- Email: [email protected]
Re: Coadministration of Anastrozole Sustains Therapeutic Testosterone Levels in Hypogonadal Men Undergoing Testosterone Pellet Insertion
1188
EUROPEAN UROLOGY 66 (2014) 1186–1193
analysis of the results at 13 yr from randomisation has now been published. Key results were compared with results at 9 and 11 yr of follow-up, showing slightly increased benefits from screening. The rate ratio of PCa incidence was 1.57 (95% confidence interval [CI], 1.51–1.62) between intervention and control (down from 1.91 at 9 yr). The rate ratio of mortality was 0.79 (95% CI, 0.69–0.91; p = 0.004) (down from 0.85 at 9 yr). In absolute terms, this finding means that 781 men need to be screened and 27 men need to have cancer detected to avert one death. The authors caution that the benefits of screening should be balanced against the risks of overdiagnosis and potential overtreatment.
The published rates of overdiagnosis (41%) may in fact be the key result from the ERSPC trial. By quantifying these rates, the authors have pushed us to further investigate ways of minimising harm from screening. Standards of care in 2014 include more accurate diagnosis with risk stratification tools, biomarkers, and the increased use of magnetic resonance imaging; more appropriate management with increased use of active surveillance for low-risk PCa; and the targeting of high-risk cancer with more aggressive treatment. This excellent study confirms the value of PSA testing in reducing PCa mortality, but it also confirms that PSA testing on its own is imperfect and will never be used as a screening tool at a population level.
Experts’ comments: The ERSPC trial is the flagship trial of screening for PCa, and the current results do not disappoint. The numbers continue to improve in favour of screening, and the CIs and p values are tightening up. The oft-quoted number needed to screen (NNS) is now down from 1410 at 9-yr follow-up to (just) 781 in the present study. This figure compares favourably with breast cancer screening, so a reasonable question might be, what NNS do we need to get to before PSA-based screening becomes acceptable? As the authors allude to, this answer unfortunately cannot be a single number, as any benefit must be weighed against the risk of overdiagnosis and overtreatment.
Conflicts of interest: The authors have nothing to disclose.
Re: Coadministration of Anastrozole Sustains Therapeutic Testosterone Levels in Hypogonadal Men Undergoing Testosterone Pellet Insertion Mechlin CW, Frankel J, McCullough A
profoundly suppressed in the group receiving only testosterone pellets. In the anastrozole group, gonadotropin levels remained normal.
J Sex Med 2014;11:254–61 Expert’s summary: In this single-center retrospective study, the authors assessed the usefulness of augmenting testosterone pellet therapy with oral anastrozole, an aromatase inhibitor, to block the conversion of testosterone to estradiol (E2). Thirty-eight hypogonadal men (65 insertions) with symptoms were analyzed. Twelve men were offered anastrozole (1 mg daily, administered orally) at the time of testosterone pellet insertion. The remaining men received testosterone pellets only. Total testosterone, free testosterone (FT), luteinizing hormone, folliclestimulating hormone, sex hormone–binding globulin (SHBG), and E2 levels were routinely obtained prior to testosterone replacement and then at approximately 6 wk and 4 mo after treatment. The timing of repeat pellet insertion relied on testosterone levels and hypogonadism symptoms. Four months after pellet insertion, serum total testosterone and FT were significantly higher in the anastrozole group than the testosterone pellet–only group (p < 0.01). SHBG levels did not significantly change in either group. E2 levels were significantly higher in the testosterone pellet– only group at all time points. Gonadotropin levels were
Simon van Rija, Declan G. Murphya,b,c,* a
Division of Cancer Surgery, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Australia b
Department of Urology, Royal Melbourne Hospital, Melbourne, Australia c
Epworth Prostate Centre, Epworth Healthcare, Richmond, Australia *Corresponding author. Division of Cancer Surgery, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria 3002, Australia. E-mail address: [email protected] (D.G. Murphy).
