Next generation antiandrogen in metastatic prostate cancer

1. Antiandrogens beyond
biclutamide in metastatic
prostate cancer
03 feb 2023

2. Prostate cancer
• Huggins and hodges:
Lowering circulating
testosterone palliate
symptoms of advanced PC
• Androgen signalling axis in
PC

3. antiandrogens

4. First vs second gen anti-androgen
First Gen Second Gen
Flutamide, Nilutamide & Biclutamide Enzalutamide, Apalutamide, Darolutamide
Competitively inhibits Androgen receptor Inhibition of AR
Inhibit translocation of AR to nucleus
Inhibit DNA binding and AR mediated transcription
AR agnostic in high AR environment No AR agonistic activity
Completely penetrable by AR mutation Overcome AR mutation
Androgen withdrawal syndrome No Androgen withdrawal syndrome
Combination strategy not efficacious Improved outcome with combination strategy

5. Enzalutamide
• Dose – 160 mg OD
• Survival benefit in mCSPC and mCRPC
• Penetrates blood brain barrier: Inhibit GABA receptors
• Adverse events
• Fatigue
• Arthralgia
• Constipation
• Seizure ( Very low risk) – 1.1% in those wih 1 risk factor for seizure (UPWARD
study)

6.  Phase III, randomized, open-label, multicenter clinical trial
 Primary endpoint: OS
 Secondary endpoints: PSA PFS (including clinical progression if occurring first), clinical PFS,
AEs, HRQoL
ENZAMET: Study Design
Sweeney. ASCO 2019. Abstr LBA2. Davis. NEJM. 2019;[Epub]. Slide credit: clinicaloptions.com
Patients with metastatic prostate
cancer, starting first-line ADT
(max 12 wks prior to
randomization); ECOG PS 0-2;
2 cycles prior docetaxel allowed
(N = 1125)
Enzalutamide 160 mg/day
+ testosterone suppression
(n = 563)
Standard NSAA*
+ testosterone suppression
(n = 562)
Stratified by volume of metastases (high vs low), antiresorptive
therapy (yes vs no), ECOG PS (0/1 vs 2), comorbidities (ACE-27:
0/1 vs 2/3), study site, planned use of early docetaxel (yes vs no)
Evaluate
every 12 wks
CRPC tx at PD
(investigator
discretion)
Follow for time
to progression
and OS
Evaluate
every 12 wks
*Bicalutamide, nilutamide, or flutamide

7. ENZAMET: OS (Primary Endpoint)
Sweeney. ASCO 2019. Abstr LBA2. Davis. NEJM. 2019;[Epub]. Reproduced with permission. Slide credit: clinicaloptions.com
Patients Alive at Month 36, %
Enzalutamide NSAA
80
(95% CI: 75-83)
72
(95% CI: 68-76)
HR: 0.67 (95% CI: 052-0.86; P = .002)
563 558 541 527 480 340 189 106 45
562 551 531 501 452 311 174 86 32
Patients at Risk, n
Enzalutamide
NSAA
Mos
Enzalutamide
NSAA
48
0 6 12 18 24 30 36 42
OS
(%)
100
60
40
20
0
80

8.  N= 1401
 nmCRPC
‒ PSA DT <10 months with castrate level testosterone
‒ No metastases by conventional imaging (CT or MRI + bone scan)
 ADT + Enza vs ADT + Placebo

10. Apalutamide
 Higher affinity for AR (7-10X higher to biclutamide)
 Dose – 240 mg OD
 Less BBB penetration than enzalutamide
 Adverse events (Favorable)
‒ Fatigue (Gd1/Gd2)
‒ Anemia

