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PSA response to antiandrogen withdrawal: a systematic review and meta-analysis

Prostate Cancer and Prostatic Diseases volume 24, pages 826–836 (2021)Cite this article

Subjects

Abstract

Background

Antiandrogen withdrawal (AAW) response is the paradoxical decrease in prostate-specific antigen (PSA) following the withdrawal of antiandrogen in patients with advanced prostate cancer. Currently, the reported literature on the proportion of patients exhibiting AAW response and the differences in PSA response between the types of antiandrogens is unclear.

Methods

This review aimed to explore the PSA response to AAW and to identify if the response depends on the type of antiandrogens. A literature search was performed using databases PubMed, Cochrane and EMBASE with a cut-off date of 23rd of November 2020. Studies reporting on outcomes of AAW and prostate cancer were included. Studies were screened by two reviewers and relevant data extracted. Meta-analysis of outcomes was reported using random-effects and fixed-effects model. A subgroup analysis was performed for type of antiandrogen.

Results

From 450 studies, 23 were included with a total of 1474 patients with advanced prostate cancer were available for further analysis. Overall, 395 (26%) patients had any reduction in PSA levels (95% CI: 20–32%) and 183 (11%) patients had a ≥50% reduction in PSA levels (95% CI: 6–16%). Among the 1212 patients on first-generation antiandrogens, 30% (95% CI: 23–38%) had any PSA decline with 15% patients having a ≥50% PSA decline (95% CI: 8–22%). In contrast, among the 108 patients on second-generation antiandrogens, 7% (95% CI: 0–13%) had any PSA decline and only 1% (95% CI: 0–5%) had a ≥50% PSA decline. Also, among the 154 patients on androgen synthesis inhibitors, 26% (95% CI: 19–33%) had any PSA decline and only 4% (95% CI: 0–13%) had a ≥50% PSA decline.

Conclusions

One-fourth of patients treated with AAW show a PSA response. However, PSA response to AAW is uncommon with second-generation antiandrogens and androgen synthesis inhibitors. Further research is required to understand the differences in response between the types of antiandrogen.

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Fig. 1: PRISMA diagram.
Fig. 2: Forest plot of any decline in PSA.
Fig. 3: Forest plot of ≥50% decline in PSA.
Fig. 4

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References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  Google Scholar 

  2. Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol. 2004;22:1025–33.

    Article  CAS  Google Scholar 

  3. Rice MA, Malhotra SV, Stoyanova T. Second-generation antiandrogens: from discovery to standard of care in castration resistant prostate cancer. Front Oncol. 2019;9:801.

    Article  Google Scholar 

  4. Griend DJV, d’Antonio JM, Isaacs JT. Hormonal Regulation of the Prostate. In: Berges R, Tombal B, editors. Androgens and prostate cancer. Belgium: Ismar Healthcare Publishing; 2009. p. 11–34.

    Google Scholar 

  5. Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev. 2004;25:276–308.

    Article  CAS  Google Scholar 

  6. Miyamoto H, Rahman MM, Chang C. Molecular basis for the antiandrogen withdrawal syndrome. J Cell Biochem. 2004;91:3–12.

    Article  CAS  Google Scholar 

  7. Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer. 2001;1:34.

    Article  CAS  Google Scholar 

  8. Scher HI, Kelly WK. Flutamide withdrawal syndrome: its impact on clinical trials in hormone-refractory prostate cancer. J Clin Oncol. 1993;11:1566–72.

    Article  CAS  Google Scholar 

  9. von Klot CA, Kramer MW, Boker A, Herrmann TR, Peters I, Kuczyk MA, et al. Is there an anti-androgen withdrawal syndrome for enzalutamide? World J Urol. 2014;32:1171–6.

    Article  Google Scholar 

  10. Dupont A, Gomez J-L, Cusan L, Koutsilieris M, Labrie F. Response to flutamide withdrawal in advanced prostate cancer in progression under combination therapy. J Urol. 1993;150:908–13.

    Article  CAS  Google Scholar 

  11. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8:336–41.

    Article  Google Scholar 

  12. MIMS Online [Internet]. MIMS Australia. 2020. Available from: http://www.mims.com.au.

  13. Veritas Health Innovation. Covidence systematic review software. Melbourne, Australia: Veritas Health Innovation.

  14. Higgins JPT, Green S. Cochrane handbook for systematic review of interventions. The Cochrane Collaboration; 2011. Available from: www.cochrane-handbook.org.

  15. Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010;36:1–48.

    Article  Google Scholar 

  16. Vatandoust S, Kichenadasse G, O’Callaghan ME, Kopsaftis T, Walsh S, Borg M, et al. Antiandrogen withdrawal (AAWD) in patients (pts) with prostate cancer (PCa): Retrospective analysis of data from the South Australian Prostate Cancer Clinical Outcome Collaborative (SA-PCCOC). J Clin Oncol. 2015;33 7_suppl:240.

