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Oligometastatic prostate cancer (PC):Current data and controversiesMedical oncologist perspective
Stéphane OUDARD, MD, PhDHead of the Oncology Department
Georges Pompidou HospitalRené Descartes University, Paris, France
Singapore, 21 september 2018
Disclosure
� Research grant agreement:
● Sanofi, Janssen, Astellas
� Consulting agreements with:
● Astellas AstraZeneca
● Janssen Roche
● MSD Sanofi
How to define oligometastasis?
� Definition by Hellman and Weichselbaum in 1995
● An intermediate state of cancer spread between localized disease and widespread metastases
Hellman S et al, JCO 1995, 13;8-10
Tran PT et al, JOP ASCO 2017, 13;1:21-24
Definition of oligometastasis
� What is oligometastatic disease based on?
� Number of mets
� What kind of imaging are referred
� A favorable tumor biology
Tosian JJ et al, Nature Urology 2017, 14;15-25
Definition of oligometastasis� What Study defining oligomets PC?
Tosian JJ et al, Nature Urology 2017, 14;15-25
Development of 3 or fewer no-castrate lesions outside PC
Bone and/or soft tissu mets
Definition of oligometastasis
Sartor O et al, The Oncologist 2013, 18:549-57
De Souza NM et al, EJC 2018; 91:153-63
*Low sensivity-specificy for detecting early metastatic spread
� What kind of imaging are referred?
� Current methods*
� Bone scan and CT-scan
� New imaging technics: PET-scan & WB-RMI
� MRI
� 18F and 11C choline
� 69Ga-prostate-specific membrane antigen
MRI: Magnetic resonance imaging ;
PET: Positron emission tomography
PSMA PET Identifies Oligometastatic Disease at Initial Diagnosis
Wu et al, Int J Rad Onc Biol Phys. 2017;99(suppl 2):E275
• USCF experience with PSMA PET prior to definitive radiation therapy
• High-risk localized disease: GS ≥ 8, CAPRA ≥ 5, or PSA ≥ 15 ng/mL
Lengana T et al, Clin Cancer Genit 2018; July 2018
� 113 pts underwent initial skeletal staging for prostate cancer
� Comparison of 99mTc-MDP bone scintigraphy (BS) and 68Ga-PSMA PET
68Ga-PSMA PET/CT showed significantly higher sensitivity and accuracy than BS (96.2% vs. 73.1%, and 99.1% vs. 84.1%) for the detection of skeletal lesions.
Oligometastasis: A favorable tumor biology?
Lussier YA et al, Plos One 2011, 6;12:e28650
� 42 parrafin embedded samples of primary and metastatic tumors (1-5 mets) from pts treated with SART
� 5 pts with both primary and mets, other either primary or mets
� Analysis of the microRNA-200 family
SART: Stereoatatic radiotherapy
How Should We Manage Oligometastatic Disease?
