PROSTATE CANCER

Karim Fizazi
Institut Gustave-Roussy
Villejuif, France
DISCLOSURE OF INTEREST

Participation to advisory boards and talks for:

Amgen, Astellas, Astrazeneca, Bayer, Clovis, Daiichi Sankyo, Janssen, MSD, Novartis/AAA, Pfizer, Sanofi

Honoraria go to Gustave Roussy, my institution.

Participation to advisory boards with personal honorarium for Arvinas, CureVac, Macrogenics and Orion.
INTRODUCTION
Learning objectives
• Promote evidence-based quality cancer care by disseminating the ESMO Clinical Practice Guidelines in the oncology
community.

• Present a clinical case for each of the selected topics for discussion in the context of the ESMO Clinical Practice Guideline
recommendations.

• Present and critically review the ESMO Clinical Practice Guideline recommendations for each selected cancer type.

• Discuss the case, the ESMO CPG recommendations, their impact on care and implementability in the daily practice setting
under the guidance of a moderator senior expert, with participation of the guideline authors, practicing oncologists and young
oncologists.

• Audit the fulfillment of the learning objectives and acceptability of the ESMO CPG recommendations by means of an online
questionnaire.
INTRODUCTION
Programme
Welcome and Introduction
Karim Fizazi

Case Presentation
Matthieu Delaye

Presentation of the ESMO Clinical Practice Guideline for Critical Analysis of the Case
Eleni Efstathiou

Considerations related to Guideline implementation in everyday clinical practice and Discussion

Alvin Tan

Q&A
All faculty
BASICS OF PROSTATE CANCER EPIDEMIOLOGY

• Most frequent cancer in males in most countries

• Lower mortality
• Risk factors:
• Age (median age at diagnosis about 68)
• Black skin phenotype
• BRCA2 germline alterations
• Family history of prostate cancer
• Exposure to Chlordecone
BASICS OF PROSTATE CANCER PATHOLOGY

• Mostly adenocarcinoma
• Importance of the Gleason score (6-10) = ISUP score (1-5) for prognosis
• Aggressive variants:
• Cribriform
• Intraductal
• Neuro-endocrine differenciation
BASICS OF PROSTATE CANCER MOLECULAR BIOLOGY

Robinson, Cell 2015

TARGETS FOR TREATMENT IN PROSTATE CANCER
• The Androgen Receptor (AR), again and again
• PSMA
• DNA repair (BRCA)
• Neo-antigens: MSI and Checkpoint inhibitors
• The bone biology:
• RANKL
• Bone matrix (Ra-223)
• And more likely to come soon:
• STEAP1
• hK2
WHEN YOU NEED INFORMATION ABOUT PROSTATE CANCER

Situation with available Situation without available

level I evidence level I evidence
PROSTATE CANCER
De novo metastatic disease

Matthieu Delaye, MD, MSc

With the precious assistance of Paul Matte
Institut Gustave-Roussy
Villejuif, France
DISCLOSURE OF INTEREST

None
CLINICAL CASE
Patient’s characteristics

Male
75 years old

No family history of cancer.

Comorbidities: hypertension, dyslipidemia.
Pharmacotherapy: bisoprolol, eplerenone, atorvastatin.

Habits and autonomy: Non-smoking. Former truck driver. Married. 2 children.

Autonomous in all aspects of daily life.
CLINICAL CASE
Disease history

09.2021: Bone pain (rib and hip). Clinical characteristics:

Weight loss (-3 kg in 1 month)
Weight: 80.0 kg Size: 170 cm
Standard biology: normal ECOG: 1
Serum protein electrophoresis: normal
G8 score: 15
PSA: 18.10 ng/mL
No palpable lymph nodes
No urinary symptoms

Digital rectal examination: hard mass in the right lobe

CLINICAL CASE
Disease history

MRI: mass located in the right prostatic lobe invading

the seminal vesicle.
Right common iliac, right external iliac and presacral
centimetric nodes.

Histology: Adenocarcinoma. ISUP: 3.

BRCA 1/2: negative

Bone scintigraphy: 4 bone metastases.

CLINICAL CASE
First-line treatment
Options to discuss:

ADT + docetaxel + abiraterone + prednisone

ADT + docetaxel + darolutamide
ADT + abiraterone/apalutamide/enzalutamide
ADT alone (Vulnerable men)

Addition of radiotherapy (low volume)

 CLINICAL CASE
First-line treatment
Options to discuss:

ADT + docetaxel + abiraterone + prednisone Recommanded L1-treatment

ADT + docetaxel + darolutamide - for fit men
- with de novo metastatic hormone-sensitive prostate cancer
ADT + abiraterone/apalutamide/enzalutamide - especially if > 3 bone metastases / visceral metastases
ADT alone (Vulnerable men)

Addition of radiotherapy (low volume)

PEACE-1 trial. Fizazi K. et al. Lancet. 2022

 CLINICAL CASE
First-line treatment

The patient received:

ADT+ oral 1000 mg abiraterone once daily plus oral 5 mg prednisone twice daily.
No radiotherapy.

