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Rationale for Radical Prostatectomy for Noncastrate Oligometastatic Prostate Cancer

Rationale for Radical Prostatectomy for Noncastrate Oligometastatic Prostate Cancer. Karim Touijer, MD, MPH, FACS. Attending Surgeon Memorial Sloan-Kettering Cancer Center Professor of Urology Weill Cornell Medical College, New York. Newly diagnosed synchronous M1 prostate cancer

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Rationale for Radical Prostatectomy for Noncastrate Oligometastatic Prostate Cancer

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  1. Rationale for Radical Prostatectomy for Noncastrate Oligometastatic Prostate Cancer Karim Touijer, MD, MPH, FACS. Attending Surgeon Memorial Sloan-Kettering Cancer Center Professor of Urology Weill Cornell Medical College, New York

  2. Newly diagnosed synchronous M1 prostate cancer Decreased incidence in PSA era (60%20%)1 1Wu et al., (2014).Cancer 120(6):818-823.

  3. Standard Treatment is Androgen Deprivation Therapy (ADT) • Newly diagnosed synchronous M1 prostate cancer Results are predictably poor !

  4. Newly diagnosed synchronous M1 prostate cancer is highly lethal • 5 –year disease-specific survival ~ 35% 1 • 5-year overall survival ~ 28% 1 1Wu et al., (2014).Cancer 120(6):818-823.

  5. Systemic Prostate Cancer Treatment in 2015: Multiple Therapies Proven to Prolong Life in Metastatic CRPC are Being Studied in Earlier “Non-Castrate” States Non-castrate Castration resistant Castration Resistant Metastatic Post- Cabazitaxel 2010 Abiraterone 2011 Enzalutamide 2012 Alpharadin 2013 Clinical Metastases: Noncastrate Castration Resistant Metastatic Pre- Provenge 2010 Abiraterone 2012 Alpharadin 2013 Enzalutamide 2014 Clinically Localized Disease Rising PSA Castration Resistant Metastatic 1st-Line Docetaxel 2004 Non- Metastatic CRPC Ipilimumab 2015 Pre-Operative Neo- Adjuvant Post-Operative Adjuvant Modified from Scher and Heller. Urology. 2000.

  6. Radiation Therapy • Systemic Therapy • Docetaxol • Cabazitaxel • Sipuleucel-T • Radium-223 • Abiraterone Acetate • Enzalutamide Surgery Newly Diagnosed Clinical Metastases: Non-Castrate Clinical Metastases: Castrate Death from Disease > Death other causes

  7. Control of the Primary Tumor in Combination with Effective Systemic Therapy in advanced malignancies 1Lancet. 2001;358(9286):966-70 2J Clin Oncol. 2002;20(5):1248-59. 3J Clin Oncol. 2003;21:3737-43

  8. A Survival Benefit for Local Therapy Including Radical Prostatectomy Was Suggested in Men With Documented Stage IV (M1a–c) PCa at Diagnosis in SEER (2004–2010) M1a: Nonregional nodes; M1b: Bone +/- nodes; M1c: Distant Culp SH et al. Eur Urol. 65: 1088, 2014.

  9. Radical Prostatectomy in Patients With Minimal Metastatic Disease A (RP) B (No RP) Number of Patients 23 38 Age 61 (42-69) 64 (47-83) Follow-up(mos) 34.5 (7-75) 47 (28-96) Time to CRPC (mos) 40 (9-65) 29 (16-59) p=0.04 Time to clinical progression (mos) 38.6 26.5 p=0.032 Cancer specific survival 95.6% 84.2% p=0.043 Local surgical palliation 0% 29% Heidenreich et al: J Urol 2014.

  10. Patient selection When the predicted cancer specific mortality risk exceeds 70%, local treatment provides no benefit LöppenbergEurUrol 2016

  11. The Therapeutic Objective To eliminate disease that is incurable by a single modality with a multimodality approach.

  12. Newly Diagnosed Noncastrate Metastatic Prostate Cancer • ADT is standard first line therapy • Results with ADT are predictably poor • 5 new agents with distinct mechanisms of action each shown to prolong survival • Despite great insight into the disease, None were successful at completely halting the disease • Role of Surgical Tx of the primary site remains untested

  13. Androgen Deprivation Therapy Is and Remains the First-Line Standard Systemic Therapy for Metastatic Disease • Overall outcomes are inversely related to disease burden • ADT alone does not eliminate metastatic disease • Systemic therapy alone does not eradicate the primary tumor • Even in the neo-adjuvant setting, prostates removed after up to 8 months of treatment are rarely tumor-free.

