Current Chemotherapy for Castration Resistant Prostate Cancer

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1 Current Chemotherapy for Castration Resistant Prostate Cancer Daniel P. Petrylak, MD Professor of Medicine at Columbia University Medical Center/NY Presbyterian Hospital

2 Disclosure Consultant: Sanofi Aventis, Celgene, GPC Biotech, Pfizer, Merck, Millineum, Dendreon Research support: Sanofi Aventis, Celgene, GPC Biotech, Pfizer, Merck, Cell Genysis, Dendreon Team Support: Rangers, Mets, Jets

3 Natural History of Metastatic Prostate Cancer Castration Tumor Volume and Activity Secondary Hormonal Rx Chemo Rx Time

4 Randomize Randomize Docetaxel HRPC Trials TAX N=1006 SWOG N=770 *Warfarin and aspirin 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 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; Petrylak et al. N Engl J Med 2004;351:

5 Overall Survival 100% 80% D+E M+P # at Risk # of Deaths Median in Months % HR: 0.80 (95% CI 0.67, 0.97), p = % 20% 0% Months Petrylak et NEJM 2004

6 Probability of Surviving Overall Survival TAX Median survival Hazard (mos) ratio P-value Combined: D 3 wkly: D wkly: Mitoxantrone Months Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Tannock et al. N Engl J Med 2004:351;

9 Atrasentan A potent, selective ET A receptor antagonist Orally bioavailable Once daily dosing t ½ = 25 hours 1800 x more selective for ET A than ET B ET A binding constant = 34 pm Opgenorth et al, Pharm Exp Ther 1996: 276 Verhaar et al, Br. J Clin Pharm 2000: 562

Endothelin-1 and the Vicious Cycle of Osteoblastic Bone Metastases Adapted from Guise TA, et al. Cancer. 2003 Feb 1;97(3 Suppl):779-84.

10 Endothelin-1 and the Vicious Cycle of Osteoblastic Bone Metastases Adapted from Guise TA, et al. Cancer Feb 1;97(3 Suppl): Copyright 2003 American Cancer Society. This material is used by permission of John Wiley & Sons, Inc. Kopetz ES, et al. Invest New Drugs May;20(2):

11 Phase III Study of Docetaxel + Placebo VS Docetaxel + Atrasentan in Patients with Hormone-Refractory Prostate Cancer (S0421) Stratification: Type of progression PS:0-1 vs 2-3 Prior RP Total ALK-PO4 < 5 vs. 5 XULN Bisphos. R A N D O M I Z E Docetaxel 75 mg/m2 Q3 wks Prednisone 10 mg Placebo Docetaxel 75 mg/m2 Q3 wks Prednisone 10mg Atrasentan 10 mg

12 Phase III Study of Docetaxel + Placebo VS Docetaxel + Atrasentan in Patients with Hormone-Refractory Prostate Cancer (S0421) 706 pts, 4 years of accrual: Power 96% to detect 33% increase in PFS (6 to 8 m) Power 85% to detect 30% increase in MS PRIMARY ENDPOINT NOT MET NO SURVIVAL

13 James et al Proc ECCO 2007 ZD4054 in Prostate Cancer Specific endothelin A antagonist, orally administered 312 patients with androgen independent prostate cancer, randomized against placebo Median survivals were 23.5, 24.5, and 17.3 months for patients treated with 15 mg ZD4054, 10 mg ZD4054, or placebo, respectively

14 ZD4054 Phase III studies ZD4054 vs placebo in CRPC and bone metastases who are pain free or mildly symptomatic. ZD4054 vs placebo in CRPC without metastatic disease Docetaxel/prednisone +/- ZD4054 in patients with sypmtomatic CRPC