Response: Tolerance:

PSA nadir: 1.3 ng/mL - Globally well tolerated, but anti-

hypertensive treatments had to be
Scintigraphy: complete response adjusted

Until 06/2023: PSA: 7.6. Multiple bone lesions on TEP-CT. - Close onco-cardiological follow-up
 CLINICAL CASE
Second-line treatment
The patient received intravenous docetaxel 75 mg/m2 (still ongoing) + ADT and denosumab

Other L2-options:
- Olaparib (BRCA 1/2 alteration)

If the patient had received a « triplet » in L1-setting:

- 177Lu-PSMA-617
- Radium-223 (bone-predominant, symptomatic mCRPC
without visceral metastases)
- Cabazitaxel

Tannock IF et al. NEJM 2004; Sartor O et al. NEJM 2021; Hussain M et al. NEJM 2020; Parker C et al. NEJM 2013, De Bono J et al. Lancet 2010
CLINICAL CASE
Conclusion

Several recent options in L1 and L2 settings

Prostate cancer -> precision medicine guided by:

- clinical parameters (general state, tumor-burden)
- genetics (BRCA testing, MSI)
- PSMA-TEP-CT (for 177Lu-PSMA-617)
…
TREATMENT STRATEGY FOR METASTATIC
HORMONE NAIVE PROSTATE CANCER

Eleni Efstathiou MD PhD

Houston Methodist Cancer Center
Eleni Efstathiou MD PhD disclosures

Research Support / P.I. : Janssen, Sanofi-Genzyme, Astellas/Medivation, Pfizer, Oric-Pharma, Astra Zeneca, Eli-Lilly

Scientific Advisory Board, Honoraria :

Janssen, Sanofi-Genzyme, Tolmar, Takeda, Bayer, Oric Pharma, Merck, Astellas, Pfizer, Myovant, AstraZeneca
 CASE STUDY PATIENT
mCSPC- Typical Case Scenario

75 years old
PS ECOG status of 1, geriatric ‘fit’
2 cardiovascular disease predisposing factors + advanced age
Medical History :
Recommend CVD further screening
Arterial Hypertension Metabolic syndrome concerns ( weight / A1c?)
Dyslipidaemia Bone Health ?
Refer to Geriatrics / Cardiology / Endocrinology vs Go at it alone ?

History of Present Illness :

De novo metastatic disease with some constitutional symptoms (bone discomfort rib and hip, weight loss)
- some pelvic nodes with 4 bone metastases, no visceral disease

◆ CHAARTED (DOI: 10.1056/NEJMoa1503747)

LATITUDE (DOI: 10.1056/NEJMoa1704174)
A HealthCare “Corporation” to treat each man with PCa

Urology 1 Radiology
8
Medical Oncology 2 Nuclear Medicine
9
Geneticists 3 Pathology/Molecular
10 Pathology/Lab Medicine
Nursing
4
Psycho-oncology
11
Social work
5
Internal
InternalMedicine/Cardiology/Endocrin
medicine disciplines/
Radiation oncology
12 (Geriatrics)/
GeriatricsSupportive Care
6
13 Pharmacy
Lifestyle improvement strategists : (
nutrition, exercise , mindset ) 7 14 Patient Advocacy
 CASE STUDY PATIENT
mCSPC- Typical Case Scenario

75 years old
PS ECOG status of 1, geriatric ‘fit’
Medical History :
Arterial Hypertension
Dyslipidaemia

Prompts for Genetic Testing

Consider systematic Germline testing for men with mHSPC
Family History ?

History of Present Illness :

De novo metastatic disease with some constitutional symptoms (bone discomfort rib and hip, weight loss)
- some pelvic nodes with 4 bone metastases, no visceral disease

◆ CHAARTED (DOI: 10.1056/NEJMoa1503747)

LATITUDE (DOI: 10.1056/NEJMoa1704174)
 Title Text
11.8% of men with mPC have
germline DNA-repair gene
mutations
Somatic mutations
BRCA1 or BRCA2 in DNA repair
mutation pathways in 19%
associated with of localized and
increased risk of 23% of mCRPC
PC tumors
ALL men with mPC should receive
genetic testing
Testing should be considered in
specific histologic/family history for
localized disease

Pritchard C, et al. N Engl J Med. 2016;375(5):443-453; NCCN Guidelines.

www.nccn.org/professionals/physician_gls/default.aspx. Accessed Nov 3,, 2020.; Loeb S, et al. Cancer Treat
Res Commun. 2020;25:100212.
 IMPORTANCE OF IDENTIFYING MUTATIONAL STATUS
(GERMLINE OR/AND SOMATIC )
Patients with advanced PCa

~25% HRR+1,2 ~75% HRR-1,2

~50% non-BRCA
~50% BRCA1/23
mutated3

HRR+ mutations are associated with

poor prognosis and unmet need1 Caution:
Germline testing
Patients with germline BRCA1/2 are is an important ethical consideration,
more likely to present with a Gleason not just for the patient
score ≥8, advanced disease, nodal
involvement, and distant metastases at but also for their family
diagnosis compared with non-carriers4

BRCA, breast cancer gene; HRR, homologous recombination repair; mCRPC, metastatic castration-resistant prostate cancer.
1. Scott RJ, et al. Oncotarget 2021;12:1600–1614; 2. Gonzalez D, et al. J Pathol Clin Res 2021;7:311–325; 3. Shore N, et al. Future Oncol 2021;17:2907–
2921; 4. Castro E, et al. J Clin Oncol 2013;31:1748–1757.
 CASE STUDY PATIENT
mCSPC- Typical Case Scenario
75 years old
PS ECOG status of 1, geriatric ‘fit’
Medical History :
Arterial Hypertension
Dyslipidaemia

History of Present Illness :

De novo metastatic disease with some constitutional symptoms (bone discomfort rib and hip, weight loss)
- some pelvic nodes with 4 bone metastases (1 extra axial Skeleton -rib), no visceral disease

◆ CHAARTED (DOI: 10.1056/NEJMoa1503747)

