1. Circulating Tumor Cell Number as an Early Response Endpoint for Metastatic Prostate Cancer
Howard I. Scher, MD, Robert McCormack, MD, Arturo Molina, MD*, Matthew R. Smith, MD, Robert Dreicer, MD, Fred Saad, MD, Ronald de Wit, MD, Dana T. Aftab, MD,
Ana Limon-Carrera, MD, Karim Fizazi, MD, PhD, Martin Fleisher, PhD,
Johann S. de Bono, MB ChB, PhD, Gary Kelloff, MD, Glenn Heller, PhD
February 14, 2019
Presented by: Howard I. Scher, MD

2. Disclosures
Consultant: Amgen (U), ESSA Pharma Inc (U), Janssen (U), Menarini Silicon Biosystems (U), Sanofi Aventis (U), WCG Oncology (C)
Grant/Research support to MSK: EPIC Sciences, Illumina, Inc, Innocrin Pharma, Menarini Silicon Biosystems, ThermoFisher
Board of Directors: Asterias Biotherapeutics
Travel reimbursement:
Amgen, Janssen, Sanofi Aventis, Menarini Silicon Biosystems
U = Uncompensated

3. The Number, Range and Type of Effective Treatment Options for Castration Resistant Prostate Cancer Continues to Increased Dramatically
FIX BOX
Presented by: Howard I. Scher, MD

4. The Majority of the Drug Approvals Were Based on Time to Event Endpoints That Occur Late
Response:
Early
Time To Event:
Late
Skeletal Related or Symptomatic Skeletal Related Events
Zoledronic acid (SRE)
Denosumab (SRE)
Alpharadin (Shown) (SSE)
Metastasis-free survival
Apalutamide
Death / Survival
Docetaxel
Sipuleucel-T
Cabazitaxel
Abiraterone
Enzalutamide
Alpharadin
Pembrolizumab
Presented by: Howard I. Scher, MD

5. With the Exception of the Control of Pain, No Approvals Were Based on a Favorable Change in a Disease Manifestation
Response:
Early
Time to Event:
Late
Control of Pain or Indicated for Symptomatic Patients
Radiopharmaceuticals
Mitoxantrone + prednisone - ? docetaxel
Alpharadin (used for patients with symptomatic osseous disease)
Skeletal Related or Symptomatic Skeletal Related Events
Zoledronic acid (SRE)
Denosumab (SRE)
Alpharadin (Shown) (SSE)
Metastasis-free survival
Apalutamide
Favorable Change in a Disease Manifestation
PSA decline
Tumor shrinkage or regression
“Favorable” change in a bone scan
Death / Survival
Docetaxel
Sipuleucel-T
Cabazitaxel
Abiraterone
Enzalutamide
Alpharadin
Pembrolizumab
Presented by: Howard I. Scher, MD

6. The Presence of Circulating Tumor Cells in Blood Have the Potential to Fulfill The Unmet Need for a Response Indicator Biomarker That is Clinically Meaningful
Well established in patients with prostate,1 breast,2 colorectal3 and other cancers is that the detection of CTCs in blood portends a poor prognosis.
Declines in the number of CTCs post-treatment predicts for an improvement in survival.
Studied in a phase 3 trial, we showed that a 13 week biomarker containing CTC satisfied all 4 Prentice Criteria of a surrogate for overall survival.
Despite rapid technological advances, there remains only one CTC assay that has achieved the level of an FDA clearance.
Presented by:

7. CellSearch™: An FDA Cleared CTC Assay (2004) “As an Aid in the Monitoring Patients … In Conjunction with Other Clinical Methods”
CTC definition:
Morphology, CK(+), CD45(-), DAPI(+)
Report: # of cells meeting criteria/7.5 mL of blood
Endpoint: Conversion Unfavorable (> 5 Pre)
Favorable (4 or less Post)
Presented by: Howard I. Scher, MD

8. Castration resistant (Lethal)
The Association of CTC and PSA Response Endpoints and Survival Was Studied in 5 Phase 3 Registration Trials Covering the Specturm of mCRPC
Castration resistant (Lethal)
Non-castrate
Rising
PSA
Clinically
Localized
Disease
Non-
Metastatic
CRPC
Clinical
Metastases:
Noncastrate
Castration
Resistant
Post-
Abiraterone- 301
JNJ
Enzalutamide
Medivation
Orteronel – 05
Millenium –
Cabozantinib
Exelixis
Pre
Orteronel - 04
Millenium
1st Line
CTC0 = 1 or more pre-treatment to zero post-treatment
Presented by: Howard I. Scher, MD

9. In Addition to the CTC Conversion Endpoint We Explored a New Endpoint - CTC0:
The detection of 1 or more CTC pre-treatment and none post-treatment.
Presented by:

10. Both CTC0 and CTC Conversion Were More Strongly Associated with Survival Than PSA50 Providing Greater Separation Between Responders and Non-Responders
Evaluable: 75% % %
.83
.74
CTC0
PSA50
More patients were evaluable using CTC0
Presented by:
Heller et al. JCO 36:572, 2017

11. Orteronel + prednisone Abiraterone + prednisone Orteronel + prednisone
Here we Explored Different CTC and PSA Response Endgpoints as “Transitional” Surrogates for Overall Survival Using Data From 5 Phase 3 Randomized Trials
Trials
ELM-PC-4
COU-AA-301
ELM-PC-5
AFFIRM
COMET-1
Patient population
Pre-Chemo
1st line
Post-Chemo
2nd line
3rdrd line
Post-Abi/Enz
& Gen Chemo
Experimental treatment
Orteronel + prednisone
Abiraterone + prednisone
Orteronel + prednisone
Enzalutamide
Cabozantinib
Control
treatment
Placebo +
prednisone
Placebo
Mitoxantrone
Prednisone
Number of patients
1560
2:1
1195
1099
1199
1:1
1028
Presented by: Howard I. Scher, MD