http://dx.doi.org/10.1016/j.eururo.2014.08.044
Expert’s comments: The Endocrine Society’s guidelines define hypogonadism in men as a clinical syndrome that results from failure of the testis to produce physiologic levels of testosterone (androgen deficiency) and a normal number of spermatozoa because of disruption of one level or more of the hypothalamic-pituitarytesticular axis [1]. It is well recognized that testosterone replacement has an important role for men who have low serum testosterone levels and associated symptoms, such as infertility, erectile dysfunction, impaired libido, and generalized weakness. Testosterone replacement can take the form of creams/ gels, injections, oral agents, buccal lozenges, and implantable pellets. In the United States, implantable pellets are becoming very popular. In addition, for men with low testosterone who have an interest in fertility preservation, the use of oral agents to improve testosterone production may be preferred. Two general classes of oral drugs have been used to increase testosterone levels: (1) estrogen receptor modulators, such as clomiphene and enclomiphene (not yet approved by the US Food and Drug Administration [FDA]) and (2) aromatase inhibitors, such as anastrozole and letrozole. Treatment with either the selective estrogen receptor modulators or aromatase inhibitors represents
1189
EUROPEAN UROLOGY 66 (2014) 1186–1193
off-label use of FDA-approved drugs, but the drugs have excellent potential to increase endogenous testosterone levels [2,3]. The authors of our reference study hypothesized that the combination of an aromatase inhibitor with exogenous testosterone can prolong the time between pellet implantations by preventing the aromatization of testosterone to estrogen. Aromatase inhibitors have been found to be well tolerated in men treated over a 1- to 2-yr period. However, aromatase inhibitors have a potential serious effect on bone health and metabolism. Although the vast majority of the literature centers on the postmenopausal breast cancer population, the biological effects of aromatase inhibitors cannot be discounted. In a multicenter randomized trial, the long-term effects of anastrozole on bone mineral density were evaluated [3,4]. After 5 yr of treatment with anastrozole, the study subjects mounted a significant increase on bone mineral density through years 6 and 7. The authors should be commended on the novel use of aromatase inhibitors that prolong the effects of implantable testosterone pellets. The potential detrimental effects on bone mineral density should be closely monitored. A ‘‘drug holiday’’ from these medications may be beneficial to ensure proper bone health.
Re: Rapid Induction of Androgen Receptor Splice Variants by Androgen Deprivation in Prostate Cancer Yu Z, Chen S, Sowalsky AG, et al. Clin Cancer Res 2014;20:1590–600 Expert’s summary: This preclinical study assessed the contribution of intratumoral androgen synthesis compared with other mechanisms, including the expression of alternatively spliced androgen receptor (AR), in the progression to abiraterone resistance. The authors showed that AR reactivation in abiraterone-resistant VCaP xenografts was not associated with restoration of intratumoral androgens. They found that increases in the major AR splice variant (AR-V), AR-V7, occurred rapidly through a feedback mechanism and were able to mediate low basal AR activity immediately after androgen deprivation but were not able to mediate the high-level AR activity in relapsed tumors. Expert’s comments: Efstathiou et al. [1] have reported that in patients with metastatic castration-resistant prostate cancer (mCRPC), androgen levels remain low in bone marrow aspirates from patients with abiraterone-resistant tumors, indicating similarly that restoration of androgen synthesis is not a common mechanism of abiraterone resistance. However, targeting AR-positive cancer cells with androgen deprivation therapy can induce constitutively active splice variants, driving clonal proliferation of AR-negative and AR-independent metastases. These AR-Vs may be one major potential mechanism of resistance to new AR-targeting drugs and may explain the cross-resistance between abiraterone acetate and enzalutamide observed in clinics.
Conflicts of interest: The author is a consultant for American Medical Systems and Coloplast.
