The document summarizes the treatment landscape for metastatic hormone-sensitive prostate cancer (mHSPC). It discusses several key trials that have established the benefit of primary intensification with the addition of docetaxel, abiraterone, enzalutamide, or apalutamide to androgen deprivation therapy (ADT). Trials like CHAARTED, LATITUDE, and STAMPEDE showed improved overall survival with these combinations compared to ADT alone. There is ongoing debate around the appropriate definition of high-volume versus low-volume disease and which patients most benefit from the triplet combination of ADT plus docetaxel plus a second agent. Overall, primary intensification beyond ADT alone is now

1. The Treatment Landscape of mHSPC
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
ISCO GU Meeting
Janssen Symposium
Sheraton Hotel Cairo
09/02/2023

2. Speaker
Disclosures:
Member of Advisory Board,
Consultant, and Speaker for:
Amgen, Astellas, AstraZeneca, Hoffman la
Roche, Janssen, Merck, Novartis,
Mundipharma, MSD, Ely Lilly, Sanofi-
Genzyme, Bayer, BMS, NewBridge, Sandoz

3. EUA 2022:
3rd Most Common Cancer
4th Most Common Cause of
Cancer Death
Bray et al. CA: Cancer J Clin. 2018;68:394-424.
Ibrahim et al. Journal of Cancer Epidemiology Volume 2014, Article ID 437971, 18 pages
40-50%
Lethal

4. Prostate Cancer as Simple as:
Androgen
Androgen Receptor
Proliferation, Growth, Invasion,
Metastases

5. AR Canonical Activity:
AR
AR AR
AR
AR
AR
AR-Vs AR-Vs
AR AR AR
AR AR AR
AR⌂LBD
DHT
DHT
DHT
DHT
DHT
DHT
Cholesterol
Adrenal
Androgen
DHT
T
CYP11A1
CYP17A1
Prof. Mohamed Abdulla Courtesy

6. Non-Canonical Activity of AR:
CM NM
AR
ARE
PROLIFERATION
DHT
T
5⍺ Reductase
Prof. Mohamed Abdulla Courtesy

7. James ND et al. EUROPEAN UROLOGY 67 (2015) 1028–1038
Data from 917 Patients in the Control
Arm of the STAMPEDE Trial (ADT Alone)
Bone & Soft Tissues Gleason Score > 8
PS 1 & 2 Age < 60 years
ADT ALONE IS NOT ALWAYS APPROPRIATE
 Intensification

9. Evolution of mCRPC Therapy after 2010:
OAS
rPFS
PSA Progression
Pain Deterioration
OoL Deterioration
mOAS : 18  35 months

10. mHSPC: Primary Intensification:
ADT
Docetaxel NHA

11. ADT + 1st AR Blockers is NOT The End of The Story:
Matsumura et al. Frontiers in Oncology. December 2021, Volume 11. Article 769068
1. No Access to NHA, Cost
2. 1st AR Blockers  Prevention of Flare with LHRH Analogues initially (Blaader Neck Obstruction, Vertebral Collapse)

12. ASCO 2022: ENZAMET Update:

13. ENZAMET: Who got the benefit?
OAS PFS
DAVIS ET AL. N Engl J Med 2019;381:121-31.

14. 3
Overall Survival Benefit With Treatment Intensification
Kyriakopoulos CE et al. J Clin Oncol. 2018 Apr 10;36(11):1080-1087. Clarke NW et al. Annals of Oncology30:1992-2003, 2019. Fizazi K et al. Lancet Oncol 2019 May; 20(5):686-700. James N et al. Int J
Cancer. 2022 Aug 1;151(3):422-434. Davis I et al. J Clin Oncol 40, 2022 (suppl17;abstr LBA5004), Armstrong AJ et al. Annal Oncol 2021;32(5):S1283-S1346, LBA25. Chi KN et al. J Clin Oncol. 2021
39:2294-2303.
DOCETAXEL
ABIRATERONE
ENZALUTAMIDE
APALUTAMIDE
CHAARTED Median follow-up: 53.7 months, Median OS: 57.6 months vs 47.2
months
STAMPEDE-C Median follow-up: 78.2 months, Median OS: 59.1months vs 43.1
months
LATITUDE
STAMPEDE-G
Median follow-up: 51.8 months, Median OS: 53.3 months vs 36.5
months
Median follow-up: 73.2 months, Median OS: 79 months vs 46 months
ENZAMET Median follow-up: 68.0 months, Median OS: NR vs 73.2%
ARCHES Median follow-up: 44.6 months, Median OS at 3 years: 71% vs 57%
TITAN Median follow-up: 44.0 months, Median OS: NR vs 52.2 months
HR=0.72
HR=0.81
HR=0.66
HR=0.60
HR=0.70
HR=0.66
HR=0.65

15. Disease Category:
Which Definition?
• CHAARTED: the presence of visceral metastasis and/or number and
location of bone lesions (> 4 bone lesions with at least one beyond the
vertebral bodies and pelvis
• LATITUDE: presence of visceral metastasis, three or more lesions on bone
scan and Gleason score at least 8.
• GRAVIS (Post-hoc Analysis: CHAARTED & GETUG – AFU15):
1. Poor Prognosis: De novo High Volume at Presentation.
2. Intermediate Prognosis: patients relapsing after curative therapy with high-volume
disease, or patients with newly diagnosed low-volume disease
3. Good Prognosis: patients relapsing after curative therapy with low-volume disease
Baston et al. Curr Opin Urol 2020, 30:576 – 583

