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 CRPC therapy 2010 Metastatic, minimally symptomatic CRPC Symptomatic or poorprognosis CRPC Progression after docetaxel chemotherapy Survival benefit Secondary hormonal Rx Docetaxel Mitoxantrone Best supportive care not known 3 months not known Zoledronic acid with CRPC (metastatic disease)
Sequencing CRPC therapy 2013 Metastatic, minimally symptomatic CRPC Symptomatic or poorprognosis CRPC Progression after docetaxel chemotherapy 2010 Survival benefit Secondary hormonal Rx Docetaxel Mitoxantrone Best supportive care not known 3 months not known 2013 Survival benefit Abiraterone Cabazitaxel Sipuleucel-T Docetaxel acetate 4 months 3 months 4 months 2.5 months MDV3100 4.8 months Denosumab or Zoledronic acid with CRPC (metastatic disease) RAD 223?
Questions for Study Is docetaxel more effective than cabazitaxel? What are the mechanisms of docetaxel resistance? Is it rational to continue combination studies? Does sequence have an effect on docetaxel efficacy and toxicity?
Randomize Randomize Docetaxel HRPC Trials TAX 327 1 N=1006 SWOG 9916 2 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;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
Docetaxel q 3 wk Weekly Docetaxel
Docetaxel Docetaxel
Evidence for Angiongenesis as a Target for Prostate Cancers 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 Imids have single agent activity in castration resistant disease.
VENICE Study Design Multinational, multicenter, double blind, randomized study R A N Docetaxel plus Pred q3w 600 pts + Aflibercept 6 mg/kg IV, over 1hr, day 1, q 3 weeks maipc D Stratification factor : ECOG PS (0,1 vs 2) O M I Z E 1: 1 Disease Progression Docetaxel plus Pred q3w 600 pts + Placebo day 1, q 3 weeks Death Safety data monitored by and DMC (Q 6 months) Treatment planned until PD, consent withdrawn, or unacceptable toxicity Follow up until death 10
Aflibercept (N=612) Placebo (N=612) Stratified HR P value Median OS (mos) (95.6% CI) 22.1 (20.3-24.1) 21.2 (19.6-23.8) 0.94 (0.82-1.08) 0.38 PSA response (%) (95% CI) 68.6 (64.7-72.4) 63.5 (59.5-67.5) 0.075 Time to SRE (mos) (95% CI) PFS (mos) (95% CI) 15.3 (14.1-16.7) 15.0 (13.7-16.4) 0.94 (0.83-1.06) 0.31 6.9 (6.2-7.4) 6.2 (5.6-6.9) 0.94 (0.84-1.06) 0.31 Grade 3-4 AE 76.9% 48.5% AEs leading to discontinuation 43.9% 20.9%
Study Design Chemotherapynaïve patients with progressive metastatic CRPC Randomization Treatment phase 21-day cycles until disease progression LEN+DP Lenalidomide 25 mg on days 1 14 Docetaxel 75 mg/m 2 on day 1 Prednisone 5 mg BID on days 1 21 PBO+DP Placebo on days 1 14 Docetaxel 75 mg/m Stratification factors: 2 on day 1 Prednisone 5 mg BID on days 1 21 ECOG PS score Geographic region Type of disease progression (rising PSA versus tumor progression) Follow-up Up to 5 years Follow-up for survival every 90 days for up to 5 years following study treatment discontinuation Endpoints: Primary: overall survival (OS) Secondary: progression-free survival (PFS); objective response rate; safety DP, docetaxel + placebo; LEN, lenalidomide; PBO, placebo; BID, twice daily; ECOG, Eastern Cooperative Oncology Group; PS, performance status; PSA, prostate-specific antigen. www.esmo2012.org 13
