Apalutamide

Apalutamide
Clinical data
Pregnancy
category
  • X (Contraindicated)
Routes of
administration		 Oral
Drug class Nonsteroidal antiandrogen
Pharmacokinetic data
Biological half-life 3–4 days[1]
Identifiers
CAS Number
PubChem CID
ChemSpider
ECHA InfoCard 100.235.115
Chemical and physical data
Formula C21H15F4N5O2S
Molar mass 477.434713 g/mol
3D model (JSmol)

Apalutamide (INN) (developmental code name ARN-509, also JNJ-56021927) is a nonsteroidal antiandrogen (NSAA) that is under development for the treatment of prostate cancer.[2] It is similar to enzalutamide both structurally and pharmacologically,[3][4] acting as a selective competitive antagonist of the androgen receptor (AR), but shows some advantages, including greater potency and several-fold reduced central nervous system permeation.[2][5][6] Apalutamide is (since 2014) in phase III clinical trials for castration-resistant prostate cancer.[7]

Side effects

Apalutamide has been found to be well-tolerated in clinical trials thus far,[3][6] with the most common side effects reported including fatigue, nausea, abdominal pain, and diarrhea.[5][8][9]

Pharmacology

Antiandrogen

Apalutamide is a silent antagonist of the AR and possesses 5- to 10-fold greater affinity for the AR than bicalutamide.[10][11]

Resistance in prostate cancer

Recently, the acquired F876L mutation of the AR identified in advanced prostate cancer cells was found to confer resistance to both enzalutamide and apalutamide.[12][13] A newer antiandrogen, darolutamide (ODM-201), is not affected by this mutation, nor has it been found to be affected by any other tested/well-known AR mutations.[14]

Apalutamide may be effective in a subset of prostate cancer patients with acquired resistance to abiraterone acetate.[3]

Other actions

Cytochrome P450 inducer

Apalutamide shows potent induction potential of CYP3A4 similarly to enzalutamide.[15][16]

GABAA receptor negative modulator

Apalutamide binds weakly to and inhibits the GABAA receptor in vitro similarly to enzalutamide (IC50 = 3.0 and 2.7 μM, respectively),[17] but due to its relatively lower central concentrations, may have a lower risk of seizures in comparison.[2][5][9]

Pharmacokinetics

The mean terminal half-life of apalutamide at steady-state is 3 to 4 days.[1]

Chemistry

The chemical structure of apalutamide is similar to that of enzalutamide.[10]

