Prostate Cancer

Robert B. Sklaroff, M.D., F.A.C.P.

[December 4, 2019]
 Objectives:
• 1. Controversies in Multidisciplinary Decision-Making
• 2. The Interface of Community Care and Clinical Research
• 3. How to Apply Critical Thinking to how Patients Accommodate these issues.

• This presentation will admix these goals while covering major educational topics.
• Psychosocial concerns will be identified through discussion of a patient narrative.
• Achieving a comfort-level with integrating tertiary/quaternary/quintenary input.
 Advanced Prostate Cancer Consensus Conference (APCCC 2019)
Programme 2019 - Areas of controversy

1. Molecular biomarkers and novel imaging

2. Locally advanced prostate cancer [Node-positive prostate cancer (N1
but M0)]
3. Biochemical recurrence of prostate cancer after local therapy
4. Management of primary tumour in the metastatic setting
5. Newly-diagnosed, castration-sensitive/naïve prostate cancer, including
oligometastatic prostate cancer
6. Management of nmCRPC (M0 CRPC)
7. Management of mCRPC
8. Bone and bone metastases
 Advanced Prostate Cancer Consensus Conference (APCCC 2019)
Programme 2019 - Areas of controversy

1. Molecular biomarkers and novel imaging

2. Locally advanced prostate cancer [Node-positive prostate cancer (N1
but M0)]
3. Biochemical recurrence of prostate cancer after local therapy
4. Management of primary tumour in the metastatic setting
5. Newly-diagnosed, castration-sensitive/naïve prostate cancer, including
oligometastatic prostate cancer
6. Management of nmCRPC (M0 CRPC)
7. Management of mCRPC
8. Bone and bone metastases
 Case Presentation
• 66-y-o, Systolic Hypertension, Overweight, R Herniorrhaphy [mesh, 1994]
• Colonic Polyps [+ family history], Malignant Melanoma [1/2018]
• Nocturia x 1, PSA = 29, normal cardiac stress-test and labs [8/2018]
• negative BRCA, multifocal primary, obturator nodes [R>L], Gleason 9-10
• R Seminal Vesicle and Neurovascular Bundle Involved, Stage IV-A
• Abutted Rectum prior to Androgen Deprivation Therapy, responded
• Bone Radionuclide Scan and Staging CT Scans [Chest/Abdomen] neg.
• Younger/healthier men may benefit from surgery, for such aggressive treatment
is warranted in high-risk patients because 5-year survival is 75%-98%.}
 National Comprehensive
Cancer Network
• Resection with node-dissection can be elected for high-risk patients
[encompassing clinical stage T2b or higher, high Gleason, PSA >10,
and >50% core involvement] who have no major comorbidity factors.
• T2b = “involvement of more than half of one lobe but does not
involve the other lobe of the prostate.” {in this case, bilateral}
• Needle Bx [node] did not yield Gleason; Needle Bx [primary] did
• ADT yielded PSA ↓ without significant change in BPH-Sx; resectable?
• PSA ↑ [2→3] and persistent 1o regression; urologist punted
• Assessed the literature and visited local entities plus NYC-Cornell
 Literature Review
• Radical prostatectomy improves progression-free and cancer-specific
survival in lymph node positive prostate cancer in the prostate-specific
antigen era: a confirmatory study. [Steuber T]
• https://onlinelibrary.wiley.com/doi/full/10.1111/j.1464-410X.2010.09730.x
• Even with positive-node cancer, surgery results in a 10-year survival rate of
76%+, though some of those people also had radiation therapy. In this
particular study it was 6% of the surgery participants.
• Surgery vs. XRT: “if a reasonable review of the updated literature doesn’t
define a survival advantage [minimal 5%] following RRLND, then XRT will
probably be desirable” {arguendo}
 Advanced Prostate Cancer Consensus Conference (APCCC 2019)
Programme 2019 - Areas of controversy

1. Molecular characterization: tissue and blood

2. Locally advanced prostate cancer [Node-positive prostate cancer (N1 but M0)]
3. Biochemical recurrence of prostate cancer after local therapy
4. Management of primary tumour in the metastatic setting
5. Newly-diagnosed, castration-sensitive/naïve prostate cancer, including oligometastatic prostate cancer
6. Management of nmCRPC (M0 CRPC)
7. Management of mCRPC
8. Bone and bone metastases
9. Heterogeneity of patients with prostate cancer (ethnicity, elderly)
10. Side effects of hormonal treatments and their management

ALL slides can be downloaded [https://www.urotoday.com/apccc-2019-slides.html?cmn=1572573743].

 1. Molecular characterization: tissue and blood

•Molecular characterization
•Clinical utility of molecular markers
•genetic testing
•PSMA PET/CT
State of the art on molecular
characterization in
advanced
prostate
Colin C. cancer (APC)
Pritchard MD, PhD
University of Washington
Department of Lab Medicine
Brotman Baty Institute for Precision
Medicine
APCCC Basel Switzerland
August 29, 2019
Emerging Model For Advanced Prostate
Cancer
Germline, tumor, liquid biopsy evaluated

Therapy guided by germline and somatic findings

Genetic counseling based on somatic and germline findings

Discoidin domain receptor family, member 1, also known as
DDR1 or CD167a (cluster of differentiation 167a), is a human
gene. Function. Receptor tyrosine kinases (RTKs) play a key role
in the communication of cells with their microenvironment.
These molecules are involved in the regulation of cell growth,
differentiation and metabolism.