Local consolidation
therapy of PC
Metastatic-
directed therapy
Systemic therapy
Patterns of Polyclonal Metastatic Spread
Gundem G et al, Nature 2015;520:353-357
� Primary tumor and existing metastases can seed new metastases
� Principal mode of spread is metastases to metastases
� Thus to cure oligometastaticdisease, we may need to ablate both the primary and the metastases
Retrospective studies for local consolidation therapy of PC
1. Culp S et al, Eur Urol 2014, 65:1058-66 ; 2. Antwi S et al, Cancer Epidemiol 2014, 38:435-441 ; 3. Gratzke C et al, Eur Urol 2014, 66:602-3 ; 4. Satkunasivam R et al, J Urol
2015, 194:378-85 ; 5. Heidenreich A et al, J Urol 2015, 193:832-38 ; 6. Cho Y et al, Plos One 2016, 11:e0147191 ; 7. Rusthoven GC et al, JCO. 2016 Aug 20;34(24):2835-42
Reference Study Design Inclusion Intervention Conclusion
Culp1
2014 SEER, n=8185 M1RP vs BT
vs no local therapyOS & CSS
favored RP and BT
Antwi2
2014SEER + propensity score analysis,
n=7858 M1RP vs BT
vs no local therapyCSM favored RP and BT
Gratzke3
2014Munich Cancer Registry Database,
n=1538 M1RP vs no RP
(ADT only or RT or other)OS favored RP
Satkunasivam4
2015 SEER + Medicare, n=4069 M1RP vs IMRT vs #D CRT
vs no local therapyOS favored RP and IMRT
Heidenreich5
2015 Case-control, n=61M1,
≤3 bone metsRP vs no RP
Time to castration resistance, PFS, CSS
favored RP
Cho6
2016 Case-control, n=140M1,
≤5 bone metsProstate vs pall RT to M1
vs no local therapyOS, bFFS favor prostate
RT
Rusthoven7
2016 NCDB, n=6382 M1RT + ADT
vs ADT aloneOS favored RT + ADT
ADT, androgen deprivation therapy; bFFS, biochemical failure-free survival; BT, brachytherapy; CSS, prostate cancer specific survival; CRT,
chemoradiation; IMRT, intensity modulated radiation therapy; RP, radical prostatectomy; RT, radiation therapy; OS, overall survival
1. Culp S et al, Eur Urol 2014, 65:1058-66 ; 2. Antwi S et al, cancer Epidemiol 2014, 38:435-441 ; 3. Gratzke C et al, Eur Urol 2014, 66:602-3 ; 4. Satkunasivam R et al, J Urol
2015, 194:378-85 ; 5. Heidenreich A et al, J Urol 2015, 193:832-38 ; 6. Cho Y et al, Plos One 2016, 11:e0147191 ; 7. Rusthoven GC et al, JCO. 2016 Aug 20;34(24):2835-42
Reference Study Design Inclusion Intervention Conclusion
Culp1
2014 SEER, n=8185 M1RP vs BT
vs no local therapyOS & CSS
favored RP and BT
Antwi2
2014SEER + propensity score analysis,
n=7858 M1RP vs BT
vs no local therapyCSM favored RP and BT
Gratzke3
2014Munich Cancer Registry Database,
n=1538 M1RP vs no RP
(ADT only or RT or other)OS favored RP
Satkunasivam4
2015 SEER + Medicare, n=4069 M1RP vs IMRT vs #D CRT
vs no local therapyOS favored RP and IMRT
Heidenreich5
2015 Case-control, n=61M1,
≤3 bone metsRP vs no RP
Time to castration resistance, PFS, CSS
favored RP
Cho6
2016 Case-control, n=140M1,
≤5 bone metsProstate vs pall RT to M1
vs no local therapyOS, bFFS favor prostate
RT
Rusthoven7
2016 NCDB, n=6382 M1RT + ADT
vs ADT aloneOS favored RT + ADT
Multiple single center, retrospective
and nonrandomized data
USING ALSO SYSTEMIC THERAPIES
RP was the most used prostate-directed therapy
Many studies suggest a benefit for local therapies
SELECTION BIAS!!!???
Multiple single center, retrospective
and nonrandomized data
USING ALSO SYSTEMIC THERAPIES
RP was the most used prostate-directed therapy
Many studies suggest a benefit for local therapies
SELECTION BIAS!!!???