16. Heterogenity is Evident  Direct Comparison?
Trial No of De Novo M1 Cases at Presentation
LATITUDE 100%
STAMPEDE 94%
TITAN 85%
CHARRRED 73%
GETUG-15 70%
ENZAMET 60%
ARCHES 67%

20. HV

21. AEs Highest Ranking Lowest Ranking
HTN AA (90%) APA (24%)
Cardiac AA (93%)
ALT ↑ AA (83%) ENZA (29%)
Fracture APA (65%) AA (42%)
Neutropenia ENZA (33%)
CNS DOC (65%)
ENZA (65%)
AA (62%)
Anemia APA (25%)
Overall AEs APA (28%)

22. https://doi.org/10.1016/j.euo.2022.06.003
• Triplet retained the highest (72%) likelihood
for the best treatment strategy, followed by
ADT plus ARAT at 28%.
• Patient selection??
• Toxicity??

23. mHSPC: Primary Intensification:
ADT
Docetaxel NHA Docetaxel
NHA
Prostate
RTH

24. rPFS OAS OAS LV vs HV
LV HV
THE LANCET. Published Online April 8, 2022 https://doi.org/10.1016/ S0140-6736(22)00367-1

26. Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.
Matsubara N et al Eur Urol 2020, ChowdhuryAUA 2020
OS according to 8m-PSA: Doublet vs Triplet
Adapted from Gwenaelle Gravis
8m-PSA
≤ 0.2 ng/mL
(n =74 )
> 0.2 ng/mL
(n =223)
Median, y
(95% CI) NE (4.0-NE) 3.5 (2.8-4.0)
P value 0.0007
ADT + D ADT + D + AAP
8m-PSA
≤ 0.2 ng/mL
(n =142 )
> 0.2 ng/mL
(n =134)
Median, y
(95% CI) NE (4.7-NE) 3.6 (2.9-NE)
P value < 0.0001
25% achieved PSA ≤0.2 51% achieved PSA ≤0.2
In comparison
LATITUDE: PSA <0.2 at 6 months: 47.6% (ADT + AAP) vs 7.5% (ADT)
TITAN PSA <0.2 at 6 months: 61% (ADT + APA) vs 21% (ADT)

27. N Engl J Med 2022;386:1132-42.

28. www.apccc.org
Advanced Prostate Cancer Consensus Conference APCCC 2022
Metastatic hormone-sensitive prostate cancer
Option Votes
Option 1 4
Option 2 71
Option 3 26
Option 4 4
Total votes 105
76. In which patients with synchronous mHSPC that are chemotherapy fit, do you recommend
the triplet therapyADT plus docetaxel plusAR pathway inhibitor?
Results obtained April 2022 based on 104 voting epxerts.
For interpretation of results please check the paper, which
will be published soon
© APC Society (apccc.org)
1. In the majority of patients independent
of disease volume
2. Only in high-volume patients
3. I usually do not recommend this
combination
4. Abstain/unqualified to answer
Option 1
4%
Option 2
70%
Option 3
26%

29. The Rationale is Dynamically Evolving:
Massive
Upfront
Attack
Think as a
Pirate

30. Fit* Synchronous
M1
«high-volume» and/or
«high-risk»
Fit* Synchronous
M1
«low-volume» and/or «low-
risk»
Fit* Metachronous
M1
«high-volume» and/or
«high-risk»
Fit* Metachronous
M1
«low-volume» and/or «low-
risk»
ADT alone No In a minority of selected
patients
No In a minority of selected
patients
ADT + Docetaxel Only selected patients No No No
ADT + Abiraterone/P
Yes
For fit patients,
consider triplet
therapy
Yes Yes Yes
ADT + Enzalutamide
ADT + Apalutamide
ADT + Docetaxel +
Abirateron/P or
Darolutamide
Triplet: selected patients Triplet: selected patients No
Treatment of the primary
tumour
Only in case of local
complications
Yes (RT) Local salvage therapy in selected cases
Metastases-directed
therapy (MDT)
Only in case of local
complications
Ideally on clinical trial.
Aim: to stop systemic therapy
after a fixed duration in case of
good response?
Only in case of local
complications
Ideally on clinical trial.
Aim: to avoid systemic therapy
or to stop systemic therapy
after a fixed duration in case of
good response?
*Frail/vulnerable patients: individualized treatment recommendation
M1 assessment: On bone scintigraphy and computed tomography
mHSPC Treatment Options 2022
Aurelius Omlin
Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.

31. ENZA APA AA DOCETAXEL
Phase III ✓ ✓ ✓ ✓
Extended Published Follow Up ✓ (44 m) ✓ (40 m) ✓ ✓
OAS ✓ ✓ ✓ ✓
PFS ✓ ✓ ✓ ✓
High Volume + +++ +++ ✓
Low Volume ++ + +/- ❌
Myocardial Disease ✓ +/- ❌ ❌
Uncontrolled Hypertension ❌ ❌ ❌ ❌
History of Convulsions ❌ ❌ ✓ ✓
Skin Disease ✓ ❌ ✓ ✓
Liver Disease ✓ ✓ ❌ +/-
Thyroid Dysfunction ✓ ✓ ❌ ✓
Hypokalemia ✓ ✓ ❌ +/-
Prof. Mohamed Abdulla Courtesy

32. Thank You
Mohamed Abdulla
mohamed.abdulla@oncologyclinic.org