EUROPEAN UROLOGY 67 (2015) 874–875
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 866–873 of this issue
Corticosteroids and Prostate Cancer: Friend or Foe? Daniel M. Geynisman a, Russell Z. Szmulewitz b, Elizabeth R. Plimack a,* a
Fox Chase Cancer Center, Temple Health, Philadelphia, PA, USA;
b
Department of Medicine, Section of Hematology/Oncology, The University of Chicago,
Chicago, IL, USA
Corticosteroids have been a mainstay of treatment of men with metastatic prostate cancer (PCa) for decades. They are used for palliation of symptoms, to prevent adverse reactions or toxicity from other therapies, and for their antitumor effects mediated by way of the decrease of adrenal androgen production, transcription factors, and cytokines. Recently, two rationally designed oral drugs targeting the androgen receptor (AR) axis have become an important part of the armamentarium in treating men with castration-resistant PCa (CRPC). Abiraterone acetate, a CYP17A1 inhibitor, decreases androgen production in testicular, adrenal, and prostatic tissues; enzalutamide is a highly selective and effective AR antagonist that limits AR nuclear localization and downstream gene regulation. Both drugs improve survival in men with CRPC; however, unlike enzalutamide, abiraterone requires concurrent corticosteroid administration to mitigate its effect of increased mineralocorticoid production. Understanding the mechanisms of the inevitably acquired resistance to these drugs is vital, so the role of corticosteroids and the glucocorticoid receptor (GR) in CRPC is now being explored. CRPC progression can result from a number of ARmediated factors, including amplification of the AR, alternative splicing, and mutations of the AR that can lead to constitutive stimulation of the receptor, ligand-independent AR activation, and paradoxical stimulation of the receptor by other steroidal hormones and antiandrogens. As shown by the eventual clinical progression of CRPC despite highly effective AR-targeted therapies such as enzalutamide and abiraterone, there are undoubtedly other, non–ARmediated mechanisms of CRPC progression. One such posited mediator of AR-independent CRPC progression is the GR. The GR, which is activated by corticosteroids, is a
nuclear hormone receptor in the same protein family as the AR, with structural homology and shared DNA response elements. Thus, the questions of how the GR and AR interact with corticosteroids and what their relationship to each other is in CRPC have been raised. GR protein levels in PCa tissue increase subsequent to AR blockade [1]. In addition, in preclinical models, corticosteroid activation of the GR can promote CRPC progression and resistance to effective second-generation AR antagonists such as enzalutamide [2,3]. A potential functional role for GR signaling in clinical CRPC progression is thus of great clinical interest. To address the role of the GR in CRPC, in this month’s issue of European Urology, a post hoc analysis by Montgomery et al. [4] examined whether baseline corticosteroid use in the phase 3 trial of abiraterone versus prednisone in men with metastatic CRPC after chemotherapy (COU-AA-301) was predictive of overall survival (OS) [5]. The study showed that the 33% of men who were receiving corticosteroids at baseline had universally worse disease characteristics at study entry than their counterparts, with inferior OS (16.1 vs 11.2 mo; hazard ratio [HR]: 0.68; p < 0.0001) and an increased risk of death (HR: 1.48; p < 0.0001) on univariate analysis. However, in a multivariate model, baseline corticosteroid status did not predict OS when other clinical factors were included. These results suggest that baseline corticosteroid use was an indicator of poor prognosis but was not predictive of response to abiraterone. Several points should be highlighted. First, the use of abiraterone led to improvement in OS, prostate-specific antigen (PSA) progression, and progression-free survival regardless of baseline corticosteroid use. Second, all patients received prednisone once the trial commenced. Third, the duration of, and indications for, baseline
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.06.042. * Corresponding author. Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA 19111, USA. Tel. +1 215 728 3889; Fax: +1 215 728 3639. E-mail address: [email protected] (E.R. Plimack). http://dx.doi.org/10.1016/j.eururo.2014.08.008 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
EUROPEAN UROLOGY 67 (2015) 874–875
