Overview of a drug on prostate cancer by Johnson & Johnson

1. APALUTAMIDE
AMEY MANKAR
1

2. CONTENT
 BRIEF INTRODUCTION
 PROSTATE CANCER
 SYMPTOMS
 TREATMENTS
 WHY APALUTAMIDE?
 MECHANISM OF ACTION
 SYNTHESIS
 PRE-CLINICAL STUDIES
 CLINICAL STUDIES
 SUMMARY
2

3. INTRODUCTION
 Biaryl thiohydantoin drug
 Patent by Aragon pharmaceuticals now acquired by Janssen Pharmaceuticals.
 Was Filed as an NDA.
 Got approved in Feb 2018
 For Non-metastatic Castration Resistant Prostate Cancer.
 Currently no treatment for the same.
3

4. PROSTATE CANCER
 2nd most common cancer in world
 Progression of disease despite Castration
 Can lead to metastatic CRPC
 No clear therapy
4

5. SYMPTOMS
 Unintentional weight loss
 Weakness
 Anaemia
 Paraneoplastic syndromes, e.g. Tendency to Venous Thromboembolism.
5

6. TREATMENTS
 ACTIVE SURVEILLANCE.
 SURGERY.
 RADIATION THERAPY.
 CRYOTHERAPY (CRYOSURGERY)
 HORMONE THERAPY.
 CHEMOTHERAPY.
6

7. ANDROGEN DEPRIVATION THERAPY
 In 1941,Charles Huggins showed that advanced PC can be inhibited by
decreasing testosterone levels.
 1966 Nobel prize in Medicine.
 Antiandrogens, such as Flutamide, Bicalutamide, Nilutamide, and Enzalutamide.
 Androgen synthesis inhibitors, such as Ketoconazole, Aminoglutethamide , and
Abiraterone Acetate.
7

8. WHY APALUTAMIDE?
 Despite decreased levels of testosterone levels continued Androgen Signalling
leading to overexpression is seen.
 This is also called as Castration Resistant Prostate Cancer.
 Apalutamide is used in its Non-Metastatic stage.
 Poor prognosis leads to Metastatic Prostate Cancer.
8

9. MECHANISM OF ACTION
9
Abbreivations: AD, androstenedione; AKR1C3, aldo-keto reductase family 1 member C3; AR, androgen receptor; CYP17A1, cytochrome P450 c17; DHEA-
dehydroepiandrosterone; D, dihydrotestosterone; HSP, heat shock protein; HSD3β1, human 3-betahydroxysteroid dehydroxynase/delta5-4 isomerase type 1; P,
androgen precursors; PSA, prostate specific antigen; T, testosterone.

10. SYNTHESIS
10
Reagents and conditions: (a) HNO3, H2SO4, rt, 3 h; (b) POBr3, DMF, 110 C, 3 h; (c) CuCN, DMF, 110 C, 16 h; (d) Fe, AcOH, EA, reflux, 16 h; (e)MeNH2HCl or CD3NH2HCl, CDI, NEt3, DCM, 3
h; (f) Fe, AcOH, EA, reflux, 16 h; (g) TMSCN, AcOH or AcOD, cyclobutanone or d4-cyclobutanone, sealed tube, 80 C, 16 h; (h) DCl,D2O, MW, 150 C, 2 h; (i) CSCl2, DMA, 60 C, 16 h, then 2 M

11. PHARMACOKINETIC STUDIES
11

12. PHARMACOKINETIC PARAMETERS
12

13. IN VITRO ACTIVITY
 Acts on Type 1 nuclear receptor
 LNCaP cells mimic the AR overexpression
 Binds to AR competitively 7-10 times efficiently than bicalutamide
13

14. IMPAIRS AR NUCLEAR LOCALIZATION
 Prevents the translocation of AR from cytoplasm to nucleus.
14

15. CLINICAL TRIALS
 Conducted with patients having high risk for progression(PSA>8ng/ml)
 Given 240mg of Apalutamide with continued androgen deprivation therapy
 PSA response were the end points
 Conclusion
 In high-risk nmCRPC patients, Apalutamide was safe with robust activity based
on durable PSA responses and disease control.
15

16. 16

17. PRIMARY END POINTS
 Median change in PSA from baseline to week 12 was found to be 85%
 Median change in PSA from baseline to any point was found to be 93%
 Maximal PSA reduction (>50%) after baseline was reported in 94% patients
17

18. SAFETY
18

19. PHASE III CLINICAL TRIALS( SPARTAN)
 COMPARISON WITH PLACEBO
 PRIMARY OUTCOME MEASURES
METASTASIS FREE SURVIVAL RATE
 SECONDARY OUTCOME MEASURES
OVERALL SURVIVAL
TIME TO PROGRESSION ETC
19

20. SUMMARY
 Competitive Antagonist of AR
 Better than other available drugs e.g; bicalutamide
 Sold as oral formulation
 Dose-240mg/day
 Well tolerated
 Marketed by Jansenn Pharmaceuticals
20

21. THANK YOU!!!
21

22. REFERENCES
 1 Crona, D.J. and Y.E. Whang, Androgen Receptor-Dependent and -Independent
Mechanisms Involved in Prostate Cancer Therapy Resistance. Cancers, 2017. 9(6).
 2. Pang, X., Y. Wang, and Y. Chen, Design, synthesis, and biological evaluation of
deuterated apalutamide with improved pharmacokinetic profiles. Bioorg Med Chem
Lett, 2017. 27(12): p. 2803-2806.
 3. Clegg, N.J., et al., ARN-509: a novel antiandrogen for prostate cancer
treatment. Cancer Res, 2012. 72(6): p. 1494-503.
 4. Smith, M.R., et al., Phase 2 Study of the Safety and Antitumor Activity of
Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk
Nonmetastatic Castration-resistant Prostate Cancer Cohort. Eur Urol, 2016. 70(6): p.
963-970.
 5. A Study of Apalutamide (ARN-509) in Men With Non-Metastatic Castration-
Resistant Prostate Cancer - Full Text View - ClinicalTrials.gov
22