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

stephane.oudard@aphp.fr

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