15 Ongoing Phase III Studies of ZD4054 Published date : 27 September 2010 AstraZeneca today announced that a study evaluating zibotentan for the treatment of men with metastatic castration resistant prostate cancer (CRPC) did not show a significant improvement in the primary endpoint of overall survival (OS). ZD4054 vs placebo in CRPC without metastatic disease Study 14 was a randomised, placebo controlled phase III study which evaluated zibotentan 10mg added to standard of care treatment in 594 patients with metastatic CRPC. The safety and tolerability profile of zibotentan this trial was line with previous studies. Based on this study result, AstraZeneca plans no regulatory submissions for zibotentan at this time. The zibotentan ENTHUSE trial programme includes two other ongoing studies with zibotentan in different CRPC settings. The full results of study 14 will be published in ZD4054 vs placebo in CRPC with bone metastases and pain-free or mild pain Docetaxel / prednisone +/- ZD4054 in patients with symptomatic CRPC Available at: Trial?itemId= Accessed October 25,

16 Role of Src in prostate tumor cell and osteoclast activities Growth factors Tumor cells Systemic factorslocal factors Osteoclast activity Src Activated osteoclast Src Osteolysis Bone complications Src Direct bone destruction Bone

17 Activity of dasatinib in prostate cancer: inhibition of tumor cells and osteoclast activity through Src Tumor cells Src Dasatinib Growth factors Systemic factorslocal factors Osteoclast activity Dasatinib Src Osteolysis Direct bone destruction Bone

18 Dasatinib: SRC, BCR-ABL, PDGFR, C-KIT TKI Phase II single-agent study in mcrpc PSA Response: 1/47 Yu E Y et al. Clin Cancer Res 2009;15:

19 Dasatinib + Docetaxel Phase I-II study 46 patients with CRPC PSA response was seen in 13/32 (41%) pts, RECIST-evaluable pts: 7 PR + 5 PR (unconfirmed) Bone markers: 12/26 (46%) had a 35% decrease in untx 17/24 (71%) had a decrease in BAP from baseline Phase III study 1500 patients: docetaxel +/- dasatinib Primary endpoint: OS Enrolment ongoing: primary data completion 12/2012 Araujo J, J Clin Oncol, 27:15s (abstr 5061), 2009

20 Ongoing Randomized Phase 3 Trial of Docetaxel +/- Dasatinib Patients Eligibility with metastatic Criteria CRPC Evidence of progression Primary endpoint: Overall survival Stratification factors Performance status R A N D O M I Z E Baseline bisphosphonate use Urine N-telopeptide level N=1,500 Docetaxel 75 mg/m 2 q3w + Dasatinib 100 mg po qd + Prednisone 5 mg po bid Docetaxel 75 mg/m 2 q3w + Placebo po qd + Prednisone 5 mg po bid

Clusterin as a Therapeutic Target for Cancer Expression in human cancer Expressed in kidney, bladder, ovary, lung, colorectal and breast cancers Prostate Cancer Increased expression with higher

21 Clusterin as a Therapeutic Target for Cancer Expression in human cancer Expressed in kidney, bladder, ovary, lung, colorectal and breast cancers Prostate Cancer Increased expression with higher Gleason Grade Increased expression after hormone therapy Overexpression confers resistance to hormone, chemo and radiation therapy in vitro and in vivo Inhibiting clusterin expression increases sensitivity to hormone therapy, radiation therapy and chemotherapy Clusterin increases after Androgen Ablation and in CRPC Steinberg, Clin Cancer Res, 1997; July, Prostate, 2002; Redondo, Am J Path, 2000; Miyake, Urology, 2000; Parczyk, J Can Res Clin Oncol, 1994; July, Mol Can Thera, 2004; Miyake, Can Res, 2000; Miyake Clin Can Res, 2000; Zellweger, Clin Can Res, 2002

