Prostate Cancer
Prostate Cancer
Prostate Cancer
• 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
•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
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
Homologous
BRCA PARPi,
Recombinatio King
1, platinum
n Repair
BRCA
(HR)
2
Mismatch Anti-
MSH2 Lynch
Repair PD1/
(MMR) PDL-1
• Consider metastatic biopsy
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
• Variant interpretation
– Commercial labs still struggling
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.
Stomach, Liver,
Kidney
Papillary
H
a
u
s
e
e
t
Prostate Cancer-Validated MSI by
NGS Outperforms Traditional
Methods
[NGS = next-generation sequencing]
PSA>10 PSA<10
CHIP?
BRCA2 Exon 14
•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)
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
tefano Fanti
Advantages of PSMA PET for imaging Prostate Cancer
STAGING
BIOCHEMICAL RECURRENCE
THERAPY PLANNING
STAGING
STAGING
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
Hepatocellular carcinoma
PeterMac
IHC courtesy of Dr Catherine Mitchell,
PSMA 1+ 10%
(low staining)
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 2
N=302 RP + ePLND |
1988-2003
All were pN1
50 (17%) were cN1 | 252 (83%) were cN0
Median follow-up 17.4y
Predictors of CaP
mortality
MVA
Gleason 8 and number of
positive nodes predicted survival
Conclusion
“cN+ status should not be a
contraindication to surgery”
RP +/- ADT
RT +/- ADT
HR 0.54
95% CI 0.19-1.52; p=0.2 OS benefit for surgery
Not significant
83.6% sensitivity
100% specificity
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.
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
60
Table 3a
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
GETUG-01
RTOG 9413 (PO)
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
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
146
Survival
56
22
“If you want to prove
something
doesn’t work,
20
WPRT for Prostate Cancer: Important & Challenging
• Practical issues:
– Small field vs Big Field?
– Potential Morbidity
– Cost (time and money)?
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%
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…
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:
– 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
Courtesy of A Briganti
STAGE MIGRATION EXTENT OF PLND
p<0.0001
Courtesy of A Briganti
Local treatment for pN+ patients
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
7 pN+
Bandini et al. Eur Urol Focus, 2019
- pT stage, pGS, R status
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.
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