Rationale for Multimodality Therapy for High Risk Localized Prostate Cancer

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1 Rationale for Multimodality Therapy for High Risk Localized Prostate Cancer Cancer Death Rates for Men, US Rate Per 100,000 Lung William K. Oh, M.D. 40 Stomach Colon & rectum Prostate Clinical Director, Lank Center for Genitourinary Oncology Dana-Farber Cancer Institute Associate Professor, Harvard Medical School 20 0 Leukemia Liver Pancreas *Age-adjusted to the 2000 US standard population. Source: US Mortality Public Use Data Tapes , US Mortality Volumes , National Center for Health Statistics, Centers for Disease Control and Prevention, Localized Prostate Cancer is Sometimes a Systemic Disease Cancer Specific Survival Is Poor In High Risk Disease High risk of failure of local therapy alone: Clinical stage T3, T4 PSA > 20 ng/ml Gleason 8-10 High volume Gleason 7 cancer PSA velocity > 2 ng/ml/yr D Amico JCO

2 Local therapy Hormonal therapy NEOADJUVANT CHEMOTHERAPY ADJUVANT CHEMOTHERAPY Why Consider Neoadjuvant Therapy For Patients? Well characterized high risk groups Cytoreduction prior to surgery or RT Control local residual disease Early treatment of micrometastases Chemotherapy Additional Benefits With Neoadjuvant Rx Prior To RP Ability to assess in vivo chemosensitivity Ability to assess molecular determinants of response in pathologic specimens Rapid ability to assess effect of new agents compared with adjuvant trials What Are Appropriate Endpoints For Neoadjuvant Trials? Randomized trials PFS OS Non-randomized trials pcr? PSA declines? Radiologic response? Molecular endpoints? Oh Urol Oncol

3 Paradigm: Locally Advanced Breast Cancer Over 6000 patients accrued to 14 phase II and 6 phase III trials ( ) Clinical response rates 60-90% Clinical CRs 15-30% Pathologic CRs 5-15% (doxorubicin-based) to 25-30% (docetaxel-based) pcr Predicts Enhanced Survival In Breast Cancer Shannon Crit Rev Oncol Hemat 2003 Kuerer JCO 1999 Radiation Therapy Radiation +/- ADT In Locally Advanced Prostate Cancer Study RTOG 8610 RTOG 8531 RTOG 9202 EORTC Control None None 4 mo None Exper 4 mo Lifelong 2 yrs 4 mo 3 yrs Better DFS? Better OS? No No 3

4 Neoadjuvant Chemotherapy + RT Trials 2 studies in 65 and 23 patients Broad definitions of high risk disease RT dose from Gy to 75.6 Gy Estramustine + vinblastine prior to and during RT Increased GI/GU toxicity 5 year freedom from PSA recurrence dependent on clinical stage: 17-49% Khil Cancer J 1997; Zelefsky JCO 2000 Phase III Trial RT +/- ADT for Intermediate Risk Disease 205 patients with PSA> 10 or Gleason >6 Randomized to RT or RT+ 6 months of ADT Median followup 4.5 years PFS and OS survival benefit with ADT D Amico JAMA 2003 Overall Survival Neoadjuvant And Concurrent Chemotherapy With ADT/RT Intermed And High Risk R A N D O M I Z E RT ADT x 6 mo Neoadj and concurrent Docetaxel RT ADT x 6 months n = 350 PI: D Amico Primary Endpoint: 5 yr OS 4

5 Neoadjuvant Leuprolide Does Not Improve 5-Year DFS With RP Radical Prostatectomy Soloway J Urol 2002 Neoadjuvant Docetaxel Prior To Radical Prostatectomy Phase II trial at DFCI Up to 6 months of weekly docetaxel prior to RP in high risk localized prostate cancer Monthly PSA, DRE assessments Endorectal coil MRI at 0, 2, and 6 months Primary endpoint: Pathologic CR Preoperative Chemotherapy Radical Prostatectomy 6 months of Taxotere before surgery Monthly PSA, DRE assessments Prostate MRI at 0, 2, and 6 months Primary endpoint: Complete eradication of cancer from surgical specimen Febbo Clin Cancer Res 2005 Febbo Clin Cancer Res