References [1] Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95:2536–59. [2] Chua ME, Escusa KG, Luna S, Tapia LC, Dofitas B, Morales M. Revisiting oestrogen antagonists (clomiphene or tamoxifen) as medical empiric therapy for idiopathic male infertility: a metaanalysis. Andrology 2013;1:749–57. [3] Raman JD, Schlegel PN. Aromatase inhibitors for male infertility. J Urol 2002;167:624–9. [4] Eastell R, Adams J, Clack G, et al. Long-term effects of anastrozole on bone mineral density: 7-year results from the ATAC trial. Ann Oncol 2011;22:857–62. Nelson E. Bennett* Lahey Clinic Medical Center, Institute of Urology, Burlington, MA, USA *Lahey Clinic Medical Center, Institute of Urology, 41 Mall Road, Burlington, MA 01803, USA. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2014.08.045
Small retrospective studies evaluating patients with progressive castration-resistant prostate cancer (CRPC) following docetaxel and enzalutamide demonstrated that subsequent abiraterone produced few responses of brief duration [2]. Similarly, retrospective analyses of patients who received enzalutamide for CRPC progressing after docetaxel and abiraterone showed a modest response rate [3,4]. The clinical relevance of AR-Vs remains to be determined. Recently, Antonarakis et al. [5] reported that the detection of AR-V7 in circulating tumor cell (CTC) samples from patients with mCRPC is possible and could predict resistance to enzalutamide and abiraterone. In their series of 62 mCRPC patients, the prevalence of AR-V7 increased after exposure to the new AR-targeted agents (before enzalutamide, before abiraterone: 11.6%; after enzalutamide only: 25.0%; after abiraterone only: 51.2%; after enzalutamide and after abiratrone: 66.7%). Consequently, mCRPC patients with detectable AR-V7 in CTCs could be steered away from receiving AR-targeting drugs and could be offered alternative treatments such as chemotherapy. The availability of a bloodbased biomarker for AR-V7 detection could also fuel the development of novel AR N-terminal domain inhibitors. Conflicts of interest: The author has nothing to disclose.
References [1] Efstathiou E, Titus M, Tsavachidou D, et al. Effects of abiraterone acetate on androgen signaling in castrate-resistant prostate cancer in bone. J Clin Oncol 2012;30:637–43. [2] Loriot Y, Bianchini D, Ileana E, et al. Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate
EUROPEAN UROLOGY 66 (2014) 1186–1193
analysis of the results at 13 yr from randomisation has now been published. Key results were compared with results at 9 and 11 yr of follow-up, showing slightly increased benefits from screening. The rate ratio of PCa incidence was 1.57 (95% confidence interval [CI], 1.51–1.62) between intervention and control (down from 1.91 at 9 yr). The rate ratio of mortality was 0.79 (95% CI, 0.69–0.91; p = 0.004) (down from 0.85 at 9 yr). In absolute terms, this finding means that 781 men need to be screened and 27 men need to have cancer detected to avert one death. The authors caution that the benefits of screening should be balanced against the risks of overdiagnosis and potential overtreatment.
The published rates of overdiagnosis (41%) may in fact be the key result from the ERSPC trial. By quantifying these rates, the authors have pushed us to further investigate ways of minimising harm from screening. Standards of care in 2014 include more accurate diagnosis with risk stratification tools, biomarkers, and the increased use of magnetic resonance imaging; more appropriate management with increased use of active surveillance for low-risk PCa; and the targeting of high-risk cancer with more aggressive treatment. This excellent study confirms the value of PSA testing in reducing PCa mortality, but it also confirms that PSA testing on its own is imperfect and will never be used as a screening tool at a population level.
Experts’ comments: The ERSPC trial is the flagship trial of screening for PCa, and the current results do not disappoint. The numbers continue to improve in favour of screening, and the CIs and p values are tightening up. The oft-quoted number needed to screen (NNS) is now down from 1410 at 9-yr follow-up to (just) 781 in the present study. This figure compares favourably with breast cancer screening, so a reasonable question might be, what NNS do we need to get to before PSA-based screening becomes acceptable? As the authors allude to, this answer unfortunately cannot be a single number, as any benefit must be weighed against the risk of overdiagnosis and overtreatment.
Conflicts of interest: The authors have nothing to disclose.