The MSH2 protein joins with one of two other proteins, MSH6
or MSH3 (each produced from a different gene), to form a
protein complex. This complex identifies locations on the DNA
where errors have been made during DNA replication. Another
group of proteins, the MLH1-PMS2 protein complex, then
repairs the errors. [MutS protein homolog 2 - microsatellite instability]
 DDR Mutation Prevalence
Estimates (Adavanced
Prostate Cancer)
Somatic Germline Combined Enriched In

BRCA2 5% 5% 10% Family history breast/ovarian,

Ductal + Intraductal
histology
BRCA1 1% 1% 2%
Family history breast/ovarian,
Ductal + Intraductal
ATM 2-3% 2% 4-5% histology

MSH2/6 4-5% 1.5% 5-6% Family history breast/ovarian

Family history colon/endometrial,

Ductal histology, Gleason pattern 5
Estimates based on Robinson 2015, Prtichard 2016, Na 2017, Annala 2017, Giri 2018, Nava Rodriquez 2018, Nicolosi 2019
Not All DDR Genes Are the
Gene
Same
Pathway Germline Prostate
Cancer Risk?
PARP/platinum
(~level of
evidence)
Anti PD1/PDL1
(~level of
evidence)
BRCA2 HR High +++++ -
BRCA1 HR Moderate ++++ -
ATM HR Moderate ++ -
CHEK2 HR Moderate + -
PALB2 HR Emerging (High?) +++ -
NBN HR Some data +/- -
RAD51C HR Unknown +/- -
RAD51D HR Unknown +/- -
BRIP1 HR Unknown +/- -
FANCA HR Unknown + -
MSH2 MMR High - +++++++
MSH6 MMR Moderate - +++++
MLH1 MMR Moderate - ++++
PMS2 MMR Some Data - ++
 Lynch: The Specific
Gene Matters
Cumulative Prostate Cancer Incidence by Gene (%)
Age MLH1 MSH2 MSH6 PMS2
50 0.3 0.8 0 4.6
60 3.2 6.3 0 4.6
70 7 15.9 4.8 4.6
75 13.8 23.8 8.9 4.6

Adapted from: Genetics in Medicine (2019) https://doi.org/10.1038/s41436-019-0596-9

DNA Repair in
Prostate Cancer
DNA Germlin
Key Genes Treatment
Repair e
Pathway Syndrom
e

Homologous
BRCA PARPi,
Recombinatio King
1, platinum
n Repair
BRCA
(HR)
2

Mismatch Anti-
MSH2 Lynch
Repair PD1/
(MMR) PDL-1
• Consider metastatic biopsy

• Consider tumor testing for MSI-H or dMMR

– Use MSI test specifically-validated for prostate cancer

• Consider germline AND tumor testing for HR DNA repair

– BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, CHEK2

MSI-H: microsatellite instability high; dMMR: deficient mismatch repair; HR: homologous recombination
 ISUP 2019
Recommendations
• Germline panel testing for DNA repair genes in:
– Metastatic AND high-risk localized

• Somatic tumor DNA testing in all metastatic:

dMMR by either IHC and/or MSI/gene sequencing AND
dHR by sequencing of BRCA1/2 at minimum

Testing on metastatic tissue or, if unavailable,

primary tissue is acceptable

ISUP= International Society of Urologic Pathologists

HR DDR Testing: Issues
• Confirming bi-allelic inactivation
– HR signature analysis (BRCA1/2)
– IHC (ATM protein)

• Variant interpretation
– Commercial labs still struggling

HR DDR= Homologous Recombination DNA Damage Repair

Bi-allelic Inactivation Matters
BRCA1 and BRCA2 (combined)

Bi-allelic
Het.
Adapted from Jonsson et al. Nature. 2019 571:576-579.
MMR DDR Testing:
Issuses
• Accuracy of MSI - genetic hypermutability that results
from impaired DNA mismatch repair. The presence of
MSI represents phenotypic evidence that MMR is not
functioning normally.

• Accuracy of IHC [Immuno-histo-chemistry]

• Technically challenging to detect underlying mutation(s)

MMR DDR= Mismatch Repair DNA Damage Repair
MSI Patterns Are Not The Same
Between Cancer Types
Colon, Rectum
Breast, Ovarian, GBM, Kidney
Clear Cell
Uterine, Lung, Head and
Neck, Bladder,
Thyroid,,
Melanoma, Prostate
Low-Grade Glioma

Stomach, Liver,
Kidney
Papillary

H
a
u
s
e

e
t
Prostate Cancer-Validated MSI by
NGS Outperforms Traditional
Methods
[NGS = next-generation sequencing]

Hempelmann et al. (2018) JITC.

 Liquid Biopsy
Adequate testing in advanced prostate
cancer depends on disease burden

PSA>10 PSA<10

Adapted from Schweizer et al. Prostate (2019) 79:701-708.

 Liquid Biopsy:
Poor congruencePitfalls
between two
commercial labs in 40 mPC patients PSA>10 PSA <10

CHIP?

