Luís Costa, MD, PhDHospital de Santa MariaInstituto de Medicina MolecularFaculdade de Medicina de LisboaPresident of ASPIC
Bone Metastases in Prostate cancer: treatment strategies
Luís Costa, MD, PhDHospital de Santa MariaInstituto de Medicina MolecularFaculdade de Medicina de LisboaPresident of ASPIC
Disclosures
Research Grants: Amgen; Novartis; Roche.
Consultant: Novartis; Amgen.
Speaker Honoraria: Amgen; Bayer; Janssen.
Prostate Cancer Develops a Phenotype That Allows for Migration to the Bone
• The bone matrix is rich in factors that stimulate the growth of tumor cells and promote a vicious cycle of metastases and bone pathology1
• Physical factors in the bone microenvironment may also enhance tumor growth2
• Cross talk between prostate cancer and the bone drives continued disease progression3,4
References: 1. Yin JJ et al. Cell Res. 2005;15(1):57-62. 2. Zheng J et al. J Bone Oncol. 2012;2(1):47-57. 3. Mundy GR. Nat Rev. 2002;2:584-593.
4. Kingsley LA et al. Mol Cancer Ther. 2007;6:2609-2617.
Cancer cells
Host cells
Soluble factors(eg, exosomes,
cytokines, hormones)
HOMELAND
MIGRATION
HOSTLANDImage courtesy of Kenneth Pienta, MD.
Most Patients With mCRPC Develop Visceral Metastases in the Final Stages of the Disease
Increased visceralinvolvement
100
90
80
70
60
50
40
% o
f P
atie
nts
30
20
10
0>24 15-24 12-15 9-12 6-9 3-6 <3
Time Prior to Death, months
Visceral involvement Bone involvement
~90%~95%
Minimal visceral involvement
Reference: Pezaro CJ et al. Eur Urol. 2014;65:270-273.
The Androgen Axis Is Not the Only Driver of Advanced Prostate Cancer Disease Progression1-5
References: 1. Yin JJ et al. Cell Res. 2005;15(1):57-62. 2. Mundy GR. Nat Rev. 2002;2:584-593. 3. Kingsley LA et al. Mol Cancer Ther. 2007;6:2609-2617. 4. Gundem G et al. Nature. 2015;520(7547):353-357.
5. Nemeth JA et al. J Natl Cancer Inst. 2002;94(1):17-25..
Androgen Bone
Course of mCRPC
Metastases
CRPC
Initial diagnosis and therapy ADT
SRE/SSE
Death
SRE/SSE
Death
PS
A /
Tu
mo
r B
urd
en
1. Adapted from Scher H, et al. Urology. 2000;55(3):323-327. 2. Dennis E, et al. J Clin Oncol. 2012;30(5):519-524.
Time
Hormone dependence
Tumor Heterogeneity
…Course of CRPC and goals of new therapies
Cancer treatment-
induced bone loss
Treatment of
bone metastases
Bone-targeted therapies in Prostate cancer: updating the landscape
Early cancer Advanced cancer
Prevention/delay
of bone metastases
???↑ ↑ ↑: mCRPC
Pockett RD, et al. Eur J Cancer Care 2010;19:75560.Review of hospital admission data for patients admitted to Spanish hospitals, January 2000
to March 2006, including 7,546 patients with prostatecancer
SREs increase the hospital burden ofProstate cancer
Mean length of hospital stay by disease type and admission status
Prostate cancerLung cancerBreast cancer
Can
cer
on
ly
Can
cer
on
ly
Can
cer
on
ly
+ b
on
em
etas
tase
s
+ b
on
em
etas
tase
s
+ b
on
em
etas
tase
s
+ SR
E
+ SR
E
+ SR
E
Mea
n le
ngt
h o
f st
ay (
day
s)
15
10
5
0
20
25
1211
6
9 9 9
13
19
16
11
21
14
10
8
12
910
15
Elective
Emergency
The Vicious Cycle of Bone Metastases: Targeting osteoclasts
Bisphosphonates
Denosumab
Time to first SRE
P = 0.021
Pat
ien
ts w
ith
≥ 1
SR
E (%
)
33.2
44.2
0
10
20
30
40
50
Zoledronicacid 4 mg(n = 214)
Placebo(n = 208)
Time after start of study drug (days)
Pat
ien
ts w
ith
ou
t ev
en
t (%
)
90
10
20
30
40
50
60
70
80
90
100
00 180 450270 540360
Zoledronic acid 4 mg (P = 0.011 vs placebo)
Placebo
Proportion of patientswith ≥ 1 SRE (primary endpoint)
Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468.