    Article  Google Scholar 

  17. Albiges L, Auclin E, Rousseau B, Boughalem E, Levy A, Loriot Y, et al. Is there a withdrawal syndrome with abiraterone acetate (AA)? J Clin Oncol. 2013;31 (6_suppl):89.

    Article  Google Scholar 

  18. Poole A, Gill D, Hahn AW, Johnson E, Carroll E, Boucher K, et al. Incidence and characterization of antiandrogen withdrawal syndrome after discontinuation of treatment with enzalutamide in castration-resistant prostate cancer. Clin Genitourin Cancer. 2018;16:e169–72.

    Article  Google Scholar 

  19. Small EJ, Srinivas S. The antiandrogen withdrawal syndrome. Experience in a large cohort of unselected patients with advanced prostate cancer. Cancer. 1995;76:1428–34.

    Article  CAS  Google Scholar 

  20. Figg WD, Sartor O, Cooper MR, Thibault A, Bergan RC, Dawson N, et al. Prostate specific antigen decline following the discontinuation of flutamide in patients with stage D2 prostate cancer. Am J Med. 1995;98:412–4.

    Article  CAS  Google Scholar 

  21. Rodriguez-Vida A, Bianchini D, Van Hemelrijck M, Hughes S, Malik Z, Powles T, et al. Is there an antiandrogen withdrawal syndrome with enzalutamide? BJU Int. 2015;115:373–80.

    Article  CAS  Google Scholar 

  22. Sella A, Flex D, Sulkes A, Baniel J. Antiandrogen withdrawal syndrome with cyproterone acetate. Urology. 1998;52:1091–3.

    Article  CAS  Google Scholar 

  23. Murakami T, Obata H, Akitake N, Shiota M, Takeuchi A, Kashiwagi E, et al. Prognostic and predictive factors for anti-androgen withdrawal in castration-resistant prostate cancer. Anticancer Res. 2018;38:4115–21.

    Article  CAS  Google Scholar 

  24. Sartor AO, Tangen CM, Hussain MHA, Eisenberger MA, Parab M, Fontana JA, et al. Antiandrogen withdrawal in castrate-refractory prostate cancer. Cancer. 2008;112:2393–400.

    Article  CAS  Google Scholar 

  25. Caffo O, Palermo A, Veccia A, Maines F, Chierichetti F, Berruti A, et al. Biochemical and objective response to abiraterone acetate withdrawal: incidence and clinical relevance of a new scenario for castration-resistant prostate cancer. Urology. 2013;82:1090–3.

    Article  Google Scholar 

  26. Herrada J, Dieringer P, Logothetis CJ. Characterization of patients with androgen-independent prostatic carcinoma whose serum prostate specific antigen decreased following flutamide withdrawal. J Urol. 1996;155:620–3.

    Article  CAS  Google Scholar 

  27. Matsumoto K, Tanaka N, Hayakawa N, Ezaki T, Suzuki K, Maeda T, et al. The type of patients who would benefit from anti-androgen withdrawal therapy: could it be performed safely for aggressive prostate cancer? Med Oncol. 2013;30:647.

    Article  Google Scholar 

  28. Higgins J, Altman D, Sterne JE. Chapter 8: Assessing risk of bias in included studies. In: Higgins J, Churchill R, Chandler J, Cumpston ME, editors. Cochrane handbook for systematic reviews of interventions. Cochrane; Chichester, UK, 2017.

  29. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787–90.

    Article  CAS  Google Scholar 

  30. Giatromanolaki A, Fasoulaki V, Kalamida D, Mitrakas A, Kakouratos C, Lialiaris T, et al. CYP17A1 and androgen-receptor expression in prostate carcinoma tissues and cancer cell lines. Cur Urol. 2019;13:157–65.

    Article  CAS  Google Scholar 

  31. Richards J, Lim AC, Hay CW, Taylor AE, Wingate A, Nowakowska K, et al. Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Res. 2012;72:2176–82.

    Article  CAS  Google Scholar 

  32. Davies A, Conteduca V, Zoubeidi A, Beltran H. Biological evolution of castration-resistant prostate cancer. Eur Urol Focus. 2019;5:147–54.

  33. Lorenzin F, Demichelis F. Evolution of the prostate cancer genome towards resistance. J Transl Genet Genom. 2019;3:5. https://doi.org/10.20517/jtgg.2019.01.

  34. Yamamoto Y, Akashi Y, Minami T, Nozawa M, Kiba K, Yoshikawa M, et al. Serious hypokalemia associated with abiraterone acetate in patients with castration-resistant prostate cancer. Case Rep Urol. 2018;2018:1414395.