Adapted from Torga and Pienta, JAMA Oncol. 2018;4(6):868-870.

Liquid Biopsy: Treatment
Resistance
Example: Following Platinum Treatment
Reversion Mutations Restore Reading Frame

BRCA2 c.7355del Reversion Mutations

BRCA2 Exon 14

Cheng et al. (2018) JCO Precision Oncology

 Summar
y
• Germline and tumor NGS testing of DNA repair genes
is increasingly recommended to guide advanced
prostate cancer treatment

• Liquid biopsy (ctDNA) testing increasingly used in

place of tissue testing and useful when patients are
carefully selected with adequate disease burden

• Sample, methods, and interpretation matter,

increasing molecular pathologist roles
 1. Molecular characterization: tissue and blood

•Molecular characterization
•Clinical utility of molecular markers
•genetic testing
•PSMA PET/CT
 Clinical Utility of Molecular
Biomarkers
for Advanced
•
Prostate
Conclusions [44 slides later….]
Cancer
• • Assay analytic validation and clinical qualification is an urgent need
• – An alteration/mutation ≠loss of function
• – Orthogonal assays may be needed for precision
• – Bespoke prospective trials needed to qualify validated biomarkers
• • Molecular stratification for mCRPC is going to become a standard
• – Assays for MMRd and BRCA2, BRCA1, PALB2, ATM, FANCA, RAD51, ATM, CDK12
• – SPOP mutated cancers: Do very well on ARSI
• • More data needed to prove utility of AR and PTEN/PI3K/AKT assays
• – AR alterations data needs active drugs eg AR degraders, AR-SV inhibitors
• – Phase III trials of ARSI and AKTi could make PI3K/AKT/PTEN assays standard of care
 MMRd responder - rectovesical fistula (2012)

Disease course
Initial diagnosis: T4N0M0 GS10 (5 + 5) (Sep 2005)
Metastasized to lymph nodes (Nov 2009)

Prior systemic therapy

Gosrelin (Sep 2005) + bicalutamide (Jan 2006)
Abiraterone (Nov 2009-Dec 2014)
Docetaxel (Mar 2015-Nov 2015)
Enzalutamide (Jan 2016-Jul 2016)

Enrolled in KEYNOTE-199 cohort 1 - Age 70 years • Found in a small percentage (≤5%) of mCRPC
MMRD [Mismatch repair defective] by IHC – Often but not always associated with high TILs
First pembro dose: Nov 25, 2016 – Sometimes but not always respond to PD-1/PD-L1 Last dose (cycle 11):
Jun 13, 2017 checkpoint inhibitors
Last survival follow-up: Summer 2020
Still in remission
 1. Molecular characterization: tissue and blood

•Molecular characterization
•Clinical utility of molecular markers / genetic
testing
•PSMA PET/CT
Azienda Ospedaliero-Universitaria di
Bologna Policlinico S.Orsola

ALMA MATER STUDIORUM

UNIVERSITÀ DI BOLOGNA

Advantages of PSMA PET

in AP imaging

tefano Fanti
Advantages of PSMA PET for imaging Prostate Cancer

STAGING

BIOCHEMICAL RECURRENCE

THERAPY PLANNING
STAGING
 STAGING

PSMA PET in prostate cancer staging

BIOCHEMICAL RECURRENCE
PSA PERSISTENCE
50yo; Gs 9 T3b iPSA 34ng/ml
Staging with pelvic MRI, CT and BS than RP December
2018 (T3b N1 M0) January 2019: PSA nadir 0.3ng/ml
(PSA persitence);

18 February 2019 C- 27 February 2019

Choline Ga-PSMA
THERAPY PLANNING
THERANOSTIC
 THERANOSTIC

177Lu

225Ac
Pitfalls of PSMA PET/CT in APC
imaging
Ian Davis
Professor of Medicine, Monash University and Eastern Health
Head, Eastern Health Clinical School
Chair, ANZUP Cancer Trials Group
NHMRC Practitioner Fellow
@Prof_IanD
 Ga-PSMA PET/CT is
68

great, but…

 False positives
 False negatives
 True positives but who cares
 Inappropriate changes in management
 Other pitfalls

 Note: the “CT” component is important.

 Shetty D et al. Tomography 4: 182-193, 2018

Costochondral junction Hofman MS et al. RadioGraphics 38: 200-217, 2018

Hepatocellular carcinoma

Polycythemia rubra vera

Recurrent NSCLC

Rectal adenoca Neuroendocrine Rib fracture

Not all prostate carcinomas are PSMA-avid

PeterMac
IHC courtesy of Dr Catherine Mitchell,
PSMA 1+ 10%
(low staining)

PSMA PET -ve MRI PIRADS

5 immunohistochemi
 Gleason 5+5=10 prostate carcinoma stry
 No uptake on 68Ga-THP-PSMA or 68Ga-HBED-PSMA PET/CT
Slide courtesy of Michael Hofman
 True positives
but who
cares?
 Known extensive metastases
– Any value above conventional imaging?
 Known likely metastases but planning local therapy
– Eg: ADT + RT to primary with high-risk features