Zoledronic Acid Was Superior to Placebo in CRPC
CI = confidence interval; HR = hazard ratio; SRE = skeletal related events.Fizazi K, et al. Lancet. 2011;377:813-22.
Significantly Longer Time Without an SRE With Denosumab vs Zoledronic Acid
18% risk reduction
HR = 0.82 (95% CI, 0.71–0.95)
P = 0.008 (superiority)
Time to first SRE
Study month
Pat
ien
ts w
ith
ou
t SR
E (%
)
0
40
60
80
100
20.7 months
17.1 months
90
70
50
30
20
10(N = 1901)
Denosumab
Zoledronic acid
0 3 6 9 12 15 18 21 24 27
*Events occurring at least 21 days apart (multiple event analysis).CI = confidence interval; RR = rate ratio; SRE = skeletal related events.Fizazi K, et al. Lancet. 2011;377:813-22.
Significantly Fewer SREs With Denosumab vs Zoledronic Acid
18% risk reduction
RR = 0.82 (95% CI, 0.71–0.94)
P = 0.008 (superiority)
Time to first andsubsequent SREs*
3 6 9 12 15 18 21 24 27 30
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
2.0
0 33Cu
mu
lati
ve m
ean
nu
mb
er
of
SREs
pe
r p
atie
nt
Study month
(N = 1901)
494
584
Denosumab
Zoledronic acid
Total SREs:
Patient incidence, n (%)Zoledronic acid
(n = 945)Denosumab
(n = 943)
Infectious adverse events (AEs) 375 (39.7) 402 (42.6)
Infectious serious AEs 108 (11.4) 130 (13.8)
Acute phase reactions (first 3 days) 168 (17.8) 79 (8.4)
Renal AEs* 153 (16.2) 139 (14.7)
Cumulative rate of osteonecrosis of the jaw (ONJ)† 12 (1.3) 22 (2.3)
Hypocalcemia 55 (5.8) 121 (12.8)
New primary malignancy 10 (1.1) 18 (1.9)
*Includes renal failure, increased blood creatinine, acute renal failure, renal impairment, increased blood urea, chronic renal failure, oliguria, hypercreatininemia, anuria, azotemia, decreased creatinine renal clearance, decreased urine output, abnormal blood creatinine, proteinuria, decreased glomerular filtration rate, and nephritis. †P = 0.09
Denosumab (120 mg Q4W) is investigational (not approved) for use in patients with advanced cancer to delay SREs.Fizazi K, et al. J Clin Oncol. 2010;28(suppl 18). Poster.
