1. Karim Touijer, MD, MPH, FACS.
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
Wu et al, 2014 California cancer registry, , primary outcome OS, secondary CSS
1Wu et al., (2014).Cancer 120(6):

3. Standard Treatment is Androgen Deprivation Therapy (ADT)
Newly diagnosed synchronous M1 prostate cancer
Standard Treatment is Androgen Deprivation Therapy (ADT)
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
Wu et al, 2014 California cancer registry, , primary outcome OS, secondary CSS
1Wu et al., (2014).Cancer 120(6):

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
Rising PSA
Castration
Resistant
Metastatic
1st-Line
Docetaxel
2004
Pre-
Provenge
2010
Abiraterone
2012
Alpharadin
2013
Enzalutamide
2014
Clinically
Localized
Disease
Non-
CRPC
Clinical
Metastases:
Noncastrate
Post-
Cabazitaxel
2011
Pre-Operative
Neo-
Adjuvant
Post-Operative
Ipilimumab
2015
Modified from Scher and Heller. Urology

6. Surgery Newly Diagnosed Non-Castrate Radiation Therapy
07/12/09
Radiation Therapy
Systemic Therapy
Docetaxol
Cabazitaxel
Sipuleucel-T
Radium-223
Abiraterone Acetate
Enzalutamide
Surgery
Clinical
Metastases:
Castrate
Newly
Diagnosed
Non-Castrate
Death from Disease > Death other causes

7. Systemic therapy + Surgical control of Primary site
Control of the Primary Tumor in Combination with Effective Systemic Therapy in advanced malignancies
Systemic therapy
Systemic therapy + Surgical control of Primary site
Overall survival
P-value
Renal cell carcinoma1
Interferon-alpha +
Radical nephrectomy
7 vs. 17 mo
0.03
Ovarian cancer2
Platinum
<25% cytoreduction
>75% cytoreduction
22.7 vs mo
0.001
Colon cancer3
5-FU + leucovorin
Aggressive excision/HIPEC
12.6 vs 22.3 mo
RCC: EORTC trial, IFNa + nephrectomy, or IFNa alone
1 Lancet. 2001;358(9286):966-70
2J Clin Oncol. 2002;20(5):
3J Clin Oncol. 2003;21:

8. 5-yr Disease Specific Survival
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) N
5-yr Overall Survival
5-yr Disease Specific Survival
Radical Prostatectomy
245
67.4%
75.8%
Brachytherapy
129
52.6%
61.3%
No Surgery or Radiotherapy
7811
22.5%
48.7%
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
Age (42-69) (47-83)
Follow-up (mos) (7-75) (28-96)
Time to CRPC (mos) (9-65) (16-59) p=0.04
Time to clinical progression (mos) p=0.032
Cancer specific survival % % p=0.043
Local surgical palliation % 29%
MMD: Clinically localized, 3 or fewer bone metastasis, and no visceral disease;
Comparable: Clinical stage, Gleason score, PSA and extent of metastases
Who Respond to ADT Prolongs the Time to CRPC and Clinical Progression, Improves Cancer Specific Survival and Reduces the Need for Local Surgical Palliation
but longer f/u in no RP group and patients were not randomized.
Heidenreich et al: J Urol 2014.

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

11. Patient selection
Löppenberg Eur Urol 2016

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

13. 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

14. 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.

15. 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 AUA abstract

16. 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
cGy to bone metastasis in some patients

17. Baseline cohort characteristics (n=20)
Baseline characteristics
Age, median (years)
61.0
(IQR 55.6, 64.7)
Frequency
Percent
Clinical presentation
Elevated PSA 11
(55%)
LUTS 6
(30%)
Pain 3
(15%)
PSA at diagnosis (ng/mL)
<10 9
(45%)
10-20 4
(20%)
>20 7
(35%)
Gleason grade at diagnosis 5
(25%) 8
9-10
Clinical T stage T1 1
(5%) T2 T3 12
(60%)
Frequency %
Clinical N stage N0 5
(25%) N1 15
(75%)
Site of distant metastasis
Bone only 13
(65%)
RP nodes only 3
(15%)
Bone + RP nodes 4
(20%)
Number of bony metastases* 1 8
(40%) 2
>2
This information is relevant to surgeons. Gives an idea of disease at presentation and resectability
* 9 bx confirmed bone mets