 Converse:
– Useful when trying to find a reason NOT to give radical therapy
 Inappropriate
changes in
management
 High risk primary:
– PSMA-detected metastases leading to decision not to treat primary
– Extrapolation of high/low volume (risk) definitions to PSMA PET findings
 Unnecessary additional investigations, or delays in treatment
– Eg: rib biopsies
 Influencing decisions on trial participation
 (Controversy alert!):
– Off-study treatment of PSMA-detected synchronous oligometastases
 Advanced Prostate Cancer Consensus Conference (APCCC 2019)
Programme 2019 - Areas of controversy

1. Molecular biomarkers and novel imaging

2. Locally advanced prostate cancer [Node-positive prostate cancer (N1
but M0)]
3. Biochemical recurrence of prostate cancer after local therapy
4. Management of primary tumour in the metastatic setting
5. Newly-diagnosed, castration-sensitive/naïve prostate cancer, including
oligometastatic prostate cancer
6. Management of nmCRPC (M0 CRPC)
7. Management of mCRPC
8. Bone and bone metastases
Surgery for cN1 M0 prostate cancer
Classical Imaging | Novel
Imaging

Professor Declan G Murphy

Urologist & Director of GU Oncology| Peter MacCallum Cancer Centre
Associate Editor | BJUI
@declangmurph
Honorary Clinical Professor | University of Melbourne y #APCCC19
 Surgery for high-risk locally advanced
prostate cancer

1 2

EAU Prostate Cancer Guidelines 2019

 1

N=302 RP + ePLND |
1988-2003
All were pN1
50 (17%) were cN1 | 252 (83%) were cN0
Median follow-up 17.4y

cN0 and cN1 compared

Cancer-Specific Mortality
Hypothesis – no difference in survival cN0 = 23%
cN1 = 26%
Patient profile
Mean PSA 32.2ng/mL
65% NCCN high risk
Median node yield = 13

Moschini et al Eur Urol 2016

 1

Predictors of CaP
mortality
MVA
Gleason 8 and number of
positive nodes predicted survival

cN status did not predict survival

Conclusion
“cN+ status should not be a
contraindication to surgery”

Moschini et al Eur Urol 2016

 2
Overall survival

• National Cancer Database 2003-2011 LT +/- ADT

• N=2967 cN1
• Local therapy (LT) +/- ADT vs ADT alone

• 67% received LT +/- ADT

• 37.8% surgery
o 32% received ADT HR 0.31 ADT alone
95% CI 0.13-0.74; p=0.007
• 62% radiotherapy
o 85% received ADT
y
local therap
• Instrumental variable analysis t in favour of
nefi
survival be
71%
Seisen et al Eur Urol 2018
 Surgery vs Radiotherapy
2
Compared using instrumental variable analysis

Seisen et al Eur Urol 2018

 Surgery vs Radiotherapy
2
Compared using instrumental variable analysis

RP +/- ADT

RT +/- ADT
HR 0.54
95% CI 0.19-1.52; p=0.2 OS benefit for surgery
Not significant

Seisen et al Eur Urol 2018

 Take home messages 1 | Conventional
imaging
• Conventional imaging performs poorly for staging cN status
• There is some low quality evidence to support surgery for cN1
prostate cancer
• Must be discussed within a multimodal framework
 Surgery for cN1 M0 prostate cancer
| Outline
1. cN1 by conventional imaging
2. cN1 by PSMA PET/CT
 PSMA-radioguided surgery for
LN detection
• Injection of 110-150MBq 111In-labeled PSMA-
ligand 24h prior to surgery
• Intraoperative detection by gamma probe
with
acoustic and visual feedback

Maurer et al., Eur Urol 2018

 PSMA-radioguided surgery for
LN detection

Maurer et al., Eur Urol 2018

 Excellent correlation
between RGS and
histopathology

83.6% sensitivity
100% specificity

Maurer et al., Eur Urol 2018

 Take home messages 2 |Novel
imaging
• Self-evident that PSMA PET/CT has superior sensitivity and
specificity in higher-risk prostate cancer
– proPSMA will provide objective evidence
• Disruptive technology
• The management impact needs to be evaluated
• Also offers radio-guided surgery possibility
 Conclusions | Surgery for cN1 prostate
cancer
• Strong evidence for local therapy in cN1 MO prostate cancer
(by conventional imaging)
• Surgery is an option as part of multi-modal therapy
• Novel imaging provides much more accurate picture of
disease extent
• Management impact needs to be evaluated
• Surgery role likely better defined
 Node + Prostate Cancer (N1/M0),
Mack Roach III, MD
Professor Radiation Radiation Options (and Evidence):
Oncology & Urology,
Where are we Now?
UCSF
APCCC Basel Switzerland 8/29/19; 11:15 – 12:45; 12 minutes
 Goal: Discuss Management of N1/M0
Prostate Cancer & the Role of Radiation
Therapy
1. Who are we talking about here?
a. Clinically node + (e.g. imaging) vs path node
+?
b. Definitive vs post Op?
c. High risk for occult node + Dz?
2. Endpoints?
a. Overall Survival , Cause Specific Survival, Mets
…
b. PSA control
Node-Positive c. Biopsies
Prostate Cancer
3. LevelQoL?
d. of evidence?
(N1/M0): Technical RT Details?
4.
Radiotherapeutic
a. SBRT vs ENRT
Approaches
b. Prophylactic Irradiation
 eau
European Association of Urology