corticosteroid use were unknown. Fourth, statistically significantly lower baseline levels of serum androgens were noted in patients with prestudy corticosteroid use, and as the authors point out [4], androgens may be an important mediator of corticosteroids’ effect on prognosis, given that lower androgen levels may lead to earlier adaptation of tumors to a milieu without androgens and thus potentially lead to quicker resistance to further AR axis manipulation [6]. To help place these results in context, recently presented post hoc work by Scher et al. examined both baseline and baseline plus on-trial corticosteroid use in men participating in the phase 3 trial of enzalutamide versus placebo in the postdocetaxel setting; the authors found that in both instances on multivariable modeling, corticosteroid use statistically significantly and negatively affected OS [7]. Differences in models, as well as in mechanisms of action of the two drugs may explain the somewhat different outcomes. Enzalutamide directly antagonizes the AR, and this interaction may be important for the corticosteroid effect on CRPC. In the enzalutamide trial, only a portion of patients (patients with use of corticosteroids at study entry) received corticosteroids during the study, whereas in the COU-AA-301 trial, all patients on trial were treated with prednisone, potentially negating the impact of baseline corticosteroids in this setting. The interaction of steroid hormones, including corticosteroids and androgens, with the GR and AR is complicated, has not been fully characterized, and may have important implications in the CRPC state. How might corticosteroids, and thus the GR, be implicated in propagation of CRPC? Studies have suggested that corticosteroids can activate a mutated or ‘‘promiscuous’’ AR [8,9]. Increased GR expression may also occur in PCa cells after androgen-lowering therapies. Recent work by Isikbay et al. showed that GR activation decreased the effects of enzalutamide on tumor cell viability, increased PSA secretion, and stimulated downstream transcriptional targets that are shared between the AR and GR in PCa cell lines [3]. These findings are further supported by work demonstrating that GR activation can stimulate cancer growth and regulation of genes that overlap with AR targets [10]. Such effects could undermine the activity of AR-targeted therapies such as enzalutamide. A prospective trial of enzalutamide and the GR antagonist mifepristone that is under way (NCT02012296) may further shed light on this subject. What are the clinical practice implications of these findings? Should corticosteroids be avoided if possible for men with CRPC as propagators of disease, or is their use ultimately simply a marker of more advanced PCa? The findings of Montgomery et al. [4] showing baseline corticosteroid use to be prognostic, but not predictive, of response to abiraterone suggest the latter, though future work will need to prospectively validate these hypothesisgenerating findings before any recommendation can be made. However, decreased early use of corticosteroids in
875
CRPC may be clinically preferred in the future as abiraterone and enzalutamide are becoming more frequently used before docetaxel plus prednisone and, as the recently reported ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) trial demonstrated, docetaxel can be safely and effectively given without daily corticosteroids [11]. A trial of abiraterone with low-dose prednisone is also being conducted (NCT01715285). Understanding resistance to AR-targeted therapy in CRPC is of vital importance as we try to improve outcomes for men with this disease. Translational research efforts to further elucidate the interaction of the GR and AR pathways are under way, and future trials of GR antagonists in men with advanced CRPC may further help in understanding the complex biology of CRPC. Conflicts of interest: The authors have nothing to disclose.
References [1] Szmulewitz RZ, Chung E, Al-Ahmadie H, et al. Serum/glucocorticoidregulated kinase 1 expression in primary human prostate cancers. Prostate 2012;72:157–64. [2] Arora VK, Schenkein E, Murali R, et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell 2013;155:1309–22. [3] Isikbay M, Otto K, Kregel S, et al. Glucocorticoid receptor activity contributes to resistance to androgen-targeted therapy in prostate cancer. Horm Cancer 2014;5:72–89. [4] Montgomery B, Kheoh T, Molina A, et al. Impact of baseline corticosteroids on survival and steroid androgens in metastatic castrationresistant prostate cancer: exploratory analysis from COU-AA-301. Eur Urol 2015;67:866–73. [5] de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364:1995– 2005. [6] Ryan CJ, Molina A, Li J, et al. Serum androgens as prognostic biomarkers in castration-resistant prostate cancer: results from an analysis of a randomized phase III trial. J Clin Oncol 2013;31:2791–8. [7] Scher HI, Fizazi K, Saad F, et al. Impact of on-study corticosteroid use on efficacy and safety in the phase III AFFIRM study of enzalutamide (ENZA), an androgen receptor inhibitor [abstract 6]. J Clin Oncol 2013;31(Suppl 6). [8] Chang CY, Walther PJ, McDonnell DP. Glucocorticoids manifest androgenic activity in a cell line derived from a metastatic prostate cancer. Cancer Res 2001;61:8712–7. [9] Richards J, Lim AC, Hay CW, 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. [10] Sahu B, Laakso M, Pihlajamaa P, et al. FoxA1 specifies unique androgen and glucocorticoid receptor binding events in prostate cancer cells. Cancer Res 2013;73:1570–80. [11] Sweeney C, Chen YH, Carducci MA, et al. Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): an ECOG-led phase III randomized trial [abstract LBA2]. J Clin Oncol 2014;32(Suppl).
