression-free survival, relative risk, and time to progression were also significantly improved – Safety profile was predictable and manageable • Neutropenia, diarrhea, fatigue and asthenia were the most common adverse events Sartor AO, et al. Presented at the 2010 Genitourinary Cancers Symposium. March 5 -7, 2010; San Francisco, CA.

Docetaxel in Novel Combination Regimens for HRPC • • Docetaxel + Thalidomide Docetaxel + Calcitriol (Vitamin D) Docetaxel / Estramustine + Herceptin Docetaxel + Exisulind

Satraplatin • • • Second line 950 patients Satraplatin/prednisone vs prednisone 40% decrease in TTP 9. 7 vs 11 weeks TTP • Petrylak et al ASCO (prostate) 2007

Satraplatin • • • Satraplatin is an orally active platinum compound that has significant activity in cisplatin-resistant tumor models. Activity in prostate cancer was suggested in early clinical studies. Satraplatin was evaluated more extensively in a phase III trial, in which 950 men who had progressed after first-line chemotherapy for castrate-resistant prostate cancer (51 percent of whom had been treated with docetaxel) were randomly assigned to prednisone plus either satraplatin (80 mg/m 2 for five days every five weeks) or placebo. Final results of this trial were presented at the American Society of Clinical Oncology (ASCO) meetings in 2008. Progression-free survival (PFS) was significantly increased in patients assigned to satraplatin compared to placebo (one-year PFS rate 17 versus 7 percent, median PFS 11. 1 versus 9. 7 weeks, hazard ratio [HR] 0. 67, 95% CI 0. 57 -0. 77). There was no difference in overall survival (61 weeks on both treatment arms, HR 0. 95, 95% CI 0. 84 -1. 15). Treatment was generally well tolerated, with myelosuppression being the major cause of grade 3 or 4 adverse events (neutropenia, thrombocytopenia, and anemia in 22, 23, and 12 percent of satraplatintreated patients, respectively).

Antiangiogenic Agents: Bevacizumab • CALGB 90401 – Phase III trial comparing docetaxel/prednisone with or without bevacizumab in hormone-resistant prostate cancer 1 - Hormone refractory prostate cancer - Metastatic disease -Testosterone <50 ng/m. L - No prior chemotherapy Every 3 weeks: Docetaxel: 75 mg/m 2 IV on Day 1 + Prednisone: 5 mg BID PO on Days 1 -21 + placebo IV on Day 1 N=1020 Every 3 weeks: Docetaxel: 75 mg/m 2 IV on Day 1 + Prednisone: 5 mg BID PO on Days 1 -21 + Bevacizumab: 15 mg/kg IV on Day 1 – Preliminary data suggest that this trial did not reach its primary endpoint of overall survival 2 • Data to be presented at the 2010 American Society of Clinical Oncology (ASCO) annual meeting, June 4 to 8, 2010. 1. Clinicaltrials. gov. www. clinicaltrials. gov/ct 2/show/NCT 00110214. 2. Kelly WK, et al. J Clin Oncol. 2010; 28: 7 s (Abstract LBA 4511).

Antiangiogenic Agents: Sunitinib • Tyrosine kinase inhibitor currently approved for renal cell carcinoma and gastrointestinal tumors • Several trials of sunitinib in CRPC: Author Patients Dror Michaelson M, et al. 20091 Sonpavde G, et al. 20102 Outcomes CRPC Group A (n=17): chemotherapy-naïve Group B (n=17): docetaxel-resistant -1 confirmed PSA response in each group - 8 and 7 men had stable PSA (week 12) in groups A and B, respectively - Improvements on radiographic imaging in the absence of post-treatment PSA declines Metastatic CRPC (post-docetaxel progression) - N=36 - 12. 1% had ≥ 50% decline in PSA - 21. 2% had ≥ 30% decline in PSA - 44% demonstrated improvements on imaging - 13. 6% reported declines in pain scores ≥ 2 points 1. Dror Michaelson M, et al. Ann Oncol. 2009; 20: 913 -920. 2. Sonpavde G, et al. Ann Oncol. 2010; 21: 319 -324.

Bone-Targeting Therapies: ZD 4054 • Endothelin-A receptor antagonist • Recent multinational phase II trial in metastatic CRPC 1 – Primary endpoint of time to progression not achieved – Improvement in overall survival observed in both treatment arms Time to progression Placebo (n=107) ZD 4054 10 mg (n=107) ZD 4054 15 mg (n=98) 3. 7 4. 6 3. 8 0. 553 0. 702 24. 5 23. 5 0. 008 0. 052 3. 7 2. 9 0. 743 0. 273 P value Overall survival 17. 3 P value Time to PSA progression 2. 8 P value • Second phase II trial in metastatic CRPC currently underway 2 1. James ND, et al. Eur Urol. 2009; 55: 1112 -1123. 2. Clinicaltrials. gov. www. clinicaltrials. gov/ct 2/show/NCT 01000948.

Bone-Targeting Therapies: Denosumab • • • Monoclonal antibody that acts against receptor activator of nuclear factorκB ligand to improve bone mineral density and fractures Useful in CRPC, as ADT is associated with bone loss and increased risk for fracture Recent study in men receiving ADT for prostate cancer 1 New Fracture (%) Cumulative Incidence of New Vertebral Fracture • 3. 9 3. 3 1. 9 0. 3 1. 0 1. 5 Current phase III trial underway in non-metastatic CRPC patients undergoing ADT 2 1. Smith MR, et al. N Engl J Med. 2009; 361: 745 -755. 2. Clinicaltrials. gov. www, clinicaltrials. gov/ct 2/show/NCT 00838201.

Immunomodulatory Therapies: Lenalidomide • Highly potent immunomodulatory derivative of thalidomide • Potentiates the action of paclitaxel in vitro against prostate cancer cell lines in co-culture with mononuclear cells • Phase I study in metastatic CRPC patients: – Combined with weekly paclitaxel – PSA declines by >50% in 2 of 7 evaluable patients – Frequent dose-limiting toxicity Mathew P, et al. Cancer Chemother Pharmacol. 2010; 65: 811 -815.

Management of Metastatic CRPC: Integrating Novel Therapeutics • Current therapeutic paradigm – Second-line hormonal therapy – Docetaxel-based chemotherapy – Retreatment with docetaxel, mitoxantrone, investigational therapy, supportive care

Custersin studies • Phase III of docetaxel vs docetaxel plus custerin docetaxel after initial response and then on progression is randomized in patient with castrate resistant prostate cancer with metastasis with symptomatic pain • Phase III first line same arms

MDV Phase III studies • Phase III AFFIRM study MDV 3100 vs placebo in patients who have progressed on docetaxel • Phase III study on chemotherapy naïve patients also being studied

Summary • Metastatic CRPC management will likely evolve over the next 12– 24 months with the introduction of novel agents, including ARtargeting agents and new chemotherapies • Introduction of new agents will challenge the clinical research community to design and conduct studies that bring some clarity into optimal use/sequence of these agents

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