Identifying the Optimal Candidate for Salvage Lymph Node Dissection for
Nodal Recurrence of Prostate Cancer: Results from a Large, Multi-
institutional Analysis. Fossati et al. Eur Urol. 2019 (176 – 183)

PSA
(SLND) =
2.1
No. PET
+nodes n=1
(51%)
n=2 (23%)
No. +nodes
n=3 (17%)
PO (9%)
n>4 n=0
Node-Positive
(9%)
Prostate Cancer n=1 (33%)
(N1/M0): n=2 (14%)
Radiotherapeutic n>3 (54%)
Approaches 70% PSA > 0.1
ng/ml PO
Analysis based on 654 pts … PSA rise and nodal recurrence after RP and … SLND ... Lymph node
recurrence was documented by PET/CT using (11)C-choline or (68)Ga-labeled PSMA.
 Metastasis-directed Therapy in Treating Nodal Oligorecurrent Prostate
Cancer: A Multi-institutional Analysis Comparing the Outcome &
Toxicity of Stereotactic Body Radiotherapy and Elective Nodal
Radiotherapy. De Bleser, Jereczek-Fossa … Ost. EU 2019
BACKGROUND: … SBRT vs ENRT … mets-directed txs in oligorecur. CAP.

OBJECTIVE: … Primary endpoint was metastasis-free survival … toxicity

PARTICIPANTS: … multi-instit. … SBRT: 309, ENRT: 197 hormone- sensitive

nodal oligorecur. (< 5 nodes (LNs; N1/M1a) (2004-2017. Med fu 36 mo.

INTERVENTION: SBRT > 5Gy per fraction (max n=10 fxs).

ENRT min. dose of > 45Gy in up to 25 fxs at the discretion of the physician.

Node-Positive OUTCOME MEASUREMENTS & STATISTICAL ANALYSIS: … 506 pts … 15

centers. Primary tx RP, RT, or their combination. Nodal recurrences … by
Prostate Cancer PET/CT (97%) or conventional imaging (3%).
(N1/M0):
RESULTS … : ENRT assoc. with fewer nodal recur. vs SBRT (p<0.001).
Radiotherapeutic
MVA, pts with 1 LN at recur. … longer aMFS after ENRT (HR: 0.50, p=0.009).
Approaches Late toxi was higher after ENRT VS SBRT (16% vs. 5%, p<0.01).

Hypothesize that ENRT should be preferred to SBRT in the treatment of

nodal oligorecurrences … needs to be evaluated in a randomized trial.
 Metastasis-directed Therapy in Treating Nodal Oligorecurrent Prostate
Cancer: A Multi-institutional Analysis Comparing the Outcome &
Toxicity of Stereotactic Body Radiotherapy and Elective Nodal
Radiotherapy. De Bleser, Jereczek-Fossa … Ost. EU 2019

Key
points:
1. Single node + benefitted more from ENRT?
a) field size issue? –
i. diff. between SBRT vs ENRT smaller if >
1 node?
ii. ENRT field not big enough if > 1 node?
Node-Positive 2. MFS vs PSA failure?
Prostate Cancer 3. Increased toxicity with ENRT (RTOG 9413 vs 0924)?
(N1/M0):
4. Role of ADT?
Radiotherapeutic
Approaches
 Salvage extended field or involved field nodal irradiation in
(18)F-fluorocholine (FCH) PET/CT oligorecurrent nodal failures
from prostate cancer.
Lépinoy … Créhange. Eur J Nucl Med Mol Imaging (2019) 46:40-48

Pts treated with salvage Involved field radiotherapy (s-IFRT) …

with salvage extended field radiotherapy (s-EFRT).

RESULTS: … 62 pts + nodes only FCH PET/CT after RP/RT.

Of these pts, 35 had s-IFRT and 27 had s-EFRT.
Med fu of 42 mo., no diff. in acute/late GI/ GI tox. of > grade 2.
3-yr failure rates … 55% vs 88% … s-IFRT vs s-EFRT (p= 0.01).
Node-Positive
… strong trend toward better outcomes with s-EFRT … after
Prostate Cancer
adjusting for concomitant ADT (HR = 0.38, p = 0.116).
(N1/M0):
Radiotherapeutic
Approaches
CONCLUSION: FCH PET+ node-targeted s-EFRT is
feasible with low … toxicity and longer TTF.
 RTOG 9413
Progression-Free Survival: Protocol Definition
100
Whole Pelvis
Prostate Only

Progression Free Survival (%)

Mini-Pelvis
80

60
Table 3a

Progression-Free Survivalby M edian Field-Size per Protocol

D efi
n ition of Biochem ical Failure
40
Field-Size Com parisons M edian PFS P value*

Tim e (yrs)
Node-Positive
Whole Pelvis vs. Prostate Only 4.9 vs. 2.6 0.001
Prostate Cancer
20 Whole Pelvis vs. Mini-Pelvis 4.9 vs. 3.4 0.015
(N1/M0):
Mini-Pelvis vs. Prostate Only 3.4 vs. 2.6 0.7697
Radiotherapeuti
*Pair-W ise Log-Rank test
c
Approaches 0
0 1 2 3 4
Time (Years)
 The Template of the Primary Lymphatic Landing Sites
of the Prostate Should be Revisited: Results of a
Multimodality Mapping Study.
Mattei … Studer. EAU 53:118-125, 2008