LATITUDE (DOI: 10.1056/NEJMoa1704174)
Therapy Evolution in mHSPC: 2015-2020 Progress Report

CHAARTED1 STAMPEDE2 LATITUDE3 STAMPEDE4

(Doc) (Doc) (AA) (AA)
ASCO 2015 ASCO 2015 ASCO 2017 ESMO 2018

TITAN7 ENZAMET6 ARCHES5

(APA) (ENZA) (ENZA)
ASCO 2019 ASCO 2019 ASCO GU 2019

AA, abiraterone acetate; APA, apalutamide; ASCO, American Society of Clinical Oncology;
ASCO GU, Genitourinary Cancers Symposium; doc, docetaxel; ENZA, enzalutamide;
ESMO, European Society for Medical Oncology; RT, radiotherapy.
1. Kyriakopoulos CE, et al. J Clin Oncol. 2018;36:1080-7. 2. Clarke NW, et al. Ann Oncol. 2019;30:1992-
2003. 3. Fizazi K, et al. N Engl J Med. 2017;377:352-60. 4. James ND, et al. N Engl J Med. 2017; 377:338-
351 5. Armstrong, MD. Oral presentation at ASCO GU 2019; abstract 687. 6. Davis ID, et al. N Engl J Med.
2019;381:121-31. 7. Chi KN, et al. J Clin Oncol. 2021;39:2294-2303.
..
8. Fizazi K, et al. Presented at ASCO 2021; abstract 5000.
 Therapy Evolution in mHSPC: 2015-2020 Progress Report

CHAARTED1 STAMPEDE2 LATITUDE3 STAMPEDE4

(Doc) (Doc) (AA) (AA)
ASCO 2015 ASCO 2015 ASCO 2017 ESMO 2018
ADT + Docetaxel = SOC 2015-2017

TITAN7 ENZAMET6 ARCHES5

(APA) (ENZA) (ENZA)
ASCO 2019 ASCO 2019 ASCO GU 2019

AA, abiraterone acetate; APA, apalutamide; ASCO, American Society of Clinical Oncology;
ASCO GU, Genitourinary Cancers Symposium; doc, docetaxel; ENZA, enzalutamide;
ESMO, European Society for Medical Oncology; RT, radiotherapy.
1. Kyriakopoulos CE, et al. J Clin Oncol. 2018;36:1080-7. 2. Clarke NW, et al. Ann Oncol. 2019;30:1992-
2003. 3. Fizazi K, et al. N Engl J Med. 2017;377:352-60. 4. James ND, et al. N Engl J Med. 2017; 377:338-
351 5. Armstrong, MD. Oral presentation at ASCO GU 2019; abstract 687. 6. Davis ID, et al. N Engl J Med.
2019;381:121-31. 7. Chi KN, et al. J Clin Oncol. 2021;39:2294-2303.
..
8. Fizazi K, et al. Presented at ASCO 2021; abstract 5000.
 Title Text

Overall Survival Failure free survival

Chen J, et al. Front Oncol. 2020;10:519388; Schulte B, et al.

Am Soc Clin Oncol Educ Book. 2020 40:1-10.
 Earlier ASI treatment seems Better
stage-related increments in survival benefit with ASIs

Median OS Median OS
Disease stage Phase 3 trials Active arm Control arm HR (95% CI) Δ survival (months)
(months) (months)
0.74
mCRPC post-taxanes COU-AA-3011 15.8 11.2 4.6
(0.64–0.86)
0.63
mCRPC post-taxanes AFFIRM2 18.4 13.6 4.8
(0.53–0.75)
0.81
mCRPC pre-taxanes COU-AA-3023 34.7 30.3 4.4
(0.70–0.93)
0.83
mCRPC pre-taxanes PREVAIL4 35.5 31.4 4.1
(0.75-0.93)
0.66
mHSPC LATITUDE5 53.3 36.5 16.8
(0.56–0.78)
CI, confidence interval; HR, hazard ratio; OS, overall survival.

A total of 17 positive and NO negative phase 3 trials reported to date

7 in mHNPC : LATITUDE,STAMPEDE, ARCHES, ENZAMET, TITAN, PEACE-1,ARASENS 1. Fizazi K, et al. Lancet Oncol. 2012;13:983-92.
2. Scher HI, et al. N Engl J Med. 2012;367:1187-97.
3. Ryan CJ, et al. Lancet Oncol. 2015;16:152-60.
4. Armstrong A, et al. Eur Urol. 2020;78:347-357.
5. Fizazi K, et al. JCO. 2019;37(7)suppl:141-141
Adding
ASI to SOC
Docetaxel +ADT vs ADT trials
2020 State of the art
How to maximize the therapeutic index ?
based on available data and in the absence of predictors

Key Message 1
Doublet Combination: ADT with Enhanced Androgen Signaling Inhibitor or Docetaxel a
REQUIREMENT for the vast majority of mHSPC with appropriate monitoring

Message 2 : Addition of Enhanced Androgen Signaling Inhibition is likely the preferred

choice over Docetaxel for ‘garden variety’ mHSPC

Message 3 : Combination should initiate at diagnosis and not be delayed.

The Inevitable Question : Is more better ?