OGX-011: Phase 1 Neoadjuvant Study Tissue Levels 7 6 5 4 3 2 1 0

22 OGX-011: Phase 1 Neoadjuvant Study Tissue Levels Dose Chi KN, Clin Cancer Res, 14:833, 2008

= No NHT <2M NHT 40 mg 80 mg 160 mg 320 mg 480 mg 640 mg 8 10 1 3 3 6 6 6

23 Relative % Clusterin mrna OGX-011: Dose Dependent Target Effects Inhibition of Clusterin mrna Inhibition of Clusterin Protein: IHC Score= N = No NHT <2M NHT 40 mg 80 mg 160 mg 320 mg 480 mg 640 mg Inhibition of Clusterin Protein: IHC Score Apoptotic Index Chi KN, Clin Cancer Res, 14:833, 2008

24 Randomized Phase II: Docetaxel +/- OGX-011 for CRPC Variable HR (95% CI) P OGX-DOC DOC PS 0 PS 1 Bone/node only Other metastases 0.50 ( ) ( ) < ( ) 0.01 Chi KN, J Clin Oncol, 28: 4247, 2010

25 SYNERGY Study First-Line Docetaxel +/- OGX-011 (Custirsen) Metastatic CRPC North America, Europe (N=800) 1:1 Custirsen 640 mg IV weekly Docetaxel 75 mg/m² q 3 wk + prednisone Docetaxel 75 mg/m² q 3 wk + prednisone Primary endpoint: Overall survival HR = 0.725, Power 90%, Alpha = 0.05, critical HR = 0.82 Primary data completion date: Dec, 2013 Secondary endpoints: PFS, PSA, patient reported outcomes, serum

26 Evidence for Angiongenesis 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 expressed in epithelial and stromal cells

27 RANDOMIZE 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 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

HR 0.91 (0.78-1.05) P = 0.181 HR 0.77 (0.68-0.88) P < 0.0001 7.5 mo 9.

28 Phase III Trial Comparing Docetaxel + Prednisone With or Without Bevacizumab (CALGB 90401): Survival Endpoints Overall Survival (1 o Endpoint) Progression-Free Survival HR 0.91 ( ) P = HR 0.77 ( ) P < mo 9.9 mo Bevacizumab Placebo n = 524 n = Kelly WK, et al. J Clin Oncol. 2010;28(18s). Abstract LBA 4511.

29 Phase III Trial Comparing Docetaxel + Prednisone With or Without Bevacizumab (CALGB 90401): Secondary Endpoints Clinical Endpoint Bevacizumab (n = 524) Placebo (n = 526) P 50% decline in PSA (95% CI) 69.5% ( ) 57.9% ( ) Objective Response (95% CI) (# with measurable disease) 53.2% ( ) (248) 42.1% ( ) (273) Adverse events > grade 3 (%) Neutropenia Fatigue Febrile neutropenia Hypertension GI hemorrhage GI perforation Mucositis Pneumonitis Thrombosis / embolism Grade 5 adverse event (%)

Multinational, multicenter, double blind, randomized

VENICE Study Design R A N D O M I Z E 1: 1 Taxotere

1hr, day 1, q 3 weeks Disease Progression Safety data

q3w 600 pts + Placebo day 1, q 3 weeks Treatment

30 Multinational, multicenter, double blind, randomized study maipc Stratification factor : ECOG PS (0,1 vs 2) VENICE Study Design R A N D O M I Z E 1: 1 Taxotere plus Pred q3w 600 pts + Aflibercept 6 mg/kg IV, over 1hr, day 1, q 3 weeks Disease Progression Safety data monitored by and DMC (Q 6 months) Taxotere plus Pred q3w 600 pts + Placebo day 1, q 3 weeks Treatment planned until PD, consent withdrawn, or unacceptable toxicity Death 32

31 IMiDs : Novel Thalidomide Analogs Thalidomide Lenalidomide (CC-5013, Revlimid ) CC-4047

32 Structure of Thalidomide and the 2nd-Generation IMiDs

33 Lenolidomide in Endocrine Resistant Prostate Cancer Lenolidomide 25 mg PO QD for 21 days with 7 days rest 19 patient entered 4 patients PSA only disease 8 patients with bone metastases 7 patients with bone/visceral disease Predominant toxicity: Neutropenia (27%) No objective responses seen 6 patients demonstrated PSA declines >50% in 2 patients (12%) Naban et al Proc ASCO GU 2010 Abstract 161