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 866–873 of this issue
Corticosteroids and Prostate Cancer: Friend or Foe? Daniel M. Geynisman a, Russell Z. Szmulewitz b, Elizabeth R. Plimack a,* a
Fox Chase Cancer Center, Temple Health, Philadelphia, PA, USA;
b
Department of Medicine, Section of Hematology/Oncology, The University of Chicago,
Chicago, IL, USA
Corticosteroids have been a mainstay of treatment of men with metastatic prostate cancer (PCa) for decades. They are used for palliation of symptoms, to prevent adverse reactions or toxicity from other therapies, and for their antitumor effects mediated by way of the decrease of adrenal androgen production, transcription factors, and cytokines. Recently, two rationally designed oral drugs targeting the androgen receptor (AR) axis have become an important part of the armamentarium in treating men with castration-resistant PCa (CRPC). Abiraterone acetate, a CYP17A1 inhibitor, decreases androgen production in testicular, adrenal, and prostatic tissues; enzalutamide is a highly selective and effective AR antagonist that limits AR nuclear localization and downstream gene regulation. Both drugs improve survival in men with CRPC; however, unlike enzalutamide, abiraterone requires concurrent corticosteroid administration to mitigate its effect of increased mineralocorticoid production. Understanding the mechanisms of the inevitably acquired resistance to these drugs is vital, so the role of corticosteroids and the glucocorticoid receptor (GR) in CRPC is now being explored. CRPC progression can result from a number of ARmediated factors, including amplification of the AR, alternative splicing, and mutations of the AR that can lead to constitutive stimulation of the receptor, ligand-independent AR activation, and paradoxical stimulation of the receptor by other steroidal hormones and antiandrogens. As shown by the eventual clinical progression of CRPC despite highly effective AR-targeted therapies such as enzalutamide and abiraterone, there are undoubtedly other, non–ARmediated mechanisms of CRPC progression. One such posited mediator of AR-independent CRPC progression is the GR. The GR, which is activated by corticosteroids, is a
nuclear hormone receptor in the same protein family as the AR, with structural homology and shared DNA response elements. Thus, the questions of how the GR and AR interact with corticosteroids and what their relationship to each other is in CRPC have been raised. GR protein levels in PCa tissue increase subsequent to AR blockade [1]. In addition, in preclinical models, corticosteroid activation of the GR can promote CRPC progression and resistance to effective second-generation AR antagonists such as enzalutamide [2,3]. A potential functional role for GR signaling in clinical CRPC progression is thus of great clinical interest. To address the role of the GR in CRPC, in this month’s issue of European Urology, a post hoc analysis by Montgomery et al. [4] examined whether baseline corticosteroid use in the phase 3 trial of abiraterone versus prednisone in men with metastatic CRPC after chemotherapy (COU-AA-301) was predictive of overall survival (OS) [5]. The study showed that the 33% of men who were receiving corticosteroids at baseline had universally worse disease characteristics at study entry than their counterparts, with inferior OS (16.1 vs 11.2 mo; hazard ratio [HR]: 0.68; p < 0.0001) and an increased risk of death (HR: 1.48; p < 0.0001) on univariate analysis. However, in a multivariate model, baseline corticosteroid status did not predict OS when other clinical factors were included. These results suggest that baseline corticosteroid use was an indicator of poor prognosis but was not predictive of response to abiraterone. Several points should be highlighted. First, the use of abiraterone led to improvement in OS, prostate-specific antigen (PSA) progression, and progression-free survival regardless of baseline corticosteroid use. Second, all patients received prednisone once the trial commenced. Third, the duration of, and indications for, baseline
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.06.042. * Corresponding author. Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA 19111, USA. Tel. +1 215 728 3889; Fax: +1 215 728 3639. E-mail address: [email protected] (E.R. Plimack). http://dx.doi.org/10.1016/j.eururo.2014.08.008 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
EUROPEAN UROLOGY 67 (2015) 874–875