 PEACE-1 A phase III study with a 2x2 factorial design of Abiraterone +/-local
radiotherapy in men with de novo mCSPC : Adding Abiraterone to SOC
Fizazi et al

✓Study Design : Adapted to evolving paradigm, close to practice

Nov 2013 – Dec 2018
Key Eligibility Criteria ESMO 2021 Report
De novo mCSPC SOC OS - on all patients
Distant metastatic disease by ≥ 1 lesion on bone scan (n = 296)
and/or CT scan 1:1:1:1 SOC :ADT +Docetaxel n 710
ECOG PS 0 -2
n = 1173 SOC+Abiraterone SOC : ADT n 463
On-Study Requirement (n = 292) Co-Primary Endpoints
Continuous ADT
Permitted rPFS /Overall Survival
SOC+Radiotherapy
ADT ≤ 3 months
(n = 293)
Stratification Important Point :
ECOG PS (0 vs 1-2) SOC+Abiraterone+
Metastatic sites (LN vs bone vs visceral) Radiotherapy
Imaging at least q6m
Type of castration (orchidectomy vs LHRH agonist vs
(n = 292) after PSA rise
LHRH antagonist)
Docetaxel (yes vs no)
 PEACE-1 Report
Regardless of Standard of Care the addition of
Abiraterone has a clinically meaningful overall survival
impact
Overall Survival : All patients SOC :
ADT +/- Docetaxel
n 1172 Overall Survival SOC = ADT +Docetaxel
Events= 490 N 710
Events= 270

Important Considerations : ADT + Docetaxel SOC includes more high volume disease
Overall Population - longer follow up / more heterogeneity
Timing of Abiraterone is of essence :
80 % of men on ADT + docetaxel received an enhanced androgen signaling inhibitor later
ARASENS Study Design
Global, randomized, double-blind, placebo-controlled phase III study (NCT02799602)
Endpoints
Docetaxel × 6 +ADT
Primary: OS
Patients (N=1306)
• mHSPC Secondary

Primary analysis
Darolutamide 600 mg twice daily
• ECOG PS 0 or 1 • Time to CRPC
• Candidates for ADT 1:1 • Time to pain progression
and docetaxel randomization • SSE-free survival
(N=1305*) • Time to first SSE
Stratification • Time to initiation of subsequent
• Extent of disease: Placebo twice daily systemic antineoplastic therapy
M1a vs M1b vs M1c • Time to worsening of disease-
• ALP < vs ≥ ULN Docetaxel × 6+ADT related physical symptoms
Data cut-off • Time to initiation of opioid use
FPFV: Nov 2016
LPFV: June 2018
Oct 25, 2021 for ≥7 consecutive days
• Safety

• The primary analysis was planned to occur after ~509 deaths

• Secondary efficacy endpoints were tested hierarchically

ALP, alkaline phosphatase; CRPC, castration-resistant prostate cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; FPFV, first patient first visit; LPFV, last patient first visit; M1a, nonregional
lymph node metastases only; M1b, bone metastases ± lymph node metastases; M1c, visceral metastases ± lymph node or bone metastases; Q3W, every 3 weeks; SSE, symptomatic skeletal event; ULN, upper limit of
normal.

39
Smith et al NEJM 2022
ARASENS Primary Endpoint*: Overall Survival
Darolutamide significantly reduced the risk of death by 32.5%

*Primary analysis occurred after 533 deaths (darolutamide, 229; placebo, 304). CI, confidence interval; NE, not estimable.
40
Smith et al NEJM 2022
ESMO GUIDELINES (2020+2023 E-
UPDATE)

Updates (2023) : Triplets

ADT +Docetaxel + Abiraterone
ADT + Docetaxel + Darolutamide

Is ADT + Docetaxel
An appropriate Doublet?
 Main Take Home Message :

Earlier Combinatorial Treatment

with ‘Enhanced’ androgen signaling
inhibition is a Requirement
For fit men with mHSPC cancer
ith ASI and docetaxel is recommended especially for hig
 Using Precision
in Advanced Prostate Cancer Therapeutics
to improve the lives of our Patients
 How Long Does it take to develop a biomarker informed strategy
1997 2015 2016 2017 2019 2020
Feasibility of
First evidence multi-institutional
of genetic molecular NCCN
PROFOUND -FDA/ EMA Approvals
predisposition characterization
Germline 2017 first Olaparib for DDR mutated
pathogenic guidelines: 1.0 mCRPC post enhanced
to prostate in mCRPC DDR

Probability of rPFS
cancer. DDR 0.9 6-mo rate androgen signaling
testing for 0.8
mutations in
m Pca and 59.76% inhibition
metastatic 0.7 12-mo rate
expanded 0.6 22.63%
prostate 28.11%
2018 to 0.5
cancer 11.8% men with, 9.40%
0.4
high risk 0.3
localized, 0.2
metastatic 0.1
or strong 0.0 0 1 234 56789101112131415161718192021
family
history
TOPAARP-A Study
Eeles RA, et al. Br J Urol. 1997. FDA approval of
Robinson et al., 2015, Cell 161, 1215–
1228 companion
Mateo J, et al. N Engl J Med. 2015
Pritchard CC, et al. N Engl J Med. diagnostics:
2016.
Giri VN, et al. J Clin Oncol. 2018.
FoundationOneC
Mateo J, et al. N Engl J Med. 2015.
Abida W et al. J Clin Oncol. 2020
Dx and
BRCAnalysis
 Why early molecular testing? Actionable and
Informative
• Predictive: treatment selection (e.g. pembrolizumab* for dMMR,1 olaparib† for dHRR)2
• Prognostic: mutation-specific outcomes3–6
Patients with BRCA2 deleterious gene Patients with dMMR have poor Hereditary cancer implications: distribution of
alterations have poor outcomes3 outcomes5 pathogenic germline mutations in mCRPC (%)6
1.0 Noncarriers (n=1,940) 1.0
Median (95% CI) time between ADT and CRPC progression,
BRCA1 mutation carriers (n=18) Cohort n
mo
BRCA2 mutation carriers (n=61)