  35. Sartor O, Parker CC, De Bono J. Reappraisal of glucocorticoids in castrate-resistant prostate cancer. Asian J Androl. 2014;16:666.

    Article  Google Scholar 

  36. Veldscholte J, Berrevoets C, Ris-Stalpers C, Kuiper G, Jenster G, Trapman J, et al. The androgen receptor in LNCaP cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens. J Steroid Biochem Mol Biol. 1992;41:665–9.

    Article  CAS  Google Scholar 

  37. Azad AA, Eigl BJ. Evaluation of prostate-specific antigen response following cessation of abiraterone acetate: is there evidence for a withdrawal syndrome? Eur Urol. 2014;65:504–5.

    Article  CAS  Google Scholar 

  38. Lau YK, Chadha MK, Litwin A, Trump DL. A dramatic, objective antiandrogen withdrawal response: case report and review of the literature. J Hematol Oncol. 2008;1:21.

    Article  Google Scholar 

  39. Leone G, Tucci M, Buttigliero C, Zichi C, Pignataro D, Bironzo P, et al. Antiandrogen withdrawal syndrome (AAWS) in the treatment of patients with prostate cancer. Endocr Relat Cancer. 2018;25:R1–9.

    Article  CAS  Google Scholar 

  40. Bracarda S, Procopio G, Alesini D, Grillone F, Massari F, Zaniboni A, et al. Enzalutamide activity in patients with metastatic castration resistant prostate cancer (mCRPC) previously responding to antiandrogen withdrawal syndrome (AWN): a preliminary report. J Clin Oncol. 2014;32:e16508.

  41. El Geneidy MM, Lewis G, Dainer P, Terris MK, Brown J, Coleman T. Factors predicting a response to anti-androgen withdrawal maneuvers in prostate cancer patients failing combined androgen blockade. J Clin Oncol. 2008;26:e16116.

    Article  Google Scholar 

  42. Momozono H, Miyake H, Tei H, Harada KI, Fujisawa M. Clinical outcomes of anti-androgen withdrawal and subsequent alternative anti-androgen therapy for advanced prostate cancer following failure of initial maximum androgen blockade. Mol Clin Oncol. 2016;4:839–44.

    Article  CAS  Google Scholar 

  43. Morote J, Bellmunt J. Bone alkaline phosphatase serum level predicts the response to antiandrogen withdrawal. Eur Urol. 2002;41:257–61.

    Article  CAS  Google Scholar 

  44. Schellhammer PF, Venner P, Haas GP, Small EJ, Nieh PT, Seabaugh DR, et al. Prostate specific antigen decreases after withdrawal of antiandrogen therapy with bicalutamide or flutamide in patients receiving combined androgen blockade. J Urol. 1997;157:1731–5.

    Article  CAS  Google Scholar 

  45. Yoneyama S, Miyoshi Y, Yasui M, Uemura K, Kawahara T, Hattori Y, et al. The evaluation of antiandrogen withdrawal syndrome after discontinuation of bicalutamide in metastatic castration-resistant prostate cancer. Int J Urol. 2017;24:38.

    Google Scholar 

  46. Figg WD, McCall NA, Reed E, Sartor O. The in-vitro response of 4 antisteroid receptor agents on the hormone-responsive prostate-cancer cell-line lncap. Oncol Rep. 1995;2:295–8.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. School of Medicine, Flinders University, Bedford Park, SA, Australia

    Alwin Soo, Sina Vatandoust & Ganessan Kichenadasse

  2. South Australian Prostate Cancer Clinical Outcomes Collaborative, Flinders Medical Centre, Bedford Park, SA, Australia

    Michael E. O’Callaghan, Tina Kopsaftis & Kim Moretti

  3. Department of Urology, Flinders Medical Centre, Bedford Park, SA, Australia

    Michael E. O’Callaghan & Tina Kopsaftis

  4. Discipline of Surgery, University of Adelaide, Adelaide, SA, Australia

    Michael E. O’Callaghan & Kim Moretti

  5. Department of Medical Oncology, Flinders Centre for Innovation in Cancer, Flinders Medical Centre/Flinders University, Bedford Park, SA, Australia

    Sina Vatandoust & Ganessan Kichenadasse

  6. School of Population Health, University of South Australia, Adelaide, SA, Australia

    Kim Moretti

  7. Monash University, Clayton, VIC, Australia

    Kim Moretti

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Correspondence to Ganessan Kichenadasse.

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Soo, A., O’Callaghan, M.E., Kopsaftis, T. et al. PSA response to antiandrogen withdrawal: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis 24, 826–836 (2021). https://doi.org/10.1038/s41391-021-00337-0

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