RTOG 0924 (WPRT)

RTOG 9413 (WPRT)

GETUG-01
RTOG 9413 (PO)

RTOG 0924 (PO)

 Long-Term Follow-up of a Randomized Study of Locally Advanced Prostate
Cancer Treated with Combined Orchiectomy and External Radiotherapy Versus
Radiotherapy Alone. Granfors et al. J of Urol 176, 544-547, 2006

Node-Positive
Prostate Cancer
(N1/M0):
Radiotherapeutic
Approaches
 Completed Contemporary Phase
III Prostate Cancer Trials (ADT
+/- RT)
Widmark et al. (2009) Warde et al. (2011)
A
100 ADT
ADT and RT
80

60

Survival
40

(%)
Survival at 7 years (95%
CI)
20
ADT: 66% (60–70)
ADT and RT: 74% (70–78)
0 Log-rank p=0·03
0 6 8 10
Number at risk 2
ADT 602 564 419 213 89 40
ADT and RT 603 4
552 419 232 99 39

Conclusion: Better survival with Conclusion: Better survival

ADT (mostly anti-androgens) + RT
Median-Follow Up: 7.6; NNT: 10.2;
Curves separate beyond 5 years
with RT+ADT (LHRH drug
used)
Median-Follow Up: 6; NNT: 9.9;
Curves
separate beyond 5 years
Prophylactic Post Op Pelvic RT
in the “Salvage” Setting
 Progression-Free Survival:
RTOG 9413 1.0

0.8

0.6
Nonfailure
Rate
0
.
4 NHT + WP RT
0.2 NHT + PO RT
Node-Positive
WP RT +
Prostate Cancer
AHT PO RT +
(N1/M0): AHT
0.0 3 4 5
0
Radiotherapeutic 1 Years since
2 Randomization
P=.008
Approaches
NHT=neoadjuvant hormonal therapy; AHT=adjuvant hormonal therapy
JCO 2003 Roach, et al.
 Sequence of Hormonal Therapy and Radiotherapy Field Size in Unfavorable
Localized Prostate Cancer: Long Term Results of a Phase III Randomized Trial
NRG Oncology / RTOG 9413. Roach et al. (Lancet Oncol 2018)

100
NHT+W PRT p= 0. 0 1 (two-sided Gray's test)
N H T + W P R T p=0.01 (two-sided
Gray's test) N H T + P O R T
NHT+PORT
W PRT+AHT
75 PORT+AHT
W PRT+AHT
Biochemical Failure

PORT+AHT

50
(%)

25

0
NHT+W P R T 318 1 6 0 8 0 3 2
NHT+P O R T 331186 1 3 8 6 6 2 3
W P R T+A H T 319 1 4 6 5 6 2 2
P O R T+A H T 136107 1 6 5 8 8 4 1

0
80 1 2 3 4 5 6 7 8 9 10 12 13 14 15
11
32
316 # o f P aT
t ii emnet sS i n c e
F aRi launr de o m i zAal ti v
i oe n, N
( Yoe a
Far si l) u r e Dead, N o Failure
NHT+WPRT 318 144 47 127
N1 H
3 8T + P O R T 316 177 43 96
WP RT+ AHT 319 156 37 126
66
PORT+AHT 317 143 53 121
23

Interaction of Sequence of Hormones and Radiation Therapy on Progression-Free

319

146
Survival
56

22
“If you want to prove
something
doesn’t work,

design an underpowered study”

Node-Positive
Prostate Cancer
(N1/M0):
Radiotherapeutic
- Mack Roach III, MD
Approaches

20
 WPRT for Prostate Cancer: Important & Challenging

• Practical issues:
– Small field vs Big Field?
– Potential Morbidity
– Cost (time and money)?

• Challenge – tough to prove:

– e.g. 1200 pts with 1/3rd (33%) having + nodes
• … then study really based on n=400 pts
• … if disease beyond pelvis in 25% down to n=300 pts
• … and local failures 1/3rd to n=200 pts
Node-Positive
Prostate
• … competing Cancerof death (e.g. 50%) n=100
causes
(N1/M0):
• … improved “salvage” treatments, delaying deaths
Radiotherapeutic
• … “study too small?”
Approaches
Thus, RTOG 0924: n=2580 (@2592 pts ()!
 Conclusions Concerning the Trial Design
for Clinically Localized but N1 prostate
cancer:
1. Composite endpoints might be necessary? :

a) MFS, QoL, freedom from ADT …

b) Phase I-II PSA based evidence?:

1. Nadir promising?
2. Complicated by a direct impact on ADT?
3. Stratification variables?
2. Prepare for unanticipated findings(e.g.
Node-Positive
Prostate Cancer
sequence, volume interactions (e.g. RTOG 9413).
(N1/M0):
Radiotherapeutic 3. Doses and techniques and drugs probably matter!
Approaches
4. Underpowered/poorly designed trial worse than none!