Safety Results of Interest
Use of bone-targeted agents with abiraterone (COU-302)
Saad F, et al. Eur Urol 2016;68:570–7
OS TT deterioration in PS
Role of Bone-Targeted therapy when Current treatment paradigm is evolving
Local therapy
Androgen deprivation therapy (ADT)
Therapies after ADT
Death
ADT
Bone –targeted agents: denosumab / zoledronic acid)
mCRPCpost-
docetaxel
mCRPCsymptomatic
mCRPCmildly
symptomatic
mCRPCasymptomatic
(failed ADT)
Hormonesensitive
Sipuleucel-T
Enzalutamide
Abiraterone Abiraterone
Docetaxel Cabazitaxel
Radium 223 (bone-targeted agent)
Enzalutamide
Abiraterone
Bone-targeted agent: denosumab ; zoledronic acid
Radium-223 is a bone targeted therapy: targets cancers cells and the microenvironment
References: 1. Body, J.-J. Casimiro, S. And Costa L. Nat. Rev. Urol. 12, 340–356 (2015)
• Radium-223 is a targeted alphatherapy, that affects the cancercells and the tumormicroenvironment and thusdisrupts the vicious cycle oftumor growth and abnormalbone formation
ALSYMPCA: Study Design
Radium-223 (50 kBq/kg* IV) 6 injections at 4-week intervals
+ best standard of careb
Placebo (saline)6 injections at 4-week intervals
+ best standard of careb
• 136 centers in 19 countries• Planned follow-up is 3 years
PATIENTS (N=921)• Confirmed symptomatic CRPC• ≥2 bone metastases• No known visceral metastases• Post-docetaxel, unfit for docetaxel, or
refused docetaxela
STRATIFICATION• Total ALP: <<220 U/L vs ≥220 U/L• Bisphosphonate use: Yes vs No• Prior docetaxel: Yes vs No
R 2:1
ALP, alkaline phosphatase; ALSYMPCA, ALpharadin in SYMptomatic Prostate CAncer; CRPC, castration-resistant prostate cancer.
*Value is based on data assessed by previously used NIST standard. Updated nominal value of Xofigo is 55 kBq/kg body weight and not 50 kBq/kg body weight. Please see: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002653/WC500156172.pdf.
a. Unfit for docetaxel includes patients who were ineligible for docetaxel, refused docetaxel, or lived where docetaxel was unavailable.
b. Best standard of care defined as a routine standard of care at each center, e.g., local external beam radiation therapy, corticosteroids, antiandrogens, estrogens (e.g., stilbestrol), estramustine, or ketoconazole.
Parker C, et al. N Engl J Med. 2013;369(3):213–223
Radium-223 Improved OS Across All Patient Subgroups
Variable Subgroup n HR (95% CI)
All patients 921 0.70 (0.58-0.83)
Total ALP< 220 U/L 517 0.82 (0.64-1.07)
≥ 220 U/L 404 0.62 (0.49-0.79)
Current bisphosphonates Yes 374 0.70 (0.52-0.93)
No 547 0.74 (0.59-0.92)
Prior docetaxelYes 526 0.71 (0.56-0.89)
No 395 0.74 (0.56-0.99)
Baseline ECOG score0 or 1 801 0.68 (0.56-0.82)
≥ 2 118 0.82 (0.50-1.35)
Favours placeboFavours
223Ra
0.5 2.01.0
Parker C. N Engl J Med. 2013;369:213-223
Radium 223 SSE impact
CI, confidence interval. CRPC, castration-resistant prostate cancer. NE, not estimable.
a. Number of patients.
b. Median time to first event.
c. P values are for descriptive purpose only and not adjusted for multiplicity; the hazard ratio is the best interpretation of radium-223 effect.
Sartor O, et al. Lancet Oncol. 2014;15(7):738–746
RADIUM-223 (N=614) PLACEBO (N=307)
INDIVIDUAL SSE COMPONENTS na (%)
MEDIAN,b
MONTHS na (%)MEDIAN,b
MONTHS HR
(95% CI) P VALUEc
External beam radiation therapy
186 (30) 17.1 105 (34) 17.5E0.67
(0.53-0.85)0.00117
Symptomatic pathologic bone fracture
32 (5) NE 20 (7) NE0.62
(0.35-1.09)0.10
Spinal cordcompression
25 (4) NE 21 (7) NE0.52
(0.29-0.93)0.03
Tumor-related orthopedic surgical intervention
12 (2) NE 7 (2) NE0.72
(0.28-1.82)0.48
FavoursRadium-223
FavoursPlacebo
0 21
Adverse events aPatients With Treatment-Related AEs
Radium-223 + BSoC (n=600) Placebo + BSoC (n=301)
All Grades, n (%) Grades 3/4, n (%) All Grades, n (%) Grades 3/4, n (%)
Anaemia 187 (31) 79 (13) 93 (31) 39 (13)
Neutropaenia 30 (5) 13 (2) 3 (1) 2 (1)
Thrombocytopaenia 69 (12) 39 (7) 17 (6) 6 (2)
Bone pain 310 (52) 132 (22) 192 (64) 79 (26)
Diarrhoea 154 (26) 8 (1) 45 (15) 6 (2)
Nausea 215 (36) 10 (2) 102 (34) 6 (2)
Vomiting 116 (19) 10 (2) 41 (14) 7 (2)
Constipation 109 (18) 7 (1) 64 (21) 4 (1)
Fatigue 160 (27) 27 (5) 79 (26) 18 (6)
No AML, MDS, or primary bone cancer
No major safety issues identified up to 3 years after the last injection
aAEs on or after the first injection and up to 12 weeks after the last injection
AML, acute myelogenous leukaemia; MDS, myelodysplastic syndrome
Parker C et al. J Clin Oncol 33, 2015 (suppl 7; abstr 195)Parker C, et al. J Clin Oncol. 33, 2015 (suppl 7; abstr 195
ALSYMPCA: 3 Year Safety Follow-up
Treatment goal: prolong symptom-free AND overall survival
Symptom-free survival
Overall survival
+
SREs
How do you Classify Radium-223?