6 Treatment Response PSA decline > 50% 11/19 patients (58%) Tumor shrinkage > 25% on MRI 13/19 (68%) Complete eradication of cancer 0/16 (0%) Chemo-treated Tumors Have Unique Molecular Signatures Conclusions Neoadjuvant docetaxel is well-tolerated PSA declines >50% are seen in the 2/3 of patients, independent of testosterone Radiographic reduction of tumor seen in 2/3 of patients No evidence of pathologic CRs 6

7 Next Steps For Neoadjuvant Therapy? Randomized trials* Novel therapeutics Immune therapy (GM-VSF, anti-ctla4) Angiogenesis inhibitor (sunitinib +/- LHRH-A) Growth factor receptor inhibitor (imatinib, bortezomib, enzastaurin, temsirolimus) Novel hormonal therapies Chemotherapy combinations CALGB 90203: Neoadjuvant Chemotherapy In High Risk Cancer High Risk <60% PFS n = 750 PI: Eastham R A N D O M I Z E RP ADT x 6 months Docetaxel x 6 cycles Primary Endpoint: 3 yr PFS RP High Risk RTOG 0521 Adjuvant Chemotherapy R A N D O M I Z E ADT x 2 yrs + RT ADT x 2 yrs + RT 6 cycles docetaxel (75 mg/m 2 ) and prednisone starting 1 mo after RT N=600 Primary Endpoint: Overall Survival Neoadjuvant GM-CSF + Thalidomide 24 high risk localized RP patients evaluable GMCSF 250 mg/m2 SQ TIW Thalidomide escalated over 10 days from 100 to 200 mg daily Max 8 weeks therapy prior to RP Grade ½ fatigue 46%, constipation 67%, skin reactions 67% parathesias/dizzy 54%. One DVT Garcia Proc ASCO Prostate

8 PSA Decline After GM-CSF and Thalidomide Persistent Prostatic Androgen Activity Despite Systemic Castration % Change in PSA Clinical trial of neoadjuvant ADT in men with clinically localized prostate cancer (M. Gleave, Vancouver) LHRH agonist + anti-androgen Patients treated for up to 9 months prior to prostatectomy Tissues collected for IHC (TMA) and gene expression analyses (LCM) Individual Patient Mostaghel Cancer Res 2007 Suppression of Prostatic Androgen Activity Is Heterogeneous After Prolonged ADT A. PSA Transcript Abundance (raw microarray data) Rank (of 3,600) Signal Intensity (Max 65,000) B. P= C. 2-4 P= D. P= Preoperative Taxotere + Bevacizumab in High Risk Cancer 0 months 3-6 months >6 months , , , , , , , , ,998 Fold Change (normalized to RPL13A) PSA mo >3-6 mo 0mo NHT 3-6mo NHT >6mo NHT AR mo >3-6 mo P= E. F. PPAP2A mo >3-6 mo P= High Risk Prostate Cancer Taxotere x 18 wks Avastin x 15 wks Surgery (RP) 2-12 FKBP mo >3-6 mo 2-10 MME mo >3-6 mo n = 42 PI: Oh Prostate MRI response 8

9 Neoadjuvant Docetaxel/Bevacizumab Followed by RP 42 high risk localized cancer Median age 55, PSA 10.5, Gleason 8 Docetaxel 75 mg/m2 x 6 cycles Bevacizumab 15 mg/kg x 5 9/23 (39%) evaluable pt had PR by ermri 65% had PSA declines Well tolerated Oh ASCO 2009 PSA Response: Preliminary ermri Response: Preliminary 60% 150% 40% 20% 100% PSA Response 0% -20% -40% % Change Tumor 50% 0% Series % -50% -80% -100% -100% 9

10 Summary: High Risk Localized Prostate Cancer Multi-modality therapy is the key to improving outcome Better systemic agents and combinations Improved understanding of biology and heterogeneity Chemoresistance New targets 10