Efficacy Results: Overall Survival PBO+DP Median overall survival: LEN+DP arm: 77 weeks PBO+DP arm: median not reached (P = 0.0017) LEN+DP Hazard ratio: 1.53 (95% CI 1.17 2.00) www.esmo2012.org
Efficacy Results: Progression-free Survival Median progression-free survival: LEN+DP arm: 45 weeks PBO+DP arm: 46 weeks (P = 0.0187) Hazard ratio: 1.32 (95% CI 1.05 1.66) PBO+DP LEN+DP www.esmo2012.org
Treatment Exposure LEN+DP N = 525 PBO+DP N = 521 Median number of cycles (range) 6 (1 30) 8 (1 30) Median relative dose intensity (range) 93.4 (17 105) 96.9 (14 103) Dose reductions, n (%) LEN/PBO 78 (14.9) 41 (7.9) Docetaxel 109 (20.8) 81 (15.5) All dose reductions were due to adverse events, except for 2 dose reductions of docetaxel due to other reasons www.esmo2012.org
Safety Results: Adverse Events Main grade 3 TEAEs, n (%) Hematologic LEN+DP PBO+DP N = 525 N = 521 Neutropenia 114 (21.7) 85 (16.3) Febrile neutropenia 62 (11.8) 24 (4.6) Anemia 33 (6.3) 27 (5.2) Leukopenia 24 (4.6) 18 (3.5) Non-hematologic Fatigue 43 (8.2) 32 (6.1) Diarrhea 37 (7.0) 12 (2.3) Asthenia 29 (5.5) 17 (3.3) Pulmonary embolism 34 (6.5) 8 (1.5) Dyspnea 22 (4.2) 9 (1.7) Pneumonia 24 (4.6) 6 (1.2) TEAEs, treatment-emergent adverse events. www.esmo2012.org
Safety Results: Deaths n (%) Deaths during treatment or 28 days from last LEN/PBO dose LEN+DP PBO+DP P value N = 525 N = 521 18 (3.4) 13 (2.5) 0.467 Death from malignant disease 5 (1.0) 2 (0.4) Death from toxicity 2 (0.4) 1 (0.2) Death because of other cause 11 (2.1) 10 (1.9) Deaths 28 days from last LEN/PBO dose 109 (20.8) 78 (15.0) 0.016 Death from malignant disease 94 (17.9) 72 (13.8) Death because of other cause 13 ( 2.5) 5 ( 1.0) Unknown 2 ( 0.4) 1 ( 0.2) www.esmo2012.org
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
Efficacy Results: Overall Survival Median Overall Survival: LEN + DP: 19.25 mo PBO + DP: median not reached (p=0.0017) Hazard ratio: 1.53 (95% CI 1.17-2.00) www.esmo2012.org 20
100% 80% SWOG S0421: Overall Survival At Risk Docetaxel + Atrasentan 498 Docetaxel + Placebo 496 Deaths 376 368 Median in Months 18 18 2-yr survival 37% 38% 60% 40% 20% 0% 0 At Risk 12 24 36 Months After Registration 48 60 498 338 150 40 496 342 159 35
Baseline Bone Markers have Previously Been Shown to be Prognostic and Response Biomarkers NTX BAP NTX Cook RJ et al. Clin Cancer Res 2006;12:3361-3367. Lipton A et al. Cancer. 2008; 113:193-201.
Figure 3 Serum Markers of Bone Metabolism are Predictive of Atrasentan Benefit in CRPC Patients with the highest bone marker levels (upper 25%ile across all markers, n=47): - Have a very poor prognosis HR = 4.3, p<0.001 - but have a significant survival benefit from atrasentan HR=0.33; interaction p = 0.005 Lara PN et al. ASCO 2012. Abstract 4547.