18. Details of multimodal disease management
Androgen Deprivation Therapy
Months
IQR
Duration neoadjuvant ADT, median
3.8
(2.7, 5.3)
Frequency
Percent
Neoadjuvant ADT type
Combined androgen blockade 11
60%
CAB + abiraterone 2
10%
LHRH agonist/antagonist 3
15%
LHRH + abiraterone
None 1 5%
Duration primary ADT (months)
<6
6-9 7
35%
>9
Continuous 9
55%
Surgical Management
Months
IQR
Time to surgery, median
3.9
(3.0, 5.5)
Frequency
Percent
PSA at time of surgery
<0.2 ng/mL 8
40%
>0.2 ng/mL 11
55%
Unknown 1 5%
Surgical procedure
RP+PLND 16
(80%)
RP+PLND+RPLND 4
(20%)
Radiotherapy
Frequency
Percent
Radiotherapy target
Bony metastasis 10
(50%)
Bone and pelvis 4
(20%)
None 6
(30%)
Time to RP median 3.9 mo (IQR 3.0, 5.5), same with radiotherapy; time to surgery duration neoadj ADT separate?

19. 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

20. Outcomes of Surgery Frequency Percent Pathologic outcomes
Extracapsular extension positive 17
85%
Seminal vesicle invasion positive 11
55%
Surgical margin positive 6
30%
Number positive lymph nodes (median 1.0, IQR ) 8
40% 1 4
20% 2 0%
>2
Surgical complications
Any, within 90 days 5%
Urinary continence (no pads)
Continent within 12 months 15
75%
Continent at last follow-up
Local recurrence

21. Early oncologic outcomes
Median follow-up = 18.7 months (IQR 10.0, 32.8)
Frequency
Percent
No evidence of progression 11
55%
Currently on primary ADT 5
ADT discontinued 6
Progression after ADT discontinued
25%
New metastasis 3
Initiation of chemotherapy
Re-initiation of ADT 2
Progression on ADT 4
20% 1 -
Progression= new mets or restart ADT or initiation of chemoTx,

22. ADT discontinued without evidence of progression
Patient
Follow-up from RP (months)
Time since last ADT (months)
Most recent PSA (ng/mL)
Serum T
(ng/dL) 1 9 7
0.95
399 2 16 10
<0.05
119 3 29 23
596 4 12 6
0.68
153 5 44 37
0.15
413
<1
<10
53 y/o, 2700 cGy to pubis, Solitary bone met with pos bone biopsy, neg LN on RP, psa 0.07 at RP, pT3b

23. 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

24. 58 YO - T3b, N1, M1b Gleason 9 Disease With
Bone Metastases Confirmed by Biopsy
Radical
Prostatectomy
Focal RT
Off systemic therapy
4+ Years – Undetectable PSA
CAB
Abiraterone – Incomplete T
suppression
On systemic
therapy
Did this patient benefit from radical surgery?

25. 58 YO - T3a, N1, M1b Gleason 9 Disease With
Bone Metastases (Sternum and T Spine) Confirmed by Biopsy
Off systemic
Therapy
3.5 years RT
Radical
Prostatectomy
CAB
PSA
Detectable
at 2.3 years
On systemic
therapy
Did this patient benefit from radical surgery?

26. 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

27. 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

28. Androgen deprivation therapy (ADT)
PEACE-1 GETUG EORTC: European Phase III Trial of Abiraterone (+/- DOCETAXEL) and Local RXT in patients with de novo metastatic prostate cancer
ADT +
Abiraterone 1000mg
Prednisone 5mg BID
+/- docetaxel
Co-primary endpoints:
Overall survival and Progression Free Survival
Local radiotherapy
R A N D O M I Z E D
Patients with newly diagnosed (hormone naïve) metastatic CaP
916 patients planned
Androgen deprivation therapy (ADT)
+ Abiraterone-Pred
Study 302: Design
Study 302 is a phase 3, randomized, double-blind, placebo-controlled trial of abiraterone acetate plus prednisone in asymptomatic or mildly symptomatic patients with metastatic CRPC who are naïve to chemotherapy
Planned enrollment is for 1000 patients
Patients will be randomized in a 1:1 ratio to receive either abiraterone acetate 1000 mg daily or placebo, and prednisone 10 mg daily
The co-primary end points are a 50% improvement in radiologic progression-free survival and 25% improvement in overall survival
Efficacy assessment in radiologic progression-free survival will utilize sequential imaging studies as suggested by PCWG2 bone scan and modified RECIST criteria (computed tomography/magnetic resonance imaging)
Survival data will be collected throughout the study treatment phase and during follow-up
Secondary end points are time to opiate use for cancer-related pain, time to initiation of cytotoxic chemotherapy, time to deterioration of ECOG performance status ≥ 1 point, time to PSA progression, and presence or absence of TMPRSS2-ERG in primary tumors or CTCs
Study sponsor: Unicancer
Courtesy of K Fizazi 28

29. 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.

30. 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.