describes the management of the new chapter of the story in view of the newly introduced drugs

1. Management of Non Metastatic
CRPC
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
JNJ Meeting
Cairo Semiramis Intercontinental Hotel
06/09/2018

2. Member of Advisory Board, Consultant, and Speaker for:
• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag,
Merck Serono, Novartis, Pfizer, Mundipharma, MSD, Ely Lilly, Sanofi-
Genzyme.
Speaker Disclosures:

3. Prostate Cancer:
Positioning of Available Therapies:
Locoregional
Disease
Biochemical
Failure
Metastatic
“Sensitive”
Metastatic
“Refractory”
Death
TIME
TumorBurden
Androgen Deprivation Therapy
1st Generation
Anti-Androgen
2nd Generation
Anti-Androgen
Biosynthesis
Cytotoxic
Anti-microtubule

4. Prostate Cancer: Emerging Challenges
• Screening Programs:
M1 or PSA > 100 ng/dl at presentation: 7.9%  2.6%
• ADT is increasingly used earlier plus other
loco-regional procedures  CRPC
• Increasing number of nmCRPC.
Schroder et al. N Engl J Med 2012; 366(11): 981–990.
Taille A. journal de l’Association francaise d’urologie et de la Societe francaise d’urologie 2009; 19(5): 313–320.
Tombal B. Annals of Oncology 23 (Supplement 10): x251–x258, 2012

5. M0 CRPC: an Overview

6. M0 CRPC: New Chapter of Story
M0CRPC M1CRPC
Longer
• Symptomatic  QoL
• Survival.
Kirby et al. Int J Clin Pract 2011; 65(11): 1180–1192.

7. Definition of M0CRPC
• A rising PSA that is 2 ng/mL higher than the
nadir with a rise of at least 25% over nadir.
• The rise must be confirmed by a second PSA at
least 3 weeks later.
• The patient must have castration levels of
testosterone (<50 ng/mL).
• No radiographic evidence of metastatic
disease.
Scher et al. Recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008;26:1148-59.

8. PSADT: The Best Predictor of Outcome:

9. M0 CRPC: Imaging Schedule:
• RADAR GROUP:
– Start on diagnosis of CRPC (or PSA > 2ng.ml)
– 2nd when 5 ng/ml
– Repeat with every doubling of PSA.
• Procedures: BS, CT, MRI.
• Other newer modalities (PSMA)??
David M. Albala. Rev Urol. 2017;19(3):200–202

10. Newer Imaging Modalities in Prostate
Cancer
Tracer Target Context/Indication Regulatory Status
C-11
Choline[1] Lipid
synthesis
Suspected prostate cancer
recurrence and
noninformative bone
scintigraphy, CT, or MRI
FDA approved (2012)
Limited availability (in US)
Fluciclovine[
2]
Amino
acid
transpor
t
Suspected prostate cancer
recurrence based on
elevated PSA following
prior Tx
FDA approved (2016)
Commercially available;
variable reimbursement
Ga68-
PSMA-11[3] PSMA Multiple; all investigational
Approved in non-US countries
Available, including trials
[F-18]-
DCFPyL[4] PSMA Multiple; all investigational
Approved in non-US countries
Available, including trials
1. Choline C 11 PI. 2012. 2. Fluciclovine F-12 PI. 2016. 3. ClinicalTrials.gov. 4. ClinicalTrials.gov. NCT03501940.

11. M0 CRPC in 2018:
APALUTAMIDE ENZALUTAMIDE
Competitive Inhibition
of AR Signaling
DNA Binding Domain
Translocation to
Nuclear Membrane
Androgen Binding
DomainLess CNS Permeation
Chandler & De Bono. Nature Reviews June 2018.
volume 15

12. Eligibility
• nmCRPC
- Negative 99mTc bonescan
- Negative CT of pelvis,
abdomen, chest, andbrain
- Pelvic nodes < 2 cmbelow
iliac bifurcation (N1)
allowed
• PSADT ≤ 10 months
On-Study Requirement
• ContinuousADT
Stratifications
• PSADT > 6 mo or ≤ 6mo
• Bone-sparing agents,y/n
• N0 or N1
Second Rx
at MD’s
discretion
including
open-label
AA+P
Apalutamide
(APA)
240 mg QD
+ ADT
(n = 806)
Placebo (PBO)
+
ADT
(n = 401)
Randomization
M
F
S
P
R
O
G
R
E
S
S
I
O
N
2nd progression-
free survival(PFS2)
Metastasis-freesurvival
(primary end point)
2:1
(N = 1207)
Smith MR, et al. N Engl J Med. 2018 Feb 8 [Epub ahead of print]
1
SPARTAN ─ Phase 3 Placebo-Controlled,
Randomized International Study
NCT01946204
• The study was conducted at 332 sites in 26 countries in North America, Europe and Asia Pacific regions