ADT, androgen deprivation therapy; bFFS, biochemical failure-free survival; BT, brachytherapy; CSS, prostate cancer specific survival; CRT,
chemoradiation; IMRT, intensity modulated radiation therapy; RP, radical prostatectomy; RT, radiation therapy; OS, overall survival
Retrospective studies for local consolidation therapy of PC
Reference N Inclusion Intervention Result
Jereczek-Fossa1
201234 M1 bone recurrence SBRT (33-36 Gy/3 fx)
30mo LC 100%
30mo PFS 0%
Ahmed2
201217 M1, ≤5 mets SBRT (20 Gy/ 1 fx) followed by ADT
6mo LC 100%;
53% undetectable PSA
Muacevic3
201340 M1, ≤2 bone mets SBRT (20.2 Gy/ 1 fx) 2y LC 95,5%
Schick4
201350
N1-M1 ≤4 regional
LN or mets
EBRT (50.4 Gy pelvic LN, 65Gy LN boost)
+ STADT
3y bRFS 55%
3y DMFS 59%
3y OS 92%
Berkovic5
201324 M1, ≤3 bone or LN mets SBRT (50Gy/10fx)
2y LC 100%
2y cPFS 42%
Median ADT-free time: 38 mo
Decaestecker6
201450 M1 ≤3 mets SBRT (50Gy/10fx or 30Gy/3fx)
2y LC 100%
2y PFS 35%
Median ADT-free time: 25 mo
Mulderman7
201666 M1, ≤5 mets, CRPC
SBRT (16Gy/1 fx, 18Gy/1fx, 30Gy/3fx,
50Gy/5fx)
2y LC 95% (≥18 Gy), 58% (16 Gy)
2y bFPFS 54%
2y OS 83%
Habl
20178 15 M1 ≤2 mets SBRT (25-35 Gy/5fx)
2y LC 100%
Median distant PFS: 7.4 mo
Median ADT-free time: 9.3 mo
Retrospective studies for metastasis-directed RT
1. Jereczek-Fossa et al, Int J Radiat Oncol Biol Phys. 2012 Feb 1;82(2):889-97; 2. Ahmed K et al, Front Oncol 2013, 2:215 ; 3. Muacevic A et al, Urol Oncol 2013, 31:455-
60 ; 4. Schick U et al, Acta Oncol 2013, 52:1622-28 ; 5. Berkovic P et al, CGC 2013, 11:27-32 ; 6. Decaestecker K et al, Radiat Oncol 2014, 9:135 ;
7. Mulderman et al, Eur Urol 2016 ; 8. Habl G et al, BMC Cancer. 2017 May 22;17(1):361
Reference N Inclusion Intervention Result
Jereczek-Fossa1
201234 M1 bone recurrence SBRT (33-36 Gy/3 fx)
30mo LC 100%
30mo PFS 0%
Ahmed2
201217 M1, ≤5 mets SBRT (20 Gy/ 1 fx) followed by ADT
6mo LC 100%;
53% undetectable PSA
Muacevic3
201340 M1, ≤2 bone mets SBRT (20.2 Gy/ 1 fx) 2y LC 95,5%
Schick4
201350
N1-M1 ≤4 regional
LN or mets
EBRT (50.4 Gy pelvic LN, 65Gy LN boost)
+ STADT
3y bRFS 55%
3y DMFS 59%
3y OS 92%
Berkovic5
201324 M1, ≤3 bone or LN mets SBRT (50Gy/10fx)
2y LC 100%
2y cPFS 42%
Median ADT-free time: 38 mo
Decaestecker6
201450 M1 ≤3 mets SBRT (50Gy/10fx or 30Gy/3fx)
2y LC 100%
2y PFS 35%
Median ADT-free time: 25 mo
Mulderman7
201666 M1, ≤5 mets, CRPC
SBRT (16Gy/1 fx, 18Gy/1fx, 30Gy/3fx,
50Gy/5fx)
2y LC 95% (≥18 Gy), 58% (16 Gy)
2y bFPFS 54%
2y OS 83%
Habl
20178 15 M1 ≤2 mets SBRT (25-35 Gy/5fx)
2y LC 100%
Median distant PFS: 7.4 mo
Median ADT-free time: 9.3 mo
Retrospective studies for metastasis-directed RT
1. Jereczek-Fossa et al, Int J Radiat Oncol Biol Phys. 2012 Feb 1;82(2):889-97; 2. Ahmed K et al, Front Oncol 2013, 2:215 ; 3. Muacevic A et al, Urol Oncol 2013, 31:455-
60 ; 4. Schick U et al, Acta Oncol 2013, 52:1622-28 ; 5. Berkovic P et al, CGC 2013, 11:27-32 ; 6. Decaestecker K et al, Radiat Oncol 2014, 9:135 ;