Phase 3 Trial of Docetaxel +/- Dasatinib Eligibility Criteria Patients with metastatic CRPC Evidence of progression R A N D O M I Z E 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 Primary endpoint: Overall survival Stratification factors Performance status Baseline bisphosphonate use Urine N-telopeptide level
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
Relative % Clusterin mrna OGX-011: Dose Dependent Target Effects Inhibition of Clusterin mrna Inhibition of Clusterin Protein: IHC Score=0 500 400 300 200 100 0 N = No NHT <2M NHT 40 mg 80 mg 160 mg 320 mg 480 mg 640 mg 8 10 1 3 3 6 6 6 Inhibition of Clusterin Protein: IHC Score Apoptotic Index Chi KN, Clin Cancer Res, 14:833, 2008
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 (0.29-0.87) 0.012 0.27 (0.14-0.51) <0.0001 0.45 (0.25-0.79) 0.01 Chi KN, J Clin Oncol, 28: 4247, 2010
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 clusterin, safety
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 Completed Negative Atrasentan Completed Negative ZD4054 Completed Negative Dasatinib Completed Negative Lenalidomide Completed Negative Custersin (OGX-011) On-going Pending To date, no combination improves on docetaxel and pred
Cabazitaxel Pre-Clinical Development Objectives for compound selection: Same potency as docetaxel against sensitive tumor models More potent than docetaxel against tumor models resistant to chemotherapy including docetaxel Screening procedure (~450 derivatives) Activity on tubulin polymerisation as initial screen In vitro activity against tumour cell lines sensitive to docetaxel In vitro activity against docetaxel-resistant tumor cell lines Tumor model developed by Rhone Poulenc induced resistance to docetaxel
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 3
Primary Endpoint: Overall Survival (ITT Analysis) Proportion of OS (%) 100 80 60 Median OS (months) Hazard Ratio 95% CI P-value MP 12.7 0.70 15.1 0.59 0.83 <.0001 CBZP 40 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 3
Subgroup Overall Survival Analysis Factor Hazard ratio (95% CI) f a v o r s C B Z P f a v o r s M P 0 0.5 1 1.5 2 All patients 0.70 (0.59 0.83) ECOG status: 0,1 0.68 (0.57 0.82) ECOG status: 2 0.81 (0.48 1.38) Measurable disease: No 0.72 (0.55 0.93) Measurable disease: Yes 0.68 (0.54 0.85) No. of prior chemo: 1 0.67 (0.55 0.83) No. of prior chemo: 2 0.75 (0.55 1.02) Age: <65 0.81 (0.61 1.08) Age: 65 0.62 (0.50 0.78) Rising PSA: No 0.88 (0.61 1.26) Rising PSA: Yes 0.65 (0.53 0.80) Total docetaxel dose: <225 mg/m² 0.96 (0.49 1.86) Total docetaxel dose: 225 to 450 mg/m² 0.60 (0.43 0.84) Total docetaxel dose: 450 to 675 mg/m² 0.83 (0.60 1.16) Total docetaxel dose: 675 to 900 mg/m² 0.73 (0.48 1.10) Total docetaxel dose: 900 mg/m² 0.51 (0.33 0.79) Progression: During last docetaxel treatment 0.65 (0.47 0.90) Progression: <3 months since last docetaxel dose 0.70 (0.55 0.91) Progression: 3 months since last docetaxel dose 0.75 (0.51 1.11) 0 0.5 1 1.5 2 3
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 88.4 39.4 95.7 57.4 Febrile neutropenia 1.3 1.3 7.5 7.5 Diarrhea 10.5 0.3 46.6 6.2 Fatigue 27.5 3 36.7 4.9 Asthenia 12.4 2.4 20.5 4.6 Back pain 12.1 3 16.2 3.8 Nausea 22.9 0.3 34.2 1.9 Vomiting 10.2 0 22.6 1.9 Hematuria 3.8 0.5 16.7 1.9 Abdominal pain 3.5 0 11.6 1.9 *Sorted by decreasing frequency of events grade 3 in the CBZP arm. 3