13. Primary End Point
Metastasis-free survival (MFS): Time from randomization to first evidence of BICR-
confirmed radiographically detectable distant metastasis (bone or soft tissue) or death
whichever comes first
Secondary End Points
Time to metastasis (TTM): Time from randomization to first evidence of BICR-confirmed
radiographically detectable bone or soft tissue distant metastasis (does not include death)
Progression-free survival (PFS): Time from randomization to first documentation of
BICR-confirmed radiographic progressive disease or death due to any cause (whichever
occurs first); includes all local and distant radiographicprogression
Symptomatic progression: Time to skeletal-related event (SRE), pain progression or
worsening of disease-related symptoms requiring initiation of a new systemic anticancer
therapy, or development of clinically significant symptoms due to loco-regional tumor
progression requiring surgery or radiation therapy
Exploratory End Point
Progression-free survival with the first subsequent therapy (PFS2): Time from
randomization to investigator-assessed disease progression after first subsequent
treatment for mCRPC or death
Smith MR, et al. N Engl J Med. 2018 Feb 8 [Epub ahead of print]
Definition of End Points
BICR, blinded independent central review.

14. Primary Endpoint: Metastasis-free Survival
72% risk reduction of distant progression or death
 The final analysis for MFS was performed after distal metastasis or death was observed in 378
patients, in 23% and 48% of patients in the APA and PBO groups, respectively
 The median MFS was 40.5 months in the APA group and 16.2 months in the PBO group
 Among patients who developed metastases, 60.5% in the APA group and 54.4% in the PBO group
had bone metastases
, 40.5 mo (median)
Smith MR, et al. N Engl J Med. 2018 Apr 12;378(15):1408-1418.
16.2 mo
(median)

15. Consistent MFS Benefit Across All Subgroups
 The treatment effect of APA was consistently favorable across prespecified subgroups
Smith MR, et al. N Engl J Med. 2018 Apr 12;378(15):1408-1418.

16. Secondary End Point: Progression-free Survival
 Patients in the APA group had a 71% risk reduction of local progression, distant progression, or
death
14.7 mo
(median)
Smith MR, et al. N Engl J Med. 2018 Apr 12;378(15):1408-1418.
, 40.5 mo (median)

17. Secondary End Point: Time to Symptomatic Progression
 Patients in the APA group had a 55% risk reduction of SREs, pain progression/ worsening
symptoms, or clinically significantsymptoms
, NR
Smith MR, et al. N Engl J Med. 2018 Apr 12;378(15):1408-1418.
, NR

18. Secondary End Point: Overall Survival
 Patients in the APA group had a 30% risk reduction ofdeath
, NR
Smith MR, et al. N Engl J Med. 2018 Apr 12;378(15):1408-1418.
39.0 mo
(median)

19. Secondary End Point: Time to Initiation of Cytotoxic
Chemotherapy
 Patients in the APA group had a 56% risk reduction in initiation of cytotoxic chemotherapy
, NR
Smith MR, et al. N Engl J Med. 2018 Apr 12;378(15):1408-1418.
, NR

20. Summary of Prespecified Secondary End Points
Smith MR, et al. N Engl J Med. 2018 Apr 12;378(15):1408-1418.
APA
(n = 806)
PBO
(n = 401)
Hazard Ratio
(95% CI)
P Value
Secondary end points Months
Median time to metastasis 40.5 16.6 0.27 (0.22–0.34) < 0.001
Median progression-free
survival
40.5 14.7 0.29 (0.24–0.36) < 0.001
Median time to symptomatic
progression
NR NR 0.45 (0.32–0.63) < 0.001*
Median overall survival NR 39.0 0.70 (0.47–1.04) 0.07†
Median time to cytotoxic
chemotherapy
NR NR 0.44 (0.29–0.66) -
 APA was associated with improvements in all secondary end points
*Crossed O’Brien-Fleming efficacy boundary (OBF) of 0.00008. † Did not cross OBF.‡ Test not done due to OS not crossing the
OBF