Re: Coadministration of Anastrozole Sustains Therapeutic Testosterone Levels in Hypogonadal Men Undergoing Testosterone Pellet Insertion Mechlin CW, Frankel J, McCullough A
profoundly suppressed in the group receiving only testosterone pellets. In the anastrozole group, gonadotropin levels remained normal.
J Sex Med 2014;11:254–61 Expert’s summary: In this single-center retrospective study, the authors assessed the usefulness of augmenting testosterone pellet therapy with oral anastrozole, an aromatase inhibitor, to block the conversion of testosterone to estradiol (E2). Thirty-eight hypogonadal men (65 insertions) with symptoms were analyzed. Twelve men were offered anastrozole (1 mg daily, administered orally) at the time of testosterone pellet insertion. The remaining men received testosterone pellets only. Total testosterone, free testosterone (FT), luteinizing hormone, folliclestimulating hormone, sex hormone–binding globulin (SHBG), and E2 levels were routinely obtained prior to testosterone replacement and then at approximately 6 wk and 4 mo after treatment. The timing of repeat pellet insertion relied on testosterone levels and hypogonadism symptoms. Four months after pellet insertion, serum total testosterone and FT were significantly higher in the anastrozole group than the testosterone pellet–only group (p < 0.01). SHBG levels did not significantly change in either group. E2 levels were significantly higher in the testosterone pellet– only group at all time points. Gonadotropin levels were
Simon van Rija, Declan G. Murphya,b,c,* a
Division of Cancer Surgery, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Australia b
Department of Urology, Royal Melbourne Hospital, Melbourne, Australia c
Epworth Prostate Centre, Epworth Healthcare, Richmond, Australia *Corresponding author. Division of Cancer Surgery, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria 3002, Australia. E-mail address: [email protected] (D.G. Murphy).
http://dx.doi.org/10.1016/j.eururo.2014.08.044
Expert’s comments: The Endocrine Society’s guidelines define hypogonadism in men as a clinical syndrome that results from failure of the testis to produce physiologic levels of testosterone (androgen deficiency) and a normal number of spermatozoa because of disruption of one level or more of the hypothalamic-pituitarytesticular axis [1]. It is well recognized that testosterone replacement has an important role for men who have low serum testosterone levels and associated symptoms, such as infertility, erectile dysfunction, impaired libido, and generalized weakness. Testosterone replacement can take the form of creams/ gels, injections, oral agents, buccal lozenges, and implantable pellets. In the United States, implantable pellets are becoming very popular. In addition, for men with low testosterone who have an interest in fertility preservation, the use of oral agents to improve testosterone production may be preferred. Two general classes of oral drugs have been used to increase testosterone levels: (1) estrogen receptor modulators, such as clomiphene and enclomiphene (not yet approved by the US Food and Drug Administration [FDA]) and (2) aromatase inhibitors, such as anastrozole and letrozole. Treatment with either the selective estrogen receptor modulators or aromatase inhibitors represents
1189
EUROPEAN UROLOGY 66 (2014) 1186–1193
off-label use of FDA-approved drugs, but the drugs have excellent potential to increase endogenous testosterone levels [2,3]. The authors of our reference study hypothesized that the combination of an aromatase inhibitor with exogenous testosterone can prolong the time between pellet implantations by preventing the aromatization of testosterone to estrogen. Aromatase inhibitors have been found to be well tolerated in men treated over a 1- to 2-yr period. However, aromatase inhibitors have a potential serious effect on bone health and metabolism. Although the vast majority of the literature centers on the postmenopausal breast cancer population, the biological effects of aromatase inhibitors cannot be discounted. In a multicenter randomized trial, the long-term effects of anastrozole on bone mineral density were evaluated [3,4]. After 5 yr of treatment with anastrozole, the study subjects mounted a significant increase on bone mineral density through years 6 and 7. The authors should be commended on the novel use of aromatase inhibitors that prolong the effects of implantable testosterone pellets. The potential detrimental effects on bone mineral density should be closely monitored. A ‘‘drug holiday’’ from these medications may be beneficial to ensure proper bone health.