corticosteroid use were unknown. Fourth, statistically significantly lower baseline levels of serum androgens were noted in patients with prestudy corticosteroid use, and as the authors point out [4], androgens may be an important mediator of corticosteroids’ effect on prognosis, given that lower androgen levels may lead to earlier adaptation of tumors to a milieu without androgens and thus potentially lead to quicker resistance to further AR axis manipulation [6]. To help place these results in context, recently presented post hoc work by Scher et al. examined both baseline and baseline plus on-trial corticosteroid use in men participating in the phase 3 trial of enzalutamide versus placebo in the postdocetaxel setting; the authors found that in both instances on multivariable modeling, corticosteroid use statistically significantly and negatively affected OS [7]. Differences in models, as well as in mechanisms of action of the two drugs may explain the somewhat different outcomes. Enzalutamide directly antagonizes the AR, and this interaction may be important for the corticosteroid effect on CRPC. In the enzalutamide trial, only a portion of patients (patients with use of corticosteroids at study entry) received corticosteroids during the study, whereas in the COU-AA-301 trial, all patients on trial were treated with prednisone, potentially negating the impact of baseline corticosteroids in this setting. The interaction of steroid hormones, including corticosteroids and androgens, with the GR and AR is complicated, has not been fully characterized, and may have important implications in the CRPC state. How might corticosteroids, and thus the GR, be implicated in propagation of CRPC? Studies have suggested that corticosteroids can activate a mutated or ‘‘promiscuous’’ AR [8,9]. Increased GR expression may also occur in PCa cells after androgen-lowering therapies. Recent work by Isikbay et al. showed that GR activation decreased the effects of enzalutamide on tumor cell viability, increased PSA secretion, and stimulated downstream transcriptional targets that are shared between the AR and GR in PCa cell lines [3]. These findings are further supported by work demonstrating that GR activation can stimulate cancer growth and regulation of genes that overlap with AR targets [10]. Such effects could undermine the activity of AR-targeted therapies such as enzalutamide. A prospective trial of enzalutamide and the GR antagonist mifepristone that is under way (NCT02012296) may further shed light on this subject. What are the clinical practice implications of these findings? Should corticosteroids be avoided if possible for men with CRPC as propagators of disease, or is their use ultimately simply a marker of more advanced PCa? The findings of Montgomery et al. [4] showing baseline corticosteroid use to be prognostic, but not predictive, of response to abiraterone suggest the latter, though future work will need to prospectively validate these hypothesisgenerating findings before any recommendation can be made. However, decreased early use of corticosteroids in
875
CRPC may be clinically preferred in the future as abiraterone and enzalutamide are becoming more frequently used before docetaxel plus prednisone and, as the recently reported ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) trial demonstrated, docetaxel can be safely and effectively given without daily corticosteroids [11]. A trial of abiraterone with low-dose prednisone is also being conducted (NCT01715285). Understanding resistance to AR-targeted therapy in CRPC is of vital importance as we try to improve outcomes for men with this disease. Translational research efforts to further elucidate the interaction of the GR and AR pathways are under way, and future trials of GR antagonists in men with advanced CRPC may further help in understanding the complex biology of CRPC. Conflicts of interest: The authors have nothing to disclose.
References [1] Szmulewitz RZ, Chung E, Al-Ahmadie H, et al. Serum/glucocorticoidregulated kinase 1 expression in primary human prostate cancers. Prostate 2012;72:157–64. [2] Arora VK, Schenkein E, Murali R, et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell 2013;155:1309–22. [3] Isikbay M, Otto K, Kregel S, et al. Glucocorticoid receptor activity contributes to resistance to androgen-targeted therapy in prostate cancer. Horm Cancer 2014;5:72–89. [4] Montgomery B, Kheoh T, Molina A, et al. Impact of baseline corticosteroids on survival and steroid androgens in metastatic castrationresistant prostate cancer: exploratory analysis from COU-AA-301. Eur Urol 2015;67:866–73. [5] de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364:1995– 2005. [6] Ryan CJ, Molina A, Li J, et al. Serum androgens as prognostic biomarkers in castration-resistant prostate cancer: results from an analysis of a randomized phase III trial. J Clin Oncol 2013;31:2791–8. [7] Scher HI, Fizazi K, Saad F, et al. Impact of on-study corticosteroid use on efficacy and safety in the phase III AFFIRM study of enzalutamide (ENZA), an androgen receptor inhibitor [abstract 6]. J Clin Oncol 2013;31(Suppl 6). [8] Chang CY, Walther PJ, McDonnell DP. Glucocorticoids manifest androgenic activity in a cell line derived from a metastatic prostate cancer. Cancer Res 2001;61:8712–7. [9] Richards J, Lim AC, Hay CW, 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. [10] Sahu B, Laakso M, Pihlajamaa P, et al. FoxA1 specifies unique androgen and glucocorticoid receptor binding events in prostate cancer cells. Cancer Res 2013;73:1570–80. [11] Sweeney C, Chen YH, Carducci MA, et al. Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): an ECOG-led phase III randomized trial [abstract LBA2]. J Clin Oncol 2014;32(Suppl).