See also

References

  1. 1 2 Rathkopf DE, Morris MJ, Fox JJ, Danila DC, Slovin SF, Hager JH, et al. (October 2013). "Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer". Journal of Clinical Oncology. 31 (28): 3525–30. PMC 3782148 Freely accessible. PMID 24002508. doi:10.1200/JCO.2013.50.1684.
  2. 1 2 3 Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, et al. (March 2012). "ARN-509: a novel antiandrogen for prostate cancer treatment". Cancer Research. 72 (6): 1494–503. PMC 3306502 Freely accessible. PMID 22266222. doi:10.1158/0008-5472.CAN-11-3948.
  3. 1 2 3 Patel JC, Maughan BL, Agarwal AM, Batten JA, Zhang TY, Agarwal N (2013). "Emerging molecularly targeted therapies in castration refractory prostate cancer". Prostate Cancer. 2013: 981684. PMC 3684034 Freely accessible. PMID 23819055. doi:10.1155/2013/981684.
  4. ↑ Ya-Xiong Tao (11 June 2014). Pharmacology and Therapeutics of Constitutively Active Receptors. Elsevier Science. pp. 351–. ISBN 978-0-12-417206-7. ARN-509 is related structurally to enzalutamide with greater in vivo activity in CRPC xenograft models (Clegg et al., 2012).
  5. 1 2 3 Schweizer MT, Antonarakis ES (August 2012). "Abiraterone and other novel androgen-directed strategies for the treatment of prostate cancer: a new era of hormonal therapies is born". Therapeutic Advances in Urology. 4 (4): 167–78. PMC 3398601 Freely accessible. PMID 22852027. doi:10.1177/1756287212452196.
  6. 1 2 Rathkopf D, Scher HI (2013). "Androgen receptor antagonists in castration-resistant prostate cancer". Cancer Journal. 19 (1): 43–9. PMC 3788593 Freely accessible. PMID 23337756. doi:10.1097/PPO.0b013e318282635a.
  7. ↑ Agarwal N, Di Lorenzo G, Sonpavde G, Bellmunt J (September 2014). "New agents for prostate cancer". Annals of Oncology. 25 (9): 1700–9. PMID 24658665. doi:10.1093/annonc/mdu038.
  8. ↑ Leibowitz-Amit R, Joshua AM (December 2012). "Targeting the androgen receptor in the management of castration-resistant prostate cancer: rationale, progress, and future directions". Current Oncology. 19 (Suppl 3): S22–31. PMC 3553559 Freely accessible. PMID 23355790. doi:10.3747/co.19.1281.
  9. 1 2 Pinto Á (February 2014). "Beyond abiraterone: new hormonal therapies for metastatic castration-resistant prostate cancer". Cancer Biology & Therapy. 15 (2): 149–55. PMC 3928129 Freely accessible. PMID 24100689. doi:10.4161/cbt.26724.
  10. 1 2 Kawahara, Takashi; Miyamoto, Hiroshi (2014). "Androgen Receptor Antagonists in the Treatment of Prostate Cancer". Clinical Immunology, Endocrine & Metabolic Drugs. 1 (1): 11–19. ISSN 2212-7070. doi:10.2174/22127070114019990002.
  11. ↑ Kim W, Ryan CJ (February 2015). "Quo vadis: advanced prostate cancer-clinical care and clinical research in the era of multiple androgen receptor-directed therapies". Cancer. 121 (3): 361–71. PMID 25236176. doi:10.1002/cncr.28929.
  12. ↑ Joseph JD, Lu N, Qian J, Sensintaffar J, Shao G, Brigham D, Moon M, Maneval EC, Chen I, Darimont B, Hager JH (September 2013). "A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509". Cancer Discovery. 3 (9): 1020–9. PMID 23779130. doi:10.1158/2159-8290.CD-13-0226.
  13. ↑ Nelson WG, Yegnasubramanian S (September 2013). "Resistance emerges to second-generation antiandrogens in prostate cancer". Cancer Discovery. 3 (9): 971–4. PMC 3800038 Freely accessible. PMID 24019330. doi:10.1158/2159-8290.CD-13-0405.
  14. ↑ Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ (July 2015). "Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies". Scientific Reports. 5: 12007. PMC 4490394 Freely accessible. PMID 26137992. doi:10.1038/srep12007.
  15. ↑ Fizazi K, Albiges L, Loriot Y, Massard C (2015). "ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer". Expert Review of Anticancer Therapy. 15 (9): 1007–17. PMC 4673554 Freely accessible. PMID 26313416. doi:10.1586/14737140.2015.1081566.
  16. ↑ Ivachtchenko AV, Mitkin OD, Kudan EV, Rjahovsky AA, Vorobiev AA, Trifelenkov AS, et al. (2014). "Preclinical Development of ONC1-13B, Novel Antiandrogen for Prostate Cancer Treatment". Journal of Cancer. 5 (2): 133–42. PMC 3909768 Freely accessible. PMID 24494031. doi:10.7150/jca.7773.
  17. ↑ Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, et al. (March 2012). "ARN-509: a novel antiandrogen for prostate cancer treatment". Cancer Research. 72 (6): 1494–503. PMC 3306502 Freely accessible. PMID 22266222. doi:10.1158/0008-5472.CAN-11-3948.
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