34 Lenalidomide/Docetaxel Clinical Trial Design Open label phase I/II study of docetaxel/revlimid in men with hormone refractory prostate cancer Castrate testosterone with evidence of progressive dieseae by 1 of 3 criteria Rising PSA Progression by CT scan Progression by bone scan

35 Schedule of Administration All patients received prednisone 5 mg PO BID daily and dexamethasone premedication prior to docetaxel Docetaxel administered every 3 weeks Revlimid administered days 1-14

36 Planned Dose Escalation Cohort Docetaxel(mg/m 2 ) Lenalidomide (mg)

37 Table 1. Patient Characteristics Characteristic No. of patients Age, median (range) 70 years (47 85) PSA, median (range) ng/ml ( ) Prior Chemotherapy, n (%) 15 (44) 1 prior chemotherapy 8 2 prior chemotherapies 7 Measurable disease, n (%) 23 (67.6) Required narcotic analgesics, n (%) 8

38 Best response by % change in PSA No prior chemotherapy Prior chemotherapy

39 PSA Declines 15 patients (44.1% ) had a >50% PSA decline 10/18 (56%) with no prior chemotherapy 5/16 (31%) patients with prior chemotherapy 7 additional patients had a >30% decline in PSA Median Duration of Response 285 days (range ) Median TTP all patients 200 days (range ) Chemotherapy naïve 233 days (range ) Previously treated 162 days (range )

40 Adverse Events Adverse Event No. of Patients Dose Level Grade Deep Vein Thrombosis 3 patients L1 L2 L Neuropathy 2 patients L2 L3 3 3 Neutropenia 12 patients L1 (n=2) L2 (n=3) L3 (n=3) L4 (n=2) L5 (n=1) 2 (n=2) 3 (n=3) 2 (n=1) 4 (n=2) L6 (n=1) 3 * In addition there was 1 each of the following events: Grade 3 facial edema, worsening Parkinson s disease, spinal cord compression, and hematemesis

41 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

42 Phase III Trials of Docetaxel Combinations Docetaxel/Pred vs Docetaxel Combined With: Status Results DN-101 Terminated early Negative GVAX Terminated early Negative Bevacizumab Completed Negative VEGF-Trap Maturing Pending Atrasentan Completed Negative ZD4054 Completed Negative Dasatinib On-going Pending Lenalidomide On-going Pending Custersin (OGX-011) Just started Pending To date, no combination improves on docetaxel and pred

43 How Long Should Docetaxel be Continued? Compared PSAWG progression vs clinical progression in men treated with docetaxel/thalidomide/bevicuzimab PSA progression: Median survival=18.6 months Clinical progression=30.5 months Clinical progression preceeded by PSA progression =34.1 months Ning et al Proc ASCO GU 2010 Abstract # 146

44 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 46

45 Primary Endpoint: Overall Survival (ITT Analysis) Proportion of OS (%) Median OS (months) Hazard Ratio 95% CI P-value MP CBZP < Number at risk 0 0 months 6 months 12 months 18 months 24 months 30 months MP CBZP

46 Progression-Free Survival (PFS) Results Proportion of PFS (%) Median PFS (months) Hazard Ratio 95% CI P-value MP <.0001 CBZP PFS composite endpoint: PSA progression, pain progression, tumor progression, symptom deterioration, or death Number at risk 0 0 months 3 months 6 months 9 months 12 months 15 months 18 months 21 months MP CBZP

47 Secondary Endpoints Response Rates and Time to Progression (TTP) MP (n=377) CBZP (n=378) Hazard ratio (95% CI) P-value Tumor assessment Response rate* (%) Median TTP (months) ( ) <.0001 PSA assessment Response rate* (%) Median TTP (months) ( ).0010 Pain assessment Response rate* (%) Median TTP (months) NR ( ).5192 NR: Not reached. *Determined only for subjects with pain or PSA 20 or measurable disease at baseline, respectively. NR=Not reached. 49