  14. MSKCC Pilot Study Objectives • Primary: To assess the safety and feasibility of radical prostatectomy and lymphadenectomy in highly-selected M1 prostate cancer patients with limited metastatic burden and good response to primary therapy • Secondary: Achievement of durable undetectable PSA Touijer, O’Shaunessy, Scher, Scardino. 2015 AUA abstract

  15. Patient selection and multimodal schema • Metastatic burden assessed by whole-body MRI or PET-CT • Androgen deprivation therapy • At least 4 months primary ADT • Surgical management • RP and extended pelvic lymphadenectomy all patients • Bilateral RPLND for patients with retroperitoneal mets >2 cm • Targeted Radiotherapy • 2400-3000 cGy to bone metastasis in some patients

  16. Baseline cohort characteristics (n=20) * 9 bx confirmed bone mets

  17. Details of multimodal disease management

  18. Extended LN Dissection for Advanced PCa In selected patients with pelvic and/or retroperitoneal lymphadenopathy with or without limited bone metastases, we have performed extended LN dissection up to the renal hilum in conjunction with systemic therapy (ADT +/- immunotherapy) and radiation of bone metastases

  19. Outcomes of Surgery

  20. Early oncologic outcomes • Median follow-up = 18.7 months (IQR 10.0, 32.8) Progression= new mets or restart ADT or initiation of chemoTx,

  21. ADT discontinued without evidence of progression

  22. 53 y/o, PSA 6.9, Bx Gl. 9 cT3bN1M1b Solitary bone met (Bx +), • Lupron followed by Abiraterone Acetate (9 months) • PSA 0.07 at RP, pT3bNo (0/24 Ln) Neuroendocrine features • 2700 cGy to pubis • PSA <0.05, Testosterone 596

  23. 58 YO - T3b, N1, M1b Gleason 9 Disease With Bone Metastases Confirmed by Biopsy Radical Prostatectomy Abiraterone – Incomplete T suppression Focal RT CAB On systemic therapy Did this patient benefit from radical surgery? Off systemic therapy 4+ Years – Undetectable PSA

  24. 58 YO - T3a, N1, M1b Gleason 9 Disease With Bone Metastases (Sternum and T Spine) Confirmed by Biopsy PSA Detectable at 2.3 years Radical Prostatectomy CAB RT On systemic therapy Did this patient benefit from radical surgery? Off systemic Therapy 3.5 years

  25. Combining Ipilimumab and Degarelix with RP to Potentially Cure Patients with Metastatic Non-Castrate Prostate Cancer ADT to maximize the apoptotic response: release of tumor antigens: prime cancer-specific T cells Ipilimumab to promote durable anti-tumor responses RP to provide control of the primary tumor site and separately, to further promote antigen release to enhance the immune response

  26. Radiation Therapy to the Primary Site Was Recently Added as ARM H in STAMPEDE Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy Parker et al., Clin Onc 23:318, 2013

  27. PEACE-1 GETUG EORTC: European Phase III Trial of Abiraterone (+/- DOCETAXEL) and Local RXT in patients with de novo metastatic prostate cancer Androgen deprivation therapy (ADT) +/- docetaxel RANDOMIZED ADT + Abiraterone 1000mg Prednisone 5mg BID +/- docetaxel • Patients with newly diagnosed (hormone naïve) metastatic CaP • 916 patients planned Co-primary endpoints: Overall survival and Progression Free Survival ADT + Local radiotherapy +/- docetaxel ADT + Local radiotherapy + Abiraterone-Pred +/- docetaxel Study sponsor: Unicancer Courtesy of K Fizazi

  28. Randomized, Phase II Trial of Best Systemic Therapy or Best Systemic Therapy (BST) Plus Definitive Treatment (Radiation or Surgery) of the Primary Tumor in Metastatic (M1) Prostate Cancer (or Surgery) ADT x 6 months, randomize to continued BST or Local Therapy Primary endpoint is progression-free survival, defined as the time interval from the start of initial best systemic therapy (BST) treatment to the date of disease progression or death, whichever occurred first. http://clinicaltrials.gov/show/NCT01751438.

  29. Radical Prostatectomy in Metastatic Disease 1. Not for everyone but certainly for some. 2. Phase 3 trials are ongoing: MDACC Multicenter: Responders STAMPEDE: ADT + RT 3. The phase 2 presented here enables a promising approaches to be identified rapidly. 4. The results inform the decision to proceed with a definitive trial.

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