2
3
Clinically node positive newly
diagnosed prostate cancer
Nicholas James
@Prof_Nick_James

1
Summary

Prostate radiotherapy did not improve survival for unselected patients
(HR=0·92, 95%CI 0·80-1·06; p=0.266)

Prostate radiotherapy did improve survival (from 73% to 81% at 3 years) in
those with a low metastatic burden (HR=0·68, 95%CI 0·52-0·90; p=0·007).
Test for interaction: p=0.0098

Mirrors benefit seen in HORRAD trial

Implies potential benefit in cN+M0 disease taken with known survival gain
with radiotherapy in N0M0 disease
Burdett S, Boeve LM, Ingleby FC, et al: Prostate Radiotherapy for Metastatic Hormone-sensitive Prostate Cancer: A STOPCAP Systematic Review and Meta-analysis. Eur Urol,
2019
Parker CC, James ND, Brawley CD, et al: Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3
trial. Lancet 392:2353-2366, 2018 MRC CTU at UCL
 M0 docetaxel: Survival
Results based on 2120 men / 346
deaths
Trial name
GETUG
STAMPEDE12 (SOC +/- Doc)
RTOG 0521 (SOC+ZA +/- Doc)
STAMPEDE
Overall HR= 0.87 (0.69, 1.09) p=0.218
.5 1
2
Favours SOC + docetaxel Favours SOC
Heterogeneity:2=1.80, df=3, p=0.614, I2=0%

5% potential improvement in survival (from 80 to 85%) at 4 years

Vale CL, Burdett S, Rydzewska LH, et al: Lancet Oncol 17:243-56, 2016
Abiraterone in M0 HSPC
• Evidence of failure free and metastasis free survival
benefit from ADT + abiraterone vs. ADT alone for 2
years
• Strong suggestion of synergy with radiotherapy

James N, De Bono JS, Spears M, et al: Adding abiraterone for patients (pts) with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT):
Outcomes in non-metastatic (M0) patients from STAMPEDE (NCT00268476). Proc ESMO Annals of Oncology, 2017
 Docetaxel vs. AR therapy in
mHSPC
• No evidence of survival difference in STAMPEDE
• Upfront abiraterone gives longer failure free and
metastasis free benefit than docetaxel
• but shorter castrate refractory phase
• Effects on failure free survival may be more
important in M0 disease as lower risk of prostate
cancer death

Sydes MR, Spears MR, Mason MD, et al: Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from
the STAMPEDE multi-arm, multi-stage platform protocol. Ann Oncol 29:1235-1248, 2018
Current knowledge of the biology of prostate cancer clearly
supports the use of chemotherapy and abiraterone.[11-13] Prostate
cancer is remarkably dependent on AR signaling, and while AR-
targeted approaches are highly effective, the emergence of
resistance is predictable.[11,12] Drugs that further suppress
intracrine androgen synthesis (abiraterone) and novel AR
antagonists (enzalutamide) result in significant benefits following
disease progression after castration, supporting the notion that
reactivation of AR signaling is an important mechanism of
resistance to ADT. However, while the benefits are clinically
meaningful, it is clear that they remain relatively short-lived; most
 Protocols
• [Philly] Phase II study of Ribociclib/Enzalutamide; no responses
• Phase I/II study of immunotherapy combination BN-Brachyury
vaccine, M7824, ALT-803 & Epacadostat (QuEST 1) [initiated 10/1/19]
How to best
treat cN1
prostate
cancer?
Karim Fizazi
Institut Gustave Roussy
France
 Non-randomized STAMPEDE
data cN1 Relapse-Free
Survival by RXT use
STAMPEDE control arm (ADT), 2005-2014
n= 286 pts with cN+ M0 (and n=434 pts with cN0M0)

cN+M0
HR=0.48 (0.29-0.79)

RXT

No RXT

OS=Immature
James N, JAMA Oncol 2016; 2: 348-57
RXT benefits may extend to cN+ men,
although biases may explained
better outcome…

RXT not planned RXT planned

James N, JAMA Oncol 2016; 2: 348-57

 There are also likely biases in the
US National database analysis

Patients in the control arm: Local treatment

- Were older (p<0.001)
n=2967 cN1 pts
- Had a worse Charlson index (p=0.03)
- Had worse insurance coverage (p<0.001)
No local treatment
- Had a higher PSA (p<0.001)
- Had a higer Gleason score (p>0.001)

Seisen T, Eur Urol 2018; 73: 452-61

 Radiotherapy for cN1?
Field side.
T, N0, M0 (and >15% risk of N+) = localized
Also quite weak evidence to support
(or not) lymphadenectomy in cN1

Only n=51 pts with cN+ …

Specific survival similar for cN0 and cN1

Moschini M, Eur Urol 2016

 Abiraterone in high-
risk M0 prostate
cancer (STAMPEDE)
• Cohort selection: Randomised by Jan-2014
N=1,917

Non-metastatic Metastatic
N=915 N=1002

N0M0 N+M0

N=530 N=384

RT RT No RT
N=519 N=314
N=70
 Conclusion: cN1
• Insufficient level of evidence
• Need more RCT, next-generation imaging
• Current treatment:

– ADT? Likely yes. Duration?