On-Study Laboratory Abnormalities Safety Population Hematology MP (n=371) CBZP (n=371) All Grades (%) Grade 3 (%) All Grades (%) Grade 3 (%) 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 3
Taxanes may also be Antiandrogens! Tubulin-Targeting Chemotherapy Impairs Androgen Receptor Activity in Prostate Cancer Meng-Lei Zhu et al. Cancer Res; 70(20); 7992 8002
Goodman et al Proc ASCO 2012
Waterfall plot showing maximum PSA falls after docetaxel administration in patients previously treated with abiraterone acetate. Mezynski J et al. Ann Oncol 2012;annonc.mds119 The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Kaplan Meier plot showing overall survival (A) and time to PSA progression (B). Mezynski J et al. Ann Oncol 2012;annonc.mds119 The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
DOCETAXEL RESISTANT PROSTATE CANCER CELL LINE MODEL DOCETAXEL ADMINISTRATION 10nM 100nM 1000nM DU145 LNCap PC3 22RV1 DU145 22RV1 DU145 22RV1 DU145 22RV1 (Domingo et al In preparation for Publication 2009)
EXPRESSION PROFILING OF CYTOKERATIN AND DEVELOPMENTAL GENES 201596_x_at KRT 18 209008_x_at KRT 8 204602_at DKK1 201650_at KRT 19 201533_at CTNNB1 202443_x_at NOTCH2 214722_at NOTCH2NL 202445_s_at NOTCH2 203237_s_at NOTCH3 206646_at GLI1 210756_s_at NOTCH2 207034_s_at GLI2 212377_s_at NOTCH2 203238_s_at NOTCH3 208522_s_at PTCH1 208057_s_at GLI2 209815_at PTCH1 209816_at PTCH1 Cytokeratins Developmental Transcription Factors
DOCETAXEL RESISTANCE & PROSTATE CANCER STEM CELLS MDR Sensitive Cell Deregulated developmental pathways Stem markers Docetaxel Resistant Cell Epithelial markers Mesenchymal Markers Apoptosis deregulation Cell cycle deregulation (Domingo et al In preparation for Publication 2009)
pck19-gfp PLASMID GENERATION Promoter CK19 GFP 5 UTR 3 UTR (Domingo et al In preparation for Publication 2009)
Tumor Cells Stable Transfected with pck19+gfp Plasmid Dapi GFP Note that a GFP Negative Cell is Present in the Cell Clone
BF FITC MERGE Tumor Cells Stable Transfected with pck19+gfp Plasmid Live Imaging Hours 0 1.5 7 11.5 24 Asymmetric Cell Division & Differentiation
BF FITC Merge Cancer Stem Cells Display a Drug Resistance Phenotype Live Imaging Hours (Docetaxel 10 nm) 0h 12h 24h 36h 48h
% Colonies In vitro effects of Hedgehog and NOTCH inhibition DU145 HLA+ DU145 HLA- 22RV1 HLA+ 22RV1 HLA- 140 120 100 80 60 40 20 0 Control D C CE D + C D + CE D + CE + C Control D C CE D + C D + CE D + C + CE 22RV1 HLA + 22RV1 HLA - DU145 HLA + DU145 HLA -
% Tumours % Tumours In vivo effects of Hedgehog and NOTCH inhibition DU145 22RV1 Control D D + C D + DBZ D + C + DBZ Control D D + C D + DBZ D + C + DBZ 100 90 80 70 60 50 40 30 20 10 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 100 90 80 70 60 50 40 30 20 10 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 weeks weeks Tumour Latency (weeks; Mean ± SD) Tumour Latency (weeks; Mean ± SD) Control D D + C D + DBZ D + C + DBZ Control D D + C D + DBZ D + C + DBZ 5.9±0. 7 6.5±0. 8 7.0±0.7 7.8±0.9 11.0±0.6* 5.4±0. 3 5.5±0. 5 5.8±1.3 6.7±0.5 9.2.0±2.2 *
% Cells HUMAN TUMOR SAMPLES METASTATIC PROSTATE CANCER CKs CKs - CKs + 100 99 98 5 Merge CK18+CK19 4 3 2 1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Patients DAPI TF1
CYTOKERATIN NEGATIVE CELLS ARE ALSO AR NEGATIVE MERGE DAPI AR CKs
Conclusions Further manipulation of docetaxel based chemotherapy is unlikely to provide therapeutic improvements Docetaxel/prednisone is still the standard of care for first line chemotherapy for metastatic disease Markers for drug resistance are being identified.