mCRPC Treatment Rationale
Anti-tumourtherapy
Bone-targeted therapy
Why?
Radium-223 prolongs survival with the added
clinical benefit of decreasing risk of SSEs
associated with skeletal disease progression,
when compared to placebo.
• Reduction of osteoblast number (72 h post dosing)
• Decline of serum PSA levels upon Ra-223 treatment (significant difference 72 h post dosing)
Number of osteoblasts Serum-PSA
Radium-223 is a bone targeted therapy
MoA in LuCaP-58 osteoblastic prostate PDX- Autoradiography upon a single dose of Ra-223 -
Suominen et al, EORTC-NCI-AACR 2014 posterECTS-IBMS 2015 poster 139, oral poster CABS OP4.3
━ Radium-223 (n=614)━ Placebo (n=307)End of cycleFollow-up visit
P <0.001
0
-40
40
80
120
140
Mea
n (
Stan
dar
d E
rro
r)P
erce
nt
Ch
ange
Fro
m B
asel
ine
100
60
20
-20
Week
0 20 28 40 4844363224124 168
Sartor O, et al. J Clin Oncol. 31, 2013 (suppl; abstr 5080). Annals of Oncol (28): 1090-1097, 2017.
1 2 3 4 5 6 1 2
━ Radium-223 614 582 561 517 465 413 353 336 252━ Placebo 307 286 260 231 193 159 130 136 100
ALSYMPCA: ALP dynamics
24
12 week tALP decline vs overall survival
*Confirmed tALP decline was defined as any decrease from baseline at week 12, confirmed ≥3 weeks later
.
Sartor O, et al. J Clin Oncol. 31, 2013 (suppl; abstr 5080). Annals of Oncol (28): 1090-1097, 2017.
20
0
40
60
80
100P
atie
nts
, %
Months
0 32 4024168
MEDIAN OS (months)━ Confirmed tALP decline (n=400) 17.8━ No confirmed tALP decline (n=97) 10.4HR (95% CI): 0.45 (0.34-0.61)P <0.0001
25
The Vicious Cycle of Bone Metastases: can we target both the cancer cell and the microenvironment (osteoclasts and osteoblasts)?
Bisphosphonates
Denosumab
Ra223
A phase 3b, international, prospective, interventional, open-label, single-arm, multicenter EAP
• Eligibility criteria were generally similar to those of ALSYMPCA, with the exception that asymptomatic patients were allowed
• Concomitant treatment with abiraterone, enzalutamide or denosumab was permitted
International Expanded Access Program (iEAP) for radium-223
*Value is based on data assessed by previously used NIST standard. Updated nominal value of Xofigo is 55 kBq/kg body weight and not 50 kBq/kg body weight. Please see: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002653/WC500156172.pdf.
§BSoC according to local clinical practice. If chemotherapy/radiotherapy is considered BSoC, Ra-223 must be discontinued. ‡473 patients entered active follow-up.†Adverse events were coded according to MedDRA version 17.1 and graded by NCI-CTCAE version 4.03.