Re: Rapid Induction of Androgen Receptor Splice Variants by Androgen Deprivation in Prostate Cancer Yu Z, Chen S, Sowalsky AG, et al. Clin Cancer Res 2014;20:1590–600 Expert’s summary: This preclinical study assessed the contribution of intratumoral androgen synthesis compared with other mechanisms, including the expression of alternatively spliced androgen receptor (AR), in the progression to abiraterone resistance. The authors showed that AR reactivation in abiraterone-resistant VCaP xenografts was not associated with restoration of intratumoral androgens. They found that increases in the major AR splice variant (AR-V), AR-V7, occurred rapidly through a feedback mechanism and were able to mediate low basal AR activity immediately after androgen deprivation but were not able to mediate the high-level AR activity in relapsed tumors. Expert’s comments: Efstathiou et al. [1] have reported that in patients with metastatic castration-resistant prostate cancer (mCRPC), androgen levels remain low in bone marrow aspirates from patients with abiraterone-resistant tumors, indicating similarly that restoration of androgen synthesis is not a common mechanism of abiraterone resistance. However, targeting AR-positive cancer cells with androgen deprivation therapy can induce constitutively active splice variants, driving clonal proliferation of AR-negative and AR-independent metastases. These AR-Vs may be one major potential mechanism of resistance to new AR-targeting drugs and may explain the cross-resistance between abiraterone acetate and enzalutamide observed in clinics.
Conflicts of interest: The author is a consultant for American Medical Systems and Coloplast.
References [1] Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95:2536–59. [2] Chua ME, Escusa KG, Luna S, Tapia LC, Dofitas B, Morales M. Revisiting oestrogen antagonists (clomiphene or tamoxifen) as medical empiric therapy for idiopathic male infertility: a metaanalysis. Andrology 2013;1:749–57. [3] Raman JD, Schlegel PN. Aromatase inhibitors for male infertility. J Urol 2002;167:624–9. [4] Eastell R, Adams J, Clack G, et al. Long-term effects of anastrozole on bone mineral density: 7-year results from the ATAC trial. Ann Oncol 2011;22:857–62. Nelson E. Bennett* Lahey Clinic Medical Center, Institute of Urology, Burlington, MA, USA *Lahey Clinic Medical Center, Institute of Urology, 41 Mall Road, Burlington, MA 01803, USA. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2014.08.045
Small retrospective studies evaluating patients with progressive castration-resistant prostate cancer (CRPC) following docetaxel and enzalutamide demonstrated that subsequent abiraterone produced few responses of brief duration [2]. Similarly, retrospective analyses of patients who received enzalutamide for CRPC progressing after docetaxel and abiraterone showed a modest response rate [3,4]. The clinical relevance of AR-Vs remains to be determined. Recently, Antonarakis et al. [5] reported that the detection of AR-V7 in circulating tumor cell (CTC) samples from patients with mCRPC is possible and could predict resistance to enzalutamide and abiraterone. In their series of 62 mCRPC patients, the prevalence of AR-V7 increased after exposure to the new AR-targeted agents (before enzalutamide, before abiraterone: 11.6%; after enzalutamide only: 25.0%; after abiraterone only: 51.2%; after enzalutamide and after abiratrone: 66.7%). Consequently, mCRPC patients with detectable AR-V7 in CTCs could be steered away from receiving AR-targeting drugs and could be offered alternative treatments such as chemotherapy. The availability of a bloodbased biomarker for AR-V7 detection could also fuel the development of novel AR N-terminal domain inhibitors. Conflicts of interest: The author has nothing to disclose.
References [1] Efstathiou E, Titus M, Tsavachidou D, et al. Effects of abiraterone acetate on androgen signaling in castrate-resistant prostate cancer in bone. J Clin Oncol 2012;30:637–43. [2] Loriot Y, Bianchini D, Ileana E, et al. Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate