New horizons in ProstateCancer Treatment
Expanding options, extendingsurvival, and improving quality of
life
Chip ReningerHematology and Oncology
Consultants of Pa
September 2015
Outline
1. Expanding Treatment Options for metastatic Prostate Cancer for hormone sensitive disease and castrate resistant disease
2. Evolving Biology of CRPC
3. Taxotere emeging role in f irst line treatment of HSMPC/high risk local disease
4. Novel Agents for the treatment of CRPC
Immunotherapies
Sipuleucel-T
Androgen Biosynthesis Inhibitors (ABI’s)/novel anti-androgens
Abiraterone, Enzalutamide (MDV-3100)
Cytotoxics
Cabazitaxel
Bone\micro-environment directed therapies
Radium 223/Xofigo
5. “Picking the right treatment for the right patients at the right time”
Hematology & OncologyConsultants of PA
2
Castration resistant:deaths from disease
Diagnoses
Rising PSA
3Clinical
Metastases:Castrate1st Line
DocetaxelStandard
2Clinical
Metastases:Castrate
Pre-
ClinicallyLocalizedDisease
1Rising PSA:
Castrate
ClinicalMetastases:
Non-Castrate
4Clinical
Metastases:Castrate2nd Line
No Standard
With detectable metastases:deaths from cancer exceed
that from other causes
28,660186,320
Non-CastrateAndrogen depletion /
blockade (bicalutamide)
Prostate Cancer Clinical States: A Framework for ClinicalPractice, Drug Development, and Biomarker Qualification
Hematology & OncologyConsultants of PA
3
Typical Timing of AvailableTreatments
Hematology & OncologyConsultants of PA
4
Systemic Medical Treatmentsof Prostate Cancer
Hematology & OncologyConsultants of PA
5
Disease States and PossibleTreatment in Prostate Cancer
Localized Disease Confned to the Prostatenewly diagnosed- surgery/RT +/-hormones +/- chemotx
Localized Disease with spread to adjancentorgans or pelvic lymph nodes – RT+hormones +/- Chemotx
Biochemical(psa) recurrence after surgery -+/- salvage radiation +/-hormones
Biochemical(psa) recurrence afterRadiation- +/- salvage surgery +/-hormones
Newly diagnosed prostate cancer withmetastatic disease outside the pelvis-hormones + chemotx
Biochemical progression with or withoutmetastatic disease after initial hormonetherapy- additional hormonal tx in the formof androgen receptor blocker (casodex)
Biochemical and/or metastatic disease afterstandard hormone treatment so calledcastrate resistant disease – newer hormonalagents (Zytiga/Xtandi), chemotx (taxotere,Jevtana), immunotherapy (Provenge), boneseeking radioisotopes (xofgo)
Hematology & OncologyConsultants of PA
6
Typical Tiiming of AvailableTreatments
Hematology & OncologyConsultants of PA
7
First Line Hormone Sensitive disease- -The Basics of Hormone Therapy
GNRHanalogs(lupron)And GNRHantagonists(frmagon)
Casodex –binds to ARto blocktestosteroneaffects
Hematology & OncologyConsultants of PA
8
Understanding the Biology of CRPCDriver Pathways of Dependency of PC
Tomlins, S. A. Eur Urol 2009Taylor, B et al, Cancer Cell 2010
Kong D. Cancer Sci 2008Jenkins, R. B. Cancer Res 1997
Khor, L. Y. Clin Cancer Res 2007
Androgen Receptor (AR) 55% 100%
PTEN loss 25%80%
PI3K/Akt, Ras/Raf, RB 42%100%
TMPRSS2-ETS fusion 50%33%
Genetic variants of androgen transporter genes
Primary Mets
Prostate Cancer: “Adapting” to castrate environment
ALTERN.SPLICING