SOURCE: Saad F, et al. Lancet Oncol. 2016 Sep;17(9):1306-16.
TREATMENT (N=696)
Radium-223 (50 kBq/kg*) q 4 wk × 6 injections + best standard of care§
PATIENTS (N=839)
• CRPC/HRPC with bone metastasis
• ≥2 skeletal mets on imaging
• No lung/liver/brain mets(lymph node metastases allowed)
TREATMENT ASSESSMENTS(each cycle)
Variables: SREs, TEAEs, ECOG PS, lab tests, QoL (BPI-SF), OS
Exploratory: SREs, ALP, PSA (changes in levels and time to event data)
FOLLOW-UP‡
Safety† TEAEs, SAEs, secondary malignancies
PRIMARY ENDPOINTS
• Safety
• OS
EXPLORATORY ENDPOINTS
• Time to first SRE
• Changes in total ALP activity and PSA levels from baseline
• Time to ALP/PSA progression
• QoL
POST HOC ANALYSES INCLUDED OS IN SUBGROUPS BASED ON:
• Previous use of docetaxel, abiraterone or enzalutamide
• Concomitant use of abiraterone, enzalutamide or denosumab
• Baseline total ALP values
• Baseline ECOG PS
• Baseline hemoglobin
• Baseline pain
OS by concomitant treatment – novel endocrine agents and denosumab*
NA = not available.
*Concomitant use is defined as an agent started after the first injection of radium-223 (concomitant), or any agent administered before the provision of patient informed consent and continued after the first injection of radium-223 (continuous).
SOURCE: Saad F, et al. Lancet Oncol. 2016 Sep;17(9):1306-16.
Median duration of treatment with concomitant abiraterone or enzalutamide, which included all abiraterone or enzalutamide exposure on or after the first injection of radium-223, was 24.9 weeks (IQR 12.6–37.9) for abiraterone and 15.5 weeks (IQR 6.7–29.1) for enzalutamide.
MEDIAN OS, months (95% CI)
━ Yes (n=189): NA (16-NA)━ No (n=507): 13 (12-16)
CONCOMITANT USE OF NOVEL ENDOCRINE AGENTS
80
100
Ove
rall
Surv
ival
(%
)
20
0
60
40
2460 12 18
Time from Start of Treatment (months)
80
100
Ove
rall
Surv
ival
(%
)
20
0
60
40
2460 12 18
Time from Start of Treatment (months)
MEDIAN OS, months (95% CI)
━ Yes (n=136): NA (15-NA)━ No (n=560): 13 (12-NA)
CONCOMITANT USE OF DENOSUMAB
Combining drug X to docetaxel: a failing strategy so far…
Fizazi K. Personal communication
• Doc + Oblimersen
• Doc + DN-101
• Doc + Bevacizumab
• Doc + VEGF-Trap
• Doc + Lenalidomide
• Doc + Atrasentan
• Doc + Zibotentan
• Doc + GVAX
• Doc + Dasatinib
• Doc + Custirsen
Negative Phase III trials
Current combination strategies (ongoing Phase III)
• Abiraterone + Enzalutamide (US)
• Abiraterone + ARN-509 (ACIS)
• Abiraterone + Radium-223 (ERA): negative impact
• Enzalutamide + Radium-223 (PEACE-3)
Systemic treatment for CRPC in 2017
K Fizazi, personal communication
Abiraterone
or Enzalutamide
Local Treatment
PSA relapse (ADT)
Metastatic Castrate-Resistant
Prostate Cancer
Castrate-resistant, M0
Metastatic Hormone-Sensitive
prostate cancer
Docetaxel
Zoledronate
Radium 223*Abi/Enza Cabazitaxel
ADT +/- Docetaxel
Denosumab
Bone-targeted agent
Anti-tumor agent agent
Bone Metastases in
Prostate cancer: treatment strategies
Integrate forefront scientific research
with medical teaching, medical training and patient care
Lisbon Academic Medical Center
Thank you for your attention,
Luís Costa