Survival fraction
0.8 0.8
Overall survival (proportion)

dMMR 11 9.1 (5.7–12.6)

p=0.00025, log-rank test
0.6 Control 199 18.2 0.6 (15.1–21.2)

0.4 0.4

0.2 0.2

0.0 0.0
0 2.5 5 7.5 10 12.5 15 17.5 20 0 50 100 150 200 250
Time between ADT initiation to CRPC progression (months)
Time (years)

*Pembrolizumab is not approved in the EU for prostate cancer indications; please see SmPC for full indication and safety information;7 †Olaparib is approved in the EU; please see SmPC for full indication and safety information.8
ADT, androgen deprivation therapy; CI, confidence interval; CRPC, castration-resistant prostate cancer; dHRR, deficient homologous recombination repair; dMMR, deficient mismatch repair; mCRPC, metastatic castration-resistant prostate cancer; mo, months.
1. Abida W et al. JAMA Oncol 2019;5:471–478; 2. Hussain M et al. N Engl J Med 2020;383:2345–2357; 3. Castro E et al. J Clin Oncol 2013;31:1748–1757; 4. Annala M et al. Cancer Discov 2018;8:444–457; 5. Ritch E et al. Clin Cancer Res 2020;26:1114–1125; 6.
Pritchard CC et al. N Engl J Med 2016;375:443–453; 7. Merck Sharp & Dohme B.V. Pembrolizumab. Summary of Product Characteristics. 2022; 8. AstraZeneca AB. Olaparib. Summary of Product Characteristics. 2022.
 IMPORTANCE OF IDENTIFYING DNA DAMAGE RESPONSE
MUTATIONAL STATUS (GERMLINE OR/AND SOMATIC )

Patients with advanced PCa

~20-25% ~75% HRR-1,2

HRR+1,2

~50% non-BRCA
~50% BRCA1/23 Caution:
mutated3
Germline testing
is an important ethical consideration,
HRR+ mutations are associated with not just for the patient
poor prognosis and unmet need1
but also for their family

Patients with germline BRCA1/2 are

more likely to present with a Gleason
score ≥8, advanced disease, nodal
involvement, and distant metastases at
diagnosis compared with non-carriers4

BRCA, breast cancer gene; HRR, homologous recombination repair; mCRPC, metastatic castration-resistant prostate cancer.
1. Scott RJ, et al. Oncotarget 2021;12:1600–1614; 2. Gonzalez D, et al. J Pathol Clin Res 2021;7:311–325; 3. Shore N, et al. Future Oncol 2021;17:2907–
2921; 4. Castro E, et al. J Clin Oncol 2013;31:1748–1757.
Combination PARP + AR pathway inhibition

• AR promotes DNA damage repair1,2 Regulation of AR chromatin binding and

• ADT upregulates PARP-mediated repair pathways with prostate gene expression5
synthetic lethality between ADT and PARP inhibition3
• PARP1 regulates AR-mediated transcriptional ERG

activation4
AR
regulated
AR-regulated transcriptome includes a number of DNA repair genes2 H3K4
Mediator
genes

AR AR AR ARE
MRE11A
ARE
NBN PARP1
ATR LIG3 H3K9
H3K4
me
DNA damage BER
sensors
FANCI H3K4
XRCC4 RAD54B MSH2 FANCC me
me
XRCC5 RAD51C MSH6 USP1
NHEJ HR MMR Fanconi

ADT, androgen deprivation therapy; AR, androgen receptor; ARE, androgen response element; ATR, serine/threonine-protein kinase gene; BER, base excision repair; ETS, erythroblast transformation-specific protein; EZH2, enhancer of zest homolog 2 protein;
FANCC, Fanconi anemia, complementation group C gene; FANCI, Fanconi anemia, complementation group I gene; FKHD, forkhead domain factor; FOX, forkhead box protein; GATA, GATA Binding Protein; H3K4, histone H3 lysine K4; HOXB13, homeobox
protein B13 gene; HR, homologous recombination; JMJD, Jumonji C domain-containing protein; LIG3, DNA ligase 3; LSD1, lysine-specific demethylase 1; me, methylation; MMR, mismatch repair; MRE11A, meiotic recombination 11 homolog A gene; MSH,
MutS homolog gene; NBN, nibrin gene; NHEJ, non-homologous DNA end joining; PARP, poly (ADP-ribose) polymerase; TF, transcription factor; USP1, ubiquitin specific peptidase 1 gene; XRCC, X-ray repair cross complementing gene.1. Goodwin JF et al.
Cancer Discov 2013;3:1254–1271; 2. Polkinghorn WR et al. Cancer Discov 2013;3:1245–1253; 3. Asim M et al. Nat Commun 2017;8:374; 4. Schiewer MJ et al. Cancer Discov 2012;2:1134–1149; 5. Jin HJ et al. Transl Androl Urol 2013;2:157–177.
 MAGNITUDE and PROpel trial designs

Eligibility Niraparib† + abiraterone§

HRR BM
MAGNITUDE1

• 1L mCRPC
positive R 1:1 Primary

for BM status*
Prescreening
• ≤4 months prior AAP allowed for mCRPC
• ECOG PS 0 or 1
(planned) Placebo + abiraterone endpoint:
• BPI-SF worst pain score ≤3 Allocation to cohort rPFS by
Stratification
central
Niraparib† + abiraterone§ review
• Prior taxane/ARi/AAP HRR BM
• BRCA1/2 vs. other HRR gene alterations negative R 1:1
(planned) Placebo + abiraterone