– Local treatment of the primary Yes
– Local treatments of nodes? Likely yes
– Large fields/PLND? Likely better than small

– Abiraterone?
if STAMPEDE RFS data translate into clinical
– Docetaxel?
Node Positive
Prostate
Cancer:
How to treat men with
pN1 Prostate Cancer?
Alberto BOSSI
Dept of Radiation Oncology
pN+ PCa patients: an increasing, important
problem
- the local treatment

- not all pN+ PCa patients are created equal

- what are we doing and what should we do

- the final picture

Alberto Bossi RT-IGR

 34,888 men treated
with RP and PLND at 3
Between 1998-2016, the rate of pN+ tertiary referral
patients increased from 5% to 18% centers

Bandini, AUA Meeting, 2018

P < 0.001

Courtesy of A Briganti
 STAGE MIGRATION EXTENT OF PLND

Low and intermediate risk , from 84.3% to 68.6%, p<0.001

p<0.0001

High risk , from 15.7% to 31.4%,p<0.001 to 68.6%, p<0.001

Bandini et al. AUA Meeting, 2018 Courtesy of A Briganti

Rates of pN+ in contemporary HIGH RISK patients

Bandini, AUA Meeting, 2018

Courtesy of A Briganti
 Local treatment for pN+ patients

Aborted RP 10-year OS:

Engel, 2010 1,413 vs. Aborted RP, 28 %
Completed RP, 64
Completed
%
RP

PLND + ADT (n=50) vs. 10-year CSS

Steuber, 2011 158 RP-PLND + PLND + ADT, 46 %
ADT( n=108) RP+PLND + ADT, 76
%

PLND + orchiectomy (n=79) vs. 20-year CSS: 18 % vs. 59 %

Bhindi, 2017 158
RP-PLND + orchiectomy (n=79) 20-year OS: 9 % vs. 22 %

10-year
NLT
Rusthoven, 2014 950 (n=657)
OS: NLT,
42 %
EBRT
EBRT, 65 RT-IGR
(n=293)
%
 SEER Database, 2004-2014 , pN+ pts
364 pts: aborted RP
3355 pts: completed RP

PSA < 50 ng/ml

7 pN+
Bandini et al. Eur Urol Focus, 2019
- pT stage, pGS, R status

- lymph node “density”

- extra-nodal extension
- size of the largest pN+
- site of pN+ (iliac vs obt. vs para-rectal)
- expression of PD-L1
-…

Boorjian 2007, Passoni 2014, Luchini 2017, Touijer 2018, Petiprez 2019
Briganti, Eur Urol, 2009
 PCa Specific Mortality Risk for pN+ pts
•OW
Recommendation Strength
s rating

Lnode
• <dissection,
Discuss three %
management options with patients
Wea HIG
0.5 based on nodal involvement % with pN+ disease after75an%extended
14characteristics: k
lymph H
1.Offer
• GSadjuvant
= 6 ADT for node-positive
GS (pN+).
= 7-10 GS = 7-10 G
• < pT3b
2.Offer adjuvant ADT with additional< radiotherapy.
pT3a pT3b – pT4 11
> %

• R0 R0 R1 S = 7-10
3.Offer observation (expectant management) to a patient after eLND and ≤2 nodes
• NEG post-RP PSA NEG post-RP PSA NEG post-RP PSA MAX4 2pos
posLNLN MAX 2
with microscopic involvement, and a PSA< 0.1 ng/mL and absence of extranodal
pos LN 3 - 4 pos LN
extension.

observation / eSalvageRT +/- ADT aRT + ADT ADT / systemic TT

 PART trial : rationale and update

“Elective Para-Aortic Radiation as part of combination Therapy

in prostate cancer patients with positive pelvic lymph nodes: a
new step to improve clinical relapse-free survival”
Prospective, non-randomised phase 2 trial

C. Berghen, S. Joniau, G. De Meerleer, UZ Leuven, Belgium

Dr. Sklaroff's case and imaging were reviewed
today in the Prostate Cancer Multidisciplinary
Clinic. Physicians in attendance included: Peter
A. Pinto, M.D. and Amir Lebastchi, M.D. of the
Urology Branch; Deborah E Citrin, M.D. and Dr.
Roy of the Radiation Oncology Branch; James L.
Gulley, M.D. and Dr. Howard Parnes of the
Medical Oncology Branch; Dr. Baris Turkbey of
the Molecular Imaging Department; Dr. Maria
Merino of the Department of Pathology; and
Monique D. Williams, CRNP. {signers} Pathology
was not submitted for review.
 Serial PSA Determinations

[PSA Doubling Time on-trial is 1.1 months invoking MSKCC tool]

08/08/2018: 29.3
08/28/2018: 23
09/24/2018: 9.56
10/01/2018: 6.57
11/20/2018: 2.86
02/15/2019: 2.33
06/17/2019: 3.46
07/03/2019: 4.08
07/08/2019: 5.05
07/17/2019: 4.85
09/03/2019: 1.66
09/05/2019: 1.58
09/10/2019: 1.62
09/19/2019: 2.38

10/08/2019: 2.47
10/15/2019: 4.13
10/22/2019: 3.17
10/29/2019: 4.5
11/12/2019: 5.1