12. Why “Transitional” as Opposed to “Traditional”?
Transitional is used because the endpoints were studied in a phase 2 setting – not phase 3.
Each arm of a trial was considered independently – a total of 10 trials.
Patient Level Discrimination: The separation between between responder and non-responder survival curves.
Trial level - Explained variation: The accuracy in predicting k-month survival in a trial with the response proportion observed – for each trial
Presented by: Howard I. Scher, MD

13. The Question:
How well does a response endpoint measured at 3 months predict survival at 6 to 18 months after the start of treatment? The response endpoints studied: CTC0 PSA50 CTC0 or PSA50 CTC0 and PSA50
Presented by:

14. BEST: A Glossary that Captures Distinctions Between Biomarkers and Their Clinical Assessment for Use in Research, Practice and Product Development
Diagnostic
Monitoring Pharmacodynamic/Response
Predictive
Prognostic
Reasonably likely surrogate
Validated Surrogate Endpoint
Presented by: Howard I. Scher, MD

15. Consort Diagram and Response Rates
Randomly Assigned Patients
(N=6,081)
Total (Combined)
No.
evaluable in both arms
CTC0 responders, n (%)
PSA50 responders,
n (%)
647
138 (21)
159 (25)
326
62 (19)
101 (31)
645
97 (15)
121 (19)
824
208 (33)
247 (4)
638
58 (9)
31 (5)
3080
19%
21%
Patients who survived
> 13 weeks
(N=5,660)
Patients who survived
> 13 weeks with
CTC > 1 & PSA > 5 ng/dl
(N=3080)
Achieved CTC 0
(N=591)
19%
Achieved PSA 50
(N=659)
21%
Presented by: Howard I. Scher, MD

16. PSA50 Response Rates Were Modestly Higher in the Experimental Arm with Little Difference in The Control Arms
Trial
COU-AA-301
AFFIRM
ELM-PC5
ELM-PC4
COMET-1
Total
Experimental arms
No. evaluable patients
CTC0 responders, n (%)
PSA50 responders, n (%)
428
116 (27)
146 (34)
219
59 (27)
99 (45)
432
82 (19)
104 (24)
414
120 (29)
161 (39)
431
52 (12)
30 (7)
1924
429 (22)
540 (28)
Control arms
No. evaluable patients
CTC0 responders, n (%)
PSA50 responders, n (%)
219
22 (10)
13 (6)
107
3 (3)
2 (2)
213
15 (7)
17 (8)
410
98 (24)
86 (21)
207
6 (3)
1 (0.4)
1156
144 (12)
119 (10)
Presented by: Howard I. Scher, MD

17. The Analyses Were Conducted at the Patient Level and Separately at the Trial Level
The endpoints were studied in a phase 2 setting – not traditional surrogacy which is done in phase 3.
Each arm of a trial was considered independently – a total of 10 trials.
Patient Level - Discrimination: The separation between between responder and non-responder survival curves.
Trial level - Explained variation: The accuracy in predicting k-month survival in a trial with the response proportion observed – for each trial
Presented by: Howard I. Scher, MD

18. Survival Probability Estimates Over Months 6 to 18 With Difference in Outcomes at 12 and 15 Months
CTC0
PSA50
0.89
0.84
0.84
0.76
0.38
0.32
0.44
0.35
0.51
0.52
0.40
0.41
CAN ADD THE DIFFERENCE ON TO THE FIGURE INSTEAD OF USING TABLE OF NUMBERS ON THE NEXT SLIDE – PATIENT NUMBERS
Black line indicates responders and red line, non-responders.
Presented by: Howard I. Scher, MD

19. The Analyses Were Conducted at the Patient Level and Separately at the Trial Level
The endpoints were studied in a phase 2 setting – not traditional surrogacy which is done in phase 3.
Each arm of a trial was considered independently – a total of 10 trials.
Patient Level - Discrimination: The separation between between responder and non-responder survival curves.
Trial level - Explained variation: The accuracy in predicting k-month survival in a trial with the response proportion observed – for each trial
Presented by: Howard I. Scher, MD

20. The 3 Month CTC0 Endpoint Provides an Early Indicator of Clinical Benefit Explaining Over 60% of the Variation in Survival and is More Informative Than PSA50 – And/Or Did Not Add
12 Mos.
0.67
0.59
Presented by: Howard I. Scher, MD

21. The 95% Confidence Intervals Around the Difference in R2 Values of CTC0 and PSA50 Endpoints Falls Below Unity: Attaining Trial Level Transitional Surrogacy Falls Short
Presented by:

22. Based on More Recent Guidance We Have Revised the Context of Use of our Qualification Program to a Response Measure that Reflects Clinical Benefit
Presented by:

23. Conclusions CTC0 is an improved measure of response relative to PSA
The result can be used to aid the management of the individual patient – failure to decline portends a poor prognosis.
For a population in a phase 2 trial the proportion of patients in whom CTC0 is achieved provides a meaningful measure of efficacy.
The result can be used to inform the decision to continue development.
Presented by: Howard I. Scher, MD

24. Conclusions 2
5. CTC0 on its own it does not meet new guidance for a reasonably likely surrogate. 6. Differences are not significant due to small number of trials.
Presented by:

25. Acknowledgements