ABERRANTMODIFICATION
• GF, cytokines• Src
Sumo
AC
P
COFACTORPERTURBATION
• CoAct gain• CoR loss/dismissal
CoACT
INTRACRINEANDROGENSYNTHESIS
T
MUTATION• gain of function
AR
selectivepressure
Hormone Therapy
adaptation
RECURRENT TUMOR DEVELOPMENTCRPC
RESTORED AR ACTIVITY(rising PSA)
>30% CRPC
ARDEREGULATION
• amplification• overexpression
Penning & Knudsen2010Hematology & Oncology
Consultants of PA10
Chemotherapy in Prostate Cancer – Taxotere
An old dog with new tricks
Taxotere approvedin CRPC
only tx shown toimprove survivalafter failure on gnrhanalog and casodex
Modest beneft of 2.5months over standardtreatment withmedian survival of 19mos vs 16.5 monthswith standard of care
Taxotere improvedsurvival in:
2014: Newlydiagnosed “highvolume” metastaticdisease incombination withhormones vshormones alone(SOC)at the time ofdiagnoses. 13 monthsimprovement inoverall survival from3.5 yrs to 4.75 yrs
2015: improvedsurvival in all menwith newlydiagnosed metastaticprostate cancer
2015:possible survivalbeneft in men withlocalized high riskcancer in 2 trials
2004 2014/ 2015
Hematology & OncologyConsultants of PA
11
“Traditional” use of chemotherapy for CRPC
Presented By Ian Tannock at 2015 ASCO Annual Meeting
Chemotherapy in Prostate Cancer Castrate Resistant DiseaseTaxotere 2004
Castrate Resistant Disease
Hematology & OncologyConsultants of PA
12
Chemotherapy in Prostate Cancer Hormone Sensitive Metastatic
–Taxotere - 2014
Hematology & OncologyConsultants of PA
13
<br />Role of chemotherapy for hormone-naïve PC<br />
Presented By Ian Tannock at 2015 ASCO Annual Meeting
Taxotere: New Standard in Hormone Naïve Metastaticdisease , high Volume disease - 2014
Hematology & OncologyConsultants of PA
14
High risk local and metastatic diseaseTaxotere 2015
Hematology & OncologyConsultants of PA
15
Taxotere- STAMPEDE-2015
Hematology & OncologyConsultants of PA
16
Taxotere- STAMPEDE-2015
Hematology & OncologyConsultants of PA
17
Taxotere 2015 – high risk locallyadvanced RTOG 0521
Hematology & OncologyConsultants of PA
18
Taxotere 2015 – high risk locallyadvanced RTOG 0521
Hematology & OncologyConsultants of PA
19
Taxotere 2015 – high risk locallyadvanced RTOG 0521
Hematology & OncologyConsultants of PA
20
Role of chemotherapy for localized high-riskPC (M0) after radiation therapy
Presented By Ian Tannock at 2015 ASCO Annual MeetingHematology & OncologyConsultants of PA
21
Taxotere 2015 – high risk locallyadvanced RTOG 0521
Hematology & OncologyConsultants of PA
22
Forest plot for Failure-Free Survival in men with M0 disease (thanks to Dr. Eitan Amir)
Presented By Ian Tannock at 2015 ASCO Annual Meeting
Chemotherapy in Prostate CancerTaxotere: Possible option in localizeddisease
Hematology & OncologyConsultants of PA
23
For the frst time an improvement in overallsurvival observed with adjuvant chemotherapyfor localized high risk hormone sensitiveprostate cancer
The effect and role of Docetaxel in hormonesensitive prostate cancer is consistent with andsupported by other studies such as chaartedand stampede
This analysis is early and additional follow upis needed in both stampede and RTOG0521
Conclusions
Hematology & OncologyConsultants of PA
24
Metastatic Castrate ResistantDisease- asymptomatic or minimally
symptomatic chemotherapy naive Observation
Antiandrogenwithdrawal
Ketoconazole
Taxotere andprednisone*
Immunotherapy
Provenge (Sipuleucel-T)*
Hormone
Abiraterone (Zytiga)and Prednisone*
Enzalutamide(Xtandi)*
Chemotx
Cabiztaxel (Jevtana)*
Bone SeekingRadioisotopes
Radium-223(xofgo)*
Prior to 2010 After 2010
*Overallsurvival inRCT
Hematology & OncologyConsultants of PA
25
Immunotherapy Approaches in PC
§ Active immunotherapy
v tumor associated antigen is directly targeted by loading in thatantigen in APC or into vaccine vector at protein or DNA level
v Antigen specifc immunotherapy
§Sipuleucel-T
§Poxvirus-based vectors
§DNA based vaccines
§ Passive immunotherapy
v Antibodies to specifc receptors/antigens
§Prostate Specifc Membrane Antigen (PSMA)
§ Immune Checkpoint Inhibitors
v Strategies to maintain activated tumor specifc T-cells by neutralizingco-inhibitory receptors
v Anti-cytotoxic T lymphocyte protein 4 (CTLA 4)
§ Ipilumimab, tremelimumab
v Anti- program death 1 (PD-1)(PDL-1)
§ MDX-1106
Hematology & OncologyConsultants of PA
26
Patient’s white bloodcells harvested
Short-term culture with protein“cassette”
Shipping
Cells infused back intopatient (IV)
GM-CSFProstatic acid
phosphatase
Active Cellular Immunotherapy(Sipuleucel-T)
Hematology & OncologyConsultants of PA
27
Hematology & OncologyConsultants of PA
28
Provenge (sipuleucel–t)
Median survivalbeneft
Survival above thecontrol group
Can be given with otherhormonal therapies andwell tolerated
Hematology & OncologyConsultants of PA
29
Targeting the AndrogenPathway
Androgen Biosynthesis Inhibitors
*Abiraterone Acetate
TAK 700
VN/124-1 (TOK-001)
Novel Anti-Androgens
*Enzalutamide
RD 162
EPI-001 (AR N-Terminal)
SNARE-1 (selective nuclear receptor exporter-1)
* FDA approvedHematology & OncologyConsultants of PA
30
Hormonal TherapyZYTIGA (abiraterone acetate)
Abiraterone acetate(ZYTIGA®)
converted in the body toabiraterone, an androgenbiosynthesis inhibitor,that inhibits an enzymevital to producingtestoterone(androgens).
enzyme is expressed intesticular, adrenal, andprostatic tumor tissuesand is required forandrogen biosynthesis.Hematology & Oncology
Consultants of PA31
Zytiga in chemotx non naïvepts-
COU-AA-301 Study Design
Phase III, multinational, multicenter, randomized, double-blind, placebo-controlledstudy (147 sites in 13 countries; USA, Europe, Australia, Canada)
Stratifcation according to
ECOG performance status (0-1 vs 2)
Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs 4-10 [present])
Prior chemotherapy (1 vs 2)
Type of progression (PSA only vs radiographic progression with or without PSAprogression)
Abiraterone 1000 mg dailyPrednisone 5 mg BID
n=797
Primary end point
• OS (25% improvement; HR0.8)
Secondary endpoints (ITT)
• TTPP
• PFS
• PSA response
Effcacy endpoints (ITT)
Placebo dailyPrednisone 5 mg BID
n=398
RANDOMIZED
2:1
• 1195 patients withprogressive mCRPC
• Failed 1 or2 chemotherapyregimens, one ofwhich containeddocetaxel
Patients
Abbreviations: ; BPI=Brief Pain Inventory; TTPP=time to PSA progression; ITT=intent to treat; mCRPC=metastaticcastrate-resistant prostate cancer.Source: Clinicaltrials.gov identifer: NCT00638690.