Eligibility Stratification
Primary endpoint:
• 1L mCRPC • Site of distant Olaparib§ + abiraterone Imaging-based PFS
• Docetaxel at mHSPC metastases
randomized 1:1 by investigator
PROpel2,3

• Docetaxel
All comers,
• No prior abiraterone
• Other second-generation
assessment or death
antiandrogen agents allowed if from any cause in the
stopped ≥12 months prior to absence of disease
enrollment progression
• Ongoing ADT Placebo + abiraterone
• ECOG PS 0–1
TALAPRO-2: Study Cohorts and Enrollment

Talazoparib + enzalutamide
All-comers (Cohort 1), N=805 (N=402)
Recruited first, data cutoff: August 16, 2022 1:1
Placebo + enzalutamide
(N=403)

rPFS in all-comers population

Nondeficient tested at 1-sided alpha 0.0125
HRRm HRRm
or unknown
N=169 N=230
N=636
Talazoparib + enzalutamide
(N=200)
HRRm only (Cohort 2), N=399 1:1
Placebo + enzalutamide
Recruitment continued after completion of (N=199)
enrollment in cohort 1, data cutoff: October 3, 2022
224 rPFS events would provide 85% power to detect an
HR of 0.64 using a 1-sided stratified log-rank test with
an alpha of 0.0125a

aAn interim analysis (IA) was planned with ~70% of the total required events. The HRRm cohort would be stopped for efficacy if the pre-specified efficacy boundary was crossed
(P ≤ 0.003). As the efficacy boundary was crossed at the IA rPFS, this became the final analysis. Survival and safety follow-up is continuing. All other endpoints are final.

PRESENTED BY:
Fizazi et al ASCO 2023
Propel, Magnitude and Talapro study results support the same
principle

Reminiscent of Drug Development that remains elusive in Prostate Cancer ?

Example of Pembrolizumab - we only know a piece of the puzzle

• Tumors with BRCA mutations respond to combination of Androgen signaling and parp
inhibition - ‘Phenotype Reversal’
• PROPEL and Talapro data suggests a subset within “wild type” DDR -that needs to be
unveiled
• Magnitude study abandoned that “question”
 Jan 2021 mHSPC : Offered ADT + RT
June 2021 mCRPC: PSA progression
Case history
Offered Docetaxel: without new imaging
• 42-year-old African American
PSA continued to Rise
• Diagnosed with mHSPC in 2021 Progression of disease in nodes and bones
• PS 0 Primary Resistance to ADT / Docetaxel

• Relevant comorbidities:
• Arterial hypertension, morbid obesity, DMII, Sep 21 -
Hyperlipidemia Imaging / Germline and Somatic Sequencing
• BMI: 33 Initiation of Abiraterone Acetate
• DRE: cT3 Sep 21 PSA :20
• Gleason score 4 + 4/ISUP 4 Oct 21 : PSA 25
• PSA: 100 ng/mL
Nov 21 PSA 32
Germline Testing gBRCA2
• CT Abdomen Pelvis multiple enlarged lymph nodes
(intraabdominal intrapelvic)
Nov 21 Imaging : Mixed Response
Bone Progression
• NO CT Chest No Bone Scan
3 new lesions/ nodes response
• NO Germline or Somatic Testing offered

ADT, androgen deprivation therapy; BMI, body mass index; BRCA, breast cancer gene; DRE, digital rectal examination; mCRPC,
metastatic castrate-resistant prostate cancer; mHSPC, metastatic hormone-sensitive prostate cancer; PSA, prostate-specific antigen. .
 PLAN OF CARE : 42 MCRPC
De novo mHSPC : Sequence of treatments
GBRCA2
1. ADT / EBRT - progression within 6 ms
2. Docetaxel - progression within 3 ms
3 Abiraterone - mixed response in 3 ms
Proposed Treatment Plan
1. Transition to Olaparib
2 Platinum Based Chemo

3. Add Parp inhibitor to Abiraterone

Outcome : Dec 2021 PSA 43 excellent tolerance
Jan 2022 PSA 45.9
Apr 2022 PSA 3.3 Imaging : Stable bone / PR nodes
Jun 2022 PSA 1.8
Aug 2022 PSA 1.5 Imaging : Stable
Nov 2022. PSA 1.2
Feb 2023 PSA 1 Imaging : Stable -
May 2023 PSA 0.8 Stable imaging- excellent tolerance
Nov 2023 PSA 0.7 continued response / CR nodes
How to Maximize “Therapeutic Index” – Dose our
“therapeutic strategy” towards the most Efficacious and
least toxic for our specific patient

Therapeutic Index :
Efficacy / Safety

Achieving the balance between

Overtreatment and
Undertreatment
Doublet Treatment for mHSPC SCORE Cards

How do Androgen Signaling Inhibitors perform - Abiraterone Acetate

Androgen Receptor Inhibitors
Triplet Therapy for mHSPC Score Cards
Contacts ESMO

European Society for Medical Oncology

Via Ginevra 4, CH-6900 Lugano
T. +41 (0)91 973 19 00
esmo@esmo.org

esmo.org
PROSTATE CANCER
Considerations in everyday clinical practice

Dr Alvin Tan, MBChB (Otago), FRACP

Head of Department, Medical Oncology Waikato Hospital, New Zealand
On behalf of the ESMO Practising Oncologist Working Group (POWG)
The ESMO POWG serves to identify the practice needs of oncologists who are
hospital and office-based by developing educational services, practice tools and
quality indicators that will facilitate the implementation of best practice at the
point of care.
The POWG members are relevant stakeholders to the ESMO Guidelines Webinars
as experts who are consulting and implementing the guidelines in their daily
practices
For more information about the ESMO POWG visit esmo.org