21. Exploratory End Point: Second Progression- free Survival
 Patients in the APA group had a 51% risk reduction of second progression (PSA, radiographic,
symptomatic, or anycombination)
, NR
Smith MR, et al. N Engl J Med. 2018 Apr 12;378(15):1408-1418.
39.0 mo
(median)

22.  Patients in the APA group had a 94% risk reduction in PSA progression
Exploratory End Point: Time to PSA Progression
, NR
Smith MR, et al. N Engl J Med. 2018 Apr 12;378(15):1408-1418.
3.7 mo
(median)

23.  Patients in the APA group showed 90% PSA response compared to 2% in the placebo group
Smith MR, et al. N Engl J Med. 2018 Apr 12;378(15):1408-1418.
Exploratory End Point: PSA response

24. Summary of Most Common Adverse Events
24Smith MR, et al. N Engl J Med. 2018 Apr 12;378(15):1408-1418.
Adverse Event*† APA (n = 803) PBO (n = 398)
All Gr 3/4 All Gr 3/4
no of patients (%)
Fatigue 244 (30.4) 7 (0.9) 84 (21.1) 1 (0.3)
Hypertension 199 (24.8) 115 (14.3) 79 (19.8) 47 (11.8)
Skin rash 191 (23.8) 42 (5.2) 22 (5.5) 1 (0.3)
Diarrhea 163 (20.3) 8 (1.0) 60 (15.1) 2 (0.5)
Nausea 145 (18.1) 0 63 (15.8) 0
Weight loss 129 (16.1) 9 (1.1) 25 (6.3) 1 (0.3)
Arthralgia 128 (15.9) 0 30 (7.5) 0
Fall 125 (15.6) 14 (1.7) 36 (9.0) 3 (0.8)
*AEs listed at ≥15% in either group up to 28 days after last dose. Adverse events of interest do not necessarily
meet the ≥15% criterion in either group.
† Incidences when adjusted for exposure (events per 100 patient-years) in the apalutamide and placebo
groups, respectively, were:
• fatigue (32.3 vs. 27.2)
• hypertension (36.3 vs. 38.7)
• skin rash (29.6 vs. 8.3)
• diarrhea (21.6 vs. 22.6)
• nausea (15.8 vs. 20.4)
• weight loss (18.3 vs. 10.5)
• arthralgia (14.7 vs. 8.0)
• fall (13.6 vs. 10.0).

25. Summary of Adverse Events of Interest
25Smith MR, et al. N Engl J Med. 2018 Apr 12;378(15):1408-1418.
Other AEs of interest APA (n = 803) PBO (n = 398)
All Gr 3/4 All Gr 3/4
no of patients (%)
Fracture 94 (11.7) 22 (2.7) 26 (6.5) 3 (0.8)
Dizziness 75 (9.3) 5 (0.6) 25 (6.3) 0
Hypothyroidism 65 (8.1) 0 8 (2.0) 0
Mental impairment
disorders‡
41 (5.1) 0 12 (3.0) 0
Seizures 2 (0.2) 0 0 0
‡ Includes any of the following adverse events: disturbance in attention, memory impairment, cognitive disorder, or
amnesia.

26. Conclusions
26
Smith MR, et al. N Engl J Med. 2018 Apr 12;378(15):1408-1418.
 Apalutamide was associated with a 30% reduction in risk of
death at this early interim analysis for survival (p = NS)
 Apalutamide resulted in a 51% risk reduction in PFS2 even in
the face of a high rate of subsequent approved treatment in
the placebo group
 Patient-reported outcomes indicate maintained overall health-
related quality of life with the addition of apalutamide to
androgen-deprivation therapy
 Consistent improvements in secondary and exploratory end
points provide support for the veracity of the primary finding

27. Conclusions
Smith MR, et al. N Engl J Med. 2018 Apr 12;378(15):1408-1418.
 Apalutamide was associated with a 30% reduction in risk of
death at this early interim analysis for survival (p = NS)
 Apalutamide resulted in a 51% risk reduction in PFS2 even in
the face of a high rate of subsequent approved treatment in
the placebo group
 Patient-reported outcomes indicate maintained overall health-
related quality of life with the addition of apalutamide to
androgen-deprivation therapy
 Consistent improvements in secondary and exploratory end
points provide support for the veracity of the primary finding