7. Mulderman et al, Eur Urol 2016 ; 8. Habl G et al, BMC Cancer. 2017 May 22;17(1):361
Single center, small number studies
Short term local control achieved only
Single center, small number studies
Short term local control achieved only
Trials for Metastases-Directed Therapy
Trial Inclusion ArmsPrimary
OutcomeCROP
(Sunnybrook)NCT02563691
M1a-b ≤5 Prostate 35-40 Gy/5fx, Nodes 25-35 Gy/5fx, Mets 30-40
Gy/5fx, ADT at least 1 yearToxicity
GETUG-P07NCT02274779
Pelvic LNs by choline PETPelvic LN 45 Gy, LN + boost 66 Gy and
ADT x 6 monthsBF
STOMPNCT01558427
N1 + M1 ≤3 lesions by choline PETArm A: active surveillance
ADT-free survivalArm B: SBRT or surgery for metastasesADT at progression
ORIOLENCT02680587
≤3 bone metsObservation vs SBRT +/- DCFPyL-PET/MR,
no ADTPFS
Univ FloridaNCT01859221
M1 exclusing CNSSBRT or stereotactic hypofractionated RT
ADT for allPFS
NRGNCT02206334
≤4 mets, NSCLC, breastor prostate
SBRT, ADT allowedRecommended
SBRT dose
CORENCT02759783
≤3 mets, NSCLC, breast or prostate SBRT vs standard of care PFS
GICORNCT02192788
N1 + M1 ≤5 by choline PET SBRT, ADT allowed PFS
Stevens DJ et al, Curr Treat Options Oncol 2016;17(2):62-70 ;
Tosoain JJ et al, Nature 2017, 14:15-25 ;SBRT: stereotactic body radiotherapy; ADT: androgen deprivation therapy
STOMP Trial� Phase II study, asymptomatic PC pts with a PSA recurrence after primary PC treatment with curative intent,
� < 3 extracranial mets (choline-PET) + testosterone level < 50 ng/mL,
� Randomization (1:1): Surveillance or MDT of all detected lesions (surgery or SBRT)
� Surveillance: PSA every 3 months, with repeated imaging at PSA progression or clinical suspicion for progression.
SBRT: stereotactic body radiotherapy; PC: Prostate cancer; MDT: Metastasis-directed therapy Ost P et al, J Clin Oncol 2018;36(5):446-54
Primary endpoint:
ADT-free survival
MDT: metastasis-directed therapyOst P et al, J Clin Oncol 2018;36(5):446-54
13 months
21 months
HR: 0.6, (CI80%, 0.4-0.9, p=0.11
ADT-free survival was longer with MDT than
with surveillance alone for oligomets PC
MDT: metastasis-directed therapy Ost P et al, J Clin Oncol 2018;36(5):446-54
Surveillance:
35% of pts had a PSA
decline
MDT:
75% of pts had a PSA
decline
PSA decline in the surveillance group
supporting a slow natural history
Trial designs for Metastases-Directed Therapy
Stevens DJ et al, Curr Treat Options Oncol 2016;17(2):62-70 ;
Tosoain JJ et al, Nature 2017, 14:15-25 ;
ADT+ Doc + Abi
HORRAD
STAMPEDE
Co-primary endpoints:
OS and
PFS (HR: 0.75)
• 916 patientsplanned
Newly diagnosed(hormone-naïve) metastatic CaP
ADT + Docetaxel
+ local RT
RAND
OMIZED
PEACE-1ADT + Docetaxel
ADT + Doc + Abi
+ Local RT
M.D. Anderson Cancer Center
Randomized Studies with Systemic Therapy for High-risk Localized Disease
1. Fizazi K, et al. Lancet Oncol. 2015;16:787-94; 2. Sandler H, et al. ASCO 2015: Abstr LBA5002;
2. 3. James ND, et al. Lancet 2016; 387: 1163–77; 4. James ND, et al. ASCO 2017: Abstr 5003.