Don’t miss:
➢ The «ESMO Checklists» on OncologyPRO
DISCLOSURE

Honorarium (speakership, article review) – Research Review (NZ)

SOME CONSIDERATIONS IN EVERYDAY CLINICAL PRACTICE

✓ Case study patient – considerations in mCSPC setting

✓ Docetaxel consideration
✓ Which ARPi / NHT
✓ Alternate Abiraterone dosing
✓ Role for radiation

✓ Case study patient – considerations in mCRPC setting

✓ Cytotoxic chemotherapy considerations
✓ Sequencing of treatment
CASE STUDY PATIENT
At diagnosis of mCSPC
75 years old male
Reasonable ECOG status of 1, geriatric ‘fit’ (G8 score 15)
Hypertension/Dyslipidaemia – on two antihypertensives (beta-blocker, diuretic), statin

De novo metastatic disease with some constitutional symptoms (bone discomfort rib and hip, weight loss)
- some pelvic nodes with 4 bone metastases, no visceral disease
- ISUP 3 disease

Whilst ESMO guidelines would recommend consideration of triple therapy (ADT, Docetaxel, NHT) in fit men with de
novo mCSPC with >3 bone or visceral metastases [I, B; MCBS score: 4], definition of high-volume disease vary
across RCTs (CHAARTED, LATITUDE).

CHAARTED (DOI: 10.1056/NEJMoa1503747)

LATITUDE (DOI: 10.1056/NEJMoa1704174)
CASE STUDY PATIENT
Docetaxel consideration
This patient would meet criteria for high volume disease as per CHAARTED/PEACE-1 trials with one of the 4 bone
metastases outside of the spine/pelvis (ie ribs) but not as per LATITUDE (>3 bone metastases, but ISUP 3 only and
PSA <20).
PEACE-1: Overall survival HR was 0.72, 5.14 years vs 3.47 years (with addition of Abi/Pred to ADT/Docetaxel)
ARASENS: Overall survival HR was 0.68 (with addition of Darolutamide to ADT/Docetaxel)

How does age factor in?

As per post-hoc analysis of CHAARTED, those >70 years old had similar OS benefit compared to younger men with
high volume disease (HR 0.43) and de novo metastatic disease (HR 0.36). However, unsurprisingly less older men
received subsequent lines of treatment or subsequent Docetaxel at disease progression.

PEACE-1 (DOI: 10.1016/S0140-6736(22)00367-1)

ARASENS (DOI: 10.1056/NEJMoa2119115)
CHAARTED (DOI: 10.1056/NEJMoa1503747)
CASE STUDY PATIENT
Docetaxel consideration
So would I give Docetaxel to this case patient?
There is currently no RCT to compare the efficacy of triplet therapy to ADT/Novel hormone therapy to guide this.
If men are fit enough to have Docetaxel, then they would benefit from Abiraterone or Darolutamide addition.

Concern would be at age 75, currently independent but with PS of 1, would AEs of chemotherapy impact his
independence/QOL ? Does he have significant burden of disease ? Is there a rapid pace of cancer progression?

Personally, I would favour ADT and a novel hormonal therapy for a case such as this to balance the expected efficacy
of ADT/NHT treatment and more adverse effects of chemotherapy for this patient.
 CASE STUDY PATIENT
What ARPi/NHT should be used?
➢ Cost / Reimbursements
➢ Access to treatment
➢ Toxicity profile
➢ Comorbidities (HTN in our case patient – need to monitor, if diabetic monitor BSL with Abi/Pred)
➢ Patient preference

All level 1 evidence (Abiraterone, Apalutamide, Enzalutamide [I, A; MCBS score: 4])
➢ Use what is available (cost/funding) and most comfortable with
➢ Discuss and manage expected AEs – short term, long term (cardiovascular, musculoskeletal, bone
density)

ESMO Clinical Practice Guidelines 2020, e-update 2022

RESOURCE-LIMITED SETTING
Abiraterone dosing schedule

➢ Phase 1 studies have shown a 4-5 fold increase in drug absorption when abiraterone acetate taken with fat meal.

➢ Prospective open-label study (Shaherose et al, 2022)

Metastatic CRPC. N=70
1000 mg/day (fasting) vs 250 mg/day (with meal). Prednisone 5 mg BD. Meal (two teaspoons Ghee, groundnut chutney,
butter).
12 week PSA progression 2/35 vs 0/35
Mean PSA response rate 68% vs 82%
Similar AEs in regards to hypertension, hypokalaemia and fluid retention

Annals of Oncology (2022) 33 (suppl_9): S1495-S1502. 10.1016/annonc/annonc1125

 RESOURCE-LIMITED SETTING
Abiraterone dosing schedule

➢ Survey (n=251 medical oncologists, Patel et al, 2019) – 55% already prescribing low-dose AA due to limited
resources, 7% changed practice, 29% would switch to low dose schedule following NCCN listing low-dose AA as
an option

➢ Prostate Cancer Consensus Conference for Developing Countries (2021) – half of panel agreed that low dose
schedule in limited-resource setting was reasonable,

➢ Personally, I would use Abiraterone/Prednisone if patient was in New Zealand due to cost/access (no current
funded NHT available in mCSPC setting) and comfortable with 1/4 dosing schedule with food if cost prohibitive.