deBono N Engl J Med. 2011 May 26;364(21):1995-2005Hematology & OncologyConsultants of PA
32
COU-AA-301: Abiraterone AcetateImproves OS in mCRPC
HR=0.646 (0.54-0.77) P <0.0001
Placebo: 10.9 months (95% CI: 10.2, 12.0)
0 100 200 300 400 500 600 700
0
20
40
60
80
100
Ov
eral
l S
urv
ival
, %
Days from Randomization
Abiraterone: 14.8 months (95% CI: 14.1, 15.4)
1 Prior Chemo OS: 15.4 months abiraterone vs 11.5 months placebo
Abiraterone 797 728 631 475 204 25 0
Placebo 398 352 296 180 69 8 1
deBono N Engl J Med. 2011 May 26;364(21):1995-2005Hematology & Oncology Consultants of PA 33
Overall Study Design of COU-AA-302
Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at151 sites in 12 countries; USA, Europe, Australia, Canada
Stratifcation by ECOG performance status 0 vs 1
AA 1000 mg dailyPrednisone 5 mg BID
(Actual n = 546)
Co-Primary:• rPFS by central review• OS
Secondary:• Time to opiate use
(cancer-related pain)• Time to initiation of
chemotherapy• Time to ECOG-PS
deterioration• TTPP
Effcacy end points
Placebo dailyPrednisone 5 mg BID
(Actual n = 542)
RANDOMIZED
1:1
• Progressive chemo-naïve mCRPCpatients(Planned N = 1088)
• Asymptomatic ormildly symptomatic
Patients
Ryan et al. ASCO 2012 Hematology & Oncology Consultants ofPA
34
Statistically Significant Improvement in rPFSPrimary End Point
NR, not reached; PL, placebo.Data cutoff 12/20/2010.
100
80
60
40
20
0
0
Pro
gre
ssio
n-F
ree
(%)
3 6 9 15 1812
546542
489400
340204
16490
123
00
AAPL
4630
Time to Progression or Death (Months)
AA + PPL + P
AA + P (median, mos): NR
PL + P (median, mos): 8.3
HR (95% CI): 0.43 (0.35-0.52)
P value: < 0.0001
Ryan et al. ASCO 2012 Hematology & Oncology Consultants of PA 35
Strong Trend in OS Primary EndPoint
546542
538534
482465
452437
2725
00
524509
503493
02
120106
258237
412387
100
80
60
40
20
0
0
Su
rviv
al (
%)
3 12 15 27
Time to Death (Months)
33
AA + PPL + P
6 9 30242118
AAPL
AA + P (median, mos): NR
PL + P (median, mos): 27.2
HR (95% CI): 0.75 (0.61-0.93)
P value: 0.0097
Updated GU ASCO 2013: Rathkopf et al. Abstract # 5-r PFS 16.5 vs. 8.3 mo. HR 0.53 (0.45-0.62) p = <0.0001- OS 35.3 vs. 30.1 mo. HR 0.79 (0.66-0.96) p= 0.0151Hematology & Oncology
Consultants of PA36
Xtandi MOA
Hematology & OncologyConsultants of PA
37
AFFIRM: Phase 3 Trial of Enzalutamidevs Placebo in Post-Chemotherapy
Castration-Resistant Prostate Cancer(CRPC)
RANDOMIZED
2:1
Primary
Endpoint:Overall Survival
Enzalutamide 160 mg daily
n = 800
Placebon = 399
PatientPopulation:
1199 patients withprogressive CRPC
* Failed docetaxel chemotherapy
*Glucocorticoids were not required but allowed
Hematology & OncologyConsultants of PA
Tran et al. Science 2009;324:787–90. 38
AFFIRM: Clinical Outcomes
Variable Enzalutamide
(800 pts.)
Placebo(399 pts.)