Reference N Inclusion PCa Therapy Arms Result
GETUG 121 413
GS≥8, T3,
PSA≥20,
N1
N0: RP/RT3y ADT ± 4 cycles DOC
8y RFS 62% ADT+DOC vs
50% ADT alone
(HR 0.71, p=0.017)N1: RT or none
RTOG 05212 562
GS≥7, PSA≥20,
any T≥T2 and GS≥8, PSA
<20
WPRT 46.8 Gy + Prostate boost
25.2-28.8 Gy
2y ADT ± 6 cycles
DOC+P
5y OS 93% ADT+DOC vs
89% ADT alone
(HR 0.70, 1-sided p=0.04)
STAMPEDE3
DOC2962
New diagnosis
high-risk, N1 or M1
or high-risk relapse
(35% N0-1 M0)
RT for N0M0 ADT±ZA Median OS 81mo ADT+DOC vs
71mo ADT alone
(HR 0.78, p=0.006)RT optional for
N1M0ADT+DOC ± ZA
STAMPEDE4
ABI1917
New diagnosis
high-risk, N1 or M1
or high-risk relapse
(46% N0-1 M0)
RT optional for N1M0 ADT±ABI
3y OS 83% ADT+ABI vs
76% ADT alone
(HR 0.63, p<0.001)
ABI, abiraterone; ADT, androgen deprivation therapy; DOC, docetaxel; GS, Gleason score; RP, radical prostatectomy; RT, radiation therapy;
WPRT, whole pelvis radiation therapy; ZA, zoledronic acid
Biochemical PSA relapse post-RP and/or RXT:ADT +/- Docetaxel (GETUG) in high-risk hormone-naïve non
metastatic patients
Oudard S et al, ESMO 2017, oral presentation, abstract 4679
Docetaxel for mHSPC Meta-Analysis
Results based on 2993 men / 1254 deaths
Trial name
OverallSTAMPEDE (SOC+ZA +/- Doc)STAMPEDE (SOC +/- Doc)GETUG15CHAARTED
HR=0.77 (0.68, 0.87) p<0.0001
.5 1 2
Heterogeneity:χ2=4.80, df=3, p=0.187, I2 = 37.5%
Favours SOC + docetaxel Favours SOC
Vale C et al, Lancet Oncol 2016;17(2):243-56Kyriakopoulos CE et al, 2018; 36(11):1080-7
ADT, androgen deprivation thearpy; DOC, docetaxel; HNCP, hormone-naive prostate cancer; NA, not available; M1, metastatic; P, prednisone; PCa, prostate cancer; SOC, standard of care; ZA, zoledronic acid
Absolute 9% OS benefit at 4 years. Results for LOW Volume
disease were NOT consistent with the global benefit*
ABIRATERONE + ADT in M1 newly diagnosed PC: Systematic review and meta-analysis
Rydzewska LHM et al, Eur J Cancer 2017; ;84:88-101
Results based on 2201 men and 774 deaths
14% absolute improvement in 3-year survival
• Oligomets PC is due to modern imaging techniques
• Prostate or metastatis-directed therapy (MDT) evaluated in mostly retrospective and heterogeneous studies
• Numerous phase III addressing the question on MDT
• Systemic therapy level 1 of evidence in mHSPC (ADT + DOC or ABI)
• Low volume disease: not advantage of systemic TT
• Research with different drugs are needed
• Biology to differentiate low vs aggressive disease is warranted
Conclusions