DOI: 10.1200/JGO.19.00341 JCO Global Oncology no. 6 (2020) 382-386. Published online March 3, 2020
DOI https://doi.org/10. 1200/GO.20.0050
 CASE STUDY PATIENT
Role for radiation?
➢ Evidence for this comes from the STAMPEDE and HORRAD trials – benefit in delaying clinical progression in
both trials when ADT combined with RT to the primary tumour [I, A]

➢ In the pre-specified subgroup of ‘low volume’ disease in the STAMPEDE trial, there was significant benefit in
failure-free survival (HR 0.59) and overall survival (HR 0.68) with the addition for RT to the primary site.

STAMPEDE (DOI: 10.1016/S0140-6736(18)32486-3)

HORRAD (DOI: 10.1016/j.eururo.2018.09.008)
ESMO Clinical Practice Guidelines 2020
CASE STUDY PATIENT
Role for radiation?
➢ Personal practice would be to discuss and refer this patient to my Radiation Oncology colleagues for an opinion:
➢ Technically has ‘ high volume’ disease by virtue of the 4 bone metastases (1 at least in ribs)
➢ But no evidence of visceral disease
➢ Although not necessarily for an OS benefit, may still be a role for local control of prostate
primary/symptoms.

➢ Would also refer for consideration of RT to local symptomatic sites of bone metastases (rib/hip pain) [I, A]

ESMO Clinical Practice Guidelines 2020

CASE STUDY PATIENT
Patient developed castrate resistance – what next?
➢ Started on Docetaxel chemotherapy (75 mg/m2) Q3 weekly
- If poorly tolerating this, could consider or even start with Q2 weekly schedule (50 mg/m2). As per PROSTY trial,
lower rates of febrile neutropenia, diarrhoea, neuropathy but potentially more treatment delays. Improved time to
treatment failure.

➢ Optimise pain relief – paracetamol, NSAIDs (with caution), opiates

➢ Bisphosphonates to reduce SRE/symptoms
➢ Local radiation to symptomatic sites
➢ Management of bone health (ESMO Clinical Practice Guidelines 2020) – weight bearing exercise, smoking
cessation, adequate calcium intake and Vit D status, bisphosphonates

Bone health in cancer: ESMO Clinical Practice Guidelines 2020

PROSTY trial (DOI: 10.1016/S1470-2045(12)70537-5)
CASE STUDY PATIENT
What other options can we consider post Docetaxel ?
If further progression:

➢ PARP-I for patients with BRCA1/2 alterations, DDR mutations [I, B; ESMO-MCBS score: 3]
➢ Cabazitaxel [I, A; ESMO-MCBS score: 3]
➢ Lutetium [I, A; ESMO-MCBS score: 4]
➢ Radium-223 [I, B; MCBS score: 4] – bone predominant, symptomatic without visceral disease
➢ Another ARPi [II, D]

ESMO Clinical Practice Guidelines 2020

SEQUENCING OF TREATMENT
In metastatic castrate resistant setting

Factors to consider:
➢ Comorbidities (diabetes, prior neuropathy if had Docetaxel)
➢ Bone marrow/blood counts with PARPi (MDS/AML risk)
➢ Sites of disease (bone, nodal vs visceral)
➢ Concordance of disease on PSMA/PET (for Lutetium consideration)
➢ Financial costs $$$
➢ Access to NGS testing/trials.
SEQUENCING OF TREATMENT
In metastatic castrate resistant setting

➢ If only ADT in mCSPC:

All options available (hope is that most men would be able to at least have a NHT in mCSPC)

➢ If already used NHT in mCSPC:

Docetaxel (symptomatic, visceral disease) or Lutetium (concordant PSMA/PET disease, $$$), Radium (symptomatic, no
visceral disease), NGS testing/PARPi (DDR mutation, $$$)

➢ If already used Docetaxel in mCSPC:

NHT (any ARPi), Lutetium (bone marrow function, concordant PSMA/PET disease, $$$), Radium (symptomatic, no visceral
disease), Cabazitaxel (comorbidities/previous toxicity, frailty), NGS testing/PARPi (DDR mutation, $$$).

➢ If already used Docetaxel/NHT in mCSPC:

Cabazitaxel or Lutetium, Radium, NGS testing/PARPi – factors as above
TAKEAWAY MESSAGE (1)
Metastatic castrate sensitive prostate cancer

Patients should be treated with the best available hormonal therapy with:
➢ Androgen deprivation therapy
➢ In combination with a Novel Hormonal Therapy – whichever is
accessible, cost-feasible

+/- Docetaxel chemotherapy (esp. high volume de novo metastatic

disease, considering patient comorbidity and frailty)
+/- Radiation therapy (local control, survival benefit in low volume
disease)
TAKEAWAY MESSAGE (2)
Metastatic castrate resistant prostate cancer

➢ Novel hormonal therapy if not already used in mCSPC setting

➢ Consider Docetaxel chemotherapy (or Cabazitaxel if prior Docetaxel)
and dosing schedule
➢ Lutetium if not candidate for Docetaxel chemotherapy (or prior
NHT/Docetaxel in CSPC setting)
➢ Consider NGS for BRCA 1/2, other DDR mutations
➢ Radium
➢ Radiation therapy
➢ Recognizing and managing long term AEs from ADT, frailty complex
Dr Alvin Tan, MBChB (Otago), FRACP
Head of Department, Medical Oncology Waikato Hospital, New Zealand
On behalf of the ESMO Practising Oncologist Working Group

Contacts ESMO

European Society for Medical Oncology

Via Ginevra 4, CH-6900 Lugano
T. +41 (0)91 973 19 00
esmo@esmo.org

Don’t miss:
esmo.org
➢ The «ESMO Checklists» on OncologyPRO