11.  N = 1207 patients
 nmCRPC
‒ CT + Bone scans
‒ PSA DT < 10 months
 ADT + Apaluatmide vs ADT + Placebo

12. Median – 40.5 vs
16.2 mo

13. Chi. ASCO 2019. Abstr 5006. Chi. NEJM. 2019;[Epub].
TITAN: Study Design
 International, randomized, double-blind, placebo-controlled phase III trial
 Primary endpoints: OS, radiographic PFS
 Secondary endpoints: time to pain progression, time to SRE, time to chronic opioid use,
time to cytotoxic chemotherapy
 Exploratory endpoints including: time to PSA progression, PFS2
Patients with metastatic castration-
sensitive prostate cancer; ECOG PS 0/1;
prior ADT ≤ 6 mos for mCSPC or ≤ 3 yrs
for local disease
(N = 1052)
Apalutamide 240 mg QD + ADT
(n = 525)
Placebo + ADT
(n = 527)
Slide credit: clinicaloptions.com
Gleason score (≤ 7 vs > 7), region (NA/EU vs other),
prior docetaxel (yes vs no)
PD

14. PFS
(%)
TITAN: Radiographic PFS
 52% reduction in risk of radiographic progression or death with apalutamide
Slide credit: clinicaloptions.com
Chi. ASCO 2019. Abstr 5006. Chi. NEJM. 2019;[Epub].
Mos
Patients at Risk, n
Apalutamide 525 469 389 315 89 2 0
Placebo 527 437 325 229 57 3 0
Median PFS, mos (95% CI)
Events
HR (95% CI)
P value
Apalutamide + ADT
(n = 525)
NE (NE-NE)
134
Placebo + ADT
(n = 527)
22.1 (18.5-32.9)
231
0.48 (0.39-0.60)
< .0001
100
75
50
20
0
36
0 6 12 18 24 30
Apalutamide + ADT
Placebo + ADT
48%
68%

15. TITAN: OS
 33% reduction in risk of death with apalutamide
Slide credit: clinicaloptions.com
Chi. ASCO 2019. Abstr 5006. Chi. NEJM. 2019;[Epub].
Mos
OS
(%)
Patients at Risk, n
Apalutamide 525 513 490 410 165 14 0
Placebo 527 509 473 387 142 16 0
Median PFS, mos (95% CI)
Events
HR (95% CI)
P value
Apalutamide + ADT
(n = 525)
NE (NE-NE)
83
Placebo + ADT
(n = 527)
NE (NE-NE)
117
0.67 (0.51-0.89)
.0053
Apalutamide + ADT
Placebo + ADT
74%
82%
36
0 6 12 18 24 30
100
75
50
20
0

16. Darolutamide
 Potent AR inhibitor
 Dose – 600mg BD
 Binds to mutated AR including F876L mutation (resistance to enzalutamide and
apalutamide)
 Very low penetration of blood brain barrier
 Limited clinically relevant drug interactions
 Adverse event (Most Gd1 and Gd2)
‒ Fatigue
‒ Nausea
‒ No reported seizure

17. ARAMIS: Study Design
 Randomized, double-blind phase III trial
 Primary endpoint: metastasis-free survival
 Secondary endpoints including: OS, safety, time to pain progression, time to first SSE
 Exploratory endpoints including: PFS, time to PSA progression, QoL
Patients with nonmetastatic
CRPC and PSADT ≤ 10 mos,
PSA ≥ 2 ng/mL, ECOG PS 0/1
(N = 1509)
Darolutamide 600 mg BID + ADT
(n = 955)
Placebo + ADT
(n = 554)
2:1
Stratified by PSADT (≤ 6 vs > 6 mos), baseline bone-targeting agent
use (yes vs no)
Fizazi. NEJM. 2019;380:1235. Fizazi. ASCO 2019. Abstr 5000. Slide credit: clinicaloptions.com

20.  N = 1306 patients
 Metastatic mCSPC
 All received Docetaxel (75mg/m2 for 6 cycles)
 Darolutamide vs placebo
 Primary end point – OS
 Tolerance – similar adverse events in both arms

21. 4 year OS – 62.7% vs 50.4%

22. Resistance to Antiandrogens
• AR point mutation
• Antagonist to agonist switch
• AR splice variants
• AR-V7
• Ligand independent activation
• Signalling via alternative nuclear
hormone receptors

23. Role of Biclutamide ?
• To inhibit surge in testosterone
following LHRH agonist
• To avoid potential flare o
symptoms
• Inferior to 2nd gen NSAA in
mCSPC, nmCRCP, mCRPC

24. Thank you