HazardRatio
P -value
OS(months)
18.4 13.6 0.631 <0.0001
PSAprogression(months)
8.3 3.0 0.218 <0.0001
rPFS(months)
8.3 2.9 0.404 <0.0001
1st SRE(months)
16.7 13.3 0.621 <0.0001
CR + PR 28.9% 3.8% - <0.0001
FACT-P 43.3% 17.8% - <0.0001
De Bono et al. ASCO 2012Hematology & Oncology Consultants ofPA
39
Enzalutamide in chemotx naïvepatients
Hematology & Oncology Consultants ofPA
40
Xtandi-Prior to chemotx incastrate resistant Prostate
cancer
Hematology & Oncology Consultantsof PA
41
Alpha Beta
Relative particle mass 7000 1
Initial energy (MeV) 3-8 0.01-2.5
Range in tissue (µm) 40-90 50-5000
LET (KeV/µm) 60-230 0.015-0.4
Charge +2 -1
Ion pairs/µm 2000-7000 5-20
DNA hits to kill cell 1-5 100-1000
Radium-223 (XOFIGO)
• Based on alpha emitter Radium-223• ideal half-life of 11.4 days• Excreted via small bowel• Safe and easy to produce, deliver and handle
Range of alpha-particle
Radium-223
Encouraging Phase II results Hematology & OncologyConsultants of PA
42
TREATMENT
6 injections at 4-week intervals
Radium-223 (50 kBq/kg) +Best standard of care
Placebo (saline) + Best standard of care
RANDOMISED
2:1
N = 922
PATIENTS
• Confirmedsymptomatic
CRPC• ≥ 2 bonemetastases
• No knownvisceral
metastases• Post-docetaxel
or unfit fordocetaxel
ALSYMPCA (ALpharadin in SYMptomaticProstate CAncer) Phase III Study Design
• Total ALP: < 220 U/L vs ≥ 220
U/L• Bisphosphonate use:
Yes vs No• Prior docetaxel:
Yes vs No
STRATIFICATION
Planned follow-up is 3 years
Hematology & OncologyConsultants of PA
43
Month 0 3 6 9 12 15 18 21 24 27
Radium- 223 541 450 330 213 120 72 30 15 3 0
Placebo 268 218 147 89 49 28 15 7 3 0
ALSYMPCA Overall Survival
0
10
20
30
40
50
60
70
80
90
100
%Radium-223, n = 541
Median OS: 14.0 months
Placebo, n = 268Median OS: 11.2 months
HR 0.695; 95% CI, 0.552-0.875
P = 0.00185
EORTC 2011Hematology & OncologyConsultants of PA
44
Xofigo -Prior to chemotx incastrate resistant Prostate
cancerBeforeXofgo
AfterXofgo
Hematology & OncologyConsultants of PA
45
Metastatic castrate resistantprostate cancer after progression on
Taxotere – Jevtana(Cabazitaxel) Microtubulestabilizer
Developed indocetaxel-resistantprostate cancer celllines
a favorablepharmacokinetic andsafety profile
decreased propensityfor P-glycoprotein(Pgp)-mediated drugresistance.
inhibited cell growthin a wide range ofhuman cancer celllines, includingtumor modelsexpressing Pgp.
Hematology & OncologyConsultants of PA
46
Support Medications not shownto improve survival but reduce
complications of disease Bone Building Drugs
Zometa
Xgeva(denosumab)
Drugs for Man fashes
SSRI
gabapentin
Hematology & OncologyConsultants of PA
47
New treatments on the Horizon
Hormonal therapy
Targeted therapy Dasatinib, Cabozantinib, Custirsen, Tasquinimod
Immunotherapy CHECKPOINT INHIBITORS
ANTI-CTLA4 IMMUNOTHERAPY: IPILIMUMAB
anti pd1, anti pdl1
, Immunostimulatory monoclonal antibodies
VACCINE, ,
PROSTVAC-VFHematology & OncologyConsultants of PA
48
Conclusion
5 new agents since 2015 approved formetastatic castrate resistant prostate cancer allof which have been shown to improve survival
2004 median survival from 17 to 20 months withtaxotere
2015 median survival has increased to between 3-4years
More therapies are on the way, cost will be an issue,fnding targets that are indicators for response aredesperately needed
Getting closer to disease state that we can control,immunotherapy may allow us to get long termremission in some pts
Combination therapy and moving treatment up inthe disease will likely be benefcial, expense/targets
Hematology & OncologyConsultants of PA
49