48 Most Frequent Grade 3 Treatment-Emergent AEs* Safety Population MP (n=371) CBZP (n=371) All grades (%) Grade 3 (%) All grades (%) Grade 3 (%) Any adverse event Febrile neutropenia Diarrhea Fatigue Asthenia Back pain Nausea Vomiting Hematuria Abdominal pain *Sorted by decreasing frequency of events grade 3 in the CBZP arm. 50

49 On-Study Laboratory Abnormalities Safety Population MP (n=371) CBZP (n=371) All Grades (%) Grade 3 (%) All Grades (%) Grade 3 (%) Hematology Anemia Leukopenia Neutropenia Thrombocytopenia Biochemistry Alkaline Phosphatase ALAT ASAT Hyperbilirubinemia Creatinine

50 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%) 52

51 Cabozantinib: Dual Inhibitor of MET and VEGFR Cabozantinib: TKI that blocks MET and VEGFR in vivo MET and its ligand HGF drive tumor cell invasion & metastasis MET and VEGFR2 synergize to promote angiogenesis Bone metastases are associated with high levels of MET expression: HGF and VEGF direct crosstalk between tumor cells, osteoblasts, and osteoclasts In Prostate Cancer: Preclinically androgen deprivation increases MET expression MET increases with progression and metastasis in bone & lymph nodes

52 Representative Images Baseline Week 12 Baseline Week 12 Baseline Week 12 Baseline Week 12 Docetaxel-pretreated Docetaxel-pretreated Docetaxel-pretreated Docetaxel-naïve Each Patient had PR + Pain Improvement

53 % Change from Baseline Effects SLD % Change in in Measurable Prostate Cancer Subjects Soft Tissue Lesions (N = 151 patients with 1 post-baseline assessment) Docetaxel-Naïve * * * Docetaxel-Pretreated Prior Abiraterone or MDV * * * * * * * -30 * * -50 * % of patients have shown evidence of tumor regression PSA changes did not correlate with radiographic changes

54 Effects on Bone Pain and Narcotic Use Bone metastases and bone pain at baseline Pain improvement at Week 6 or 12 N (%) (67) Narcotics for bone pain at baseline Pain improvement at Week 6 or 12 Evaluable for narcotics change Decrease or discontinuation of narcotics (70) (56) Post hoc investigator survey Limited to patients with 1 post-baseline assessment

55 % Best Change from Baseline Effects on Osteoblast (t-alp) and Osteoclast (CTx) Activity Bisphosphonate-Treated Bisphosphonate-Naïve -100 Serum t-alp -100 Plasma CTx Patients with baseline t-alp levels 2x ULN and 12 weeks of follow up (N = 28) Samples from Week 6 and 12 (N = 118)

56 Proportion Progression-Free by Docetaxel Pretreatment Status (N = 154) Median PFS 1.00 Docetaxel-Naïve (n = 90) Docetaxel-Pretreated (n = 64) 29 weeks 24 weeks Overall median PFS: 29 weeks * Excludes patients randomized to placebo PFS per mrecist (weeks) PFS (95% CI) 70 # Events Docetaxel-naïve (24, NE) 21 Docetaxel-pretreated (18, 33) 25

57 Conclusions Standard of care for first line chemotherapy for CRPC is docetaxel/prednisone Carbaztaxel is the standard of care for second line therapy Phase IIII studies are combining docetaxel with novel targeted agents New agents demonstrate promising activity in castration resistant prostate cancer.

Advances in Chemotherapy for Castration Resistant Prostate Cancer

Advances in Chemotherapy for Castration Resistant Prostate Cancer Daniel P. Petrylak, MD Director, Genitourinary Oncology Co Director, Signal Transduction Program Yale Comprehensive Cancer Center Sequencing