Selective androgen receptor modulators as improved androgen therapy for advanced breast cancer

Steroids 90 (2014) 94–100

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Selective androgen receptor modulators as improved androgen therapy for advanced breast cancer Christopher C. Coss, Amanda Jones, James T. Dalton ⇑ GTx, Inc., Memphis, TN 38103, United States

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Article history: Available online 16 June 2014 Keywords: Androgen Receptor Breast Cancer Nonsteroidal

a b s t r a c t Androgens were at one time a therapeutic mainstay in the treatment of advanced breast cancer. Despite comparable efficacy, SERMs and aromatase inhibitors eventually became the therapies of choice due to in part to preferred side-effect profiles. Molecular characterization of breast tumors has revealed an abundance of androgen receptor expression but the choice of an appropriate androgen receptor ligand (agonist or antagonist) has been confounded by multiple conflicting reports concerning the role of the receptor in the disease. Modern clinical efforts have almost exclusively utilized antagonists. However, the recent clinical development of selective androgen receptor modulators with greatly improved side-effect profiles has renewed interest in androgen agonist therapy for advanced breast cancer. Ó 2014 Elsevier Inc. All rights reserved.

1. Introduction Selective androgen receptor modulators (SARM) were initially reported in the 1990’s as non-steroidal androgen receptor (AR) agonists [1]. Aside from remarkable improvements in drug-like properties compared to existing steroidal agents, early research efforts demonstrated that these novel androgens exhibited tissue selective pharmacology by acting as full agonists in anabolic tissues (muscle and bone) but only partial agonists in androgenic tissues (prostate, skin and hair) [2]. The attractiveness of this particular pharmacology in expanding androgen therapy to men at risk for prostate disease as well as women was immediately apparent and followed by extensive investment from the pharmaceutical industry [3]. A 2009 review of the patent literature outlined more than a dozen SARM scaffolds with many lead molecules evaluated to some degree clinically [4]. The renaissance for androgen therapy following the discovery and development of SARMs has initially concerned itself with diseases where anabolic efficacy with reduced side effects were the primary goals [5,6]. Broader potential therapeutic application of an AR agonist amenable to once daily oral dosing such as gonadal suppression for male hormonal contraception or female libido remain in the pre-clinical space [7,8]. As terminal androgens, neither subject to 5a reduction nor aromatizable to estrogens, aryl propionamide SARMs are of particular interest in the treatment ⇑ Corresponding author. Address: 175 Toyota Plaza, 7th Floor, Memphis, TN 38103, United States. Tel.: +1 901 523 9700; fax: +1 901 844 8078. E-mail address: [email protected] (J.T. Dalton). http://dx.doi.org/10.1016/j.steroids.2014.06.010 0039-128X/Ó 2014 Elsevier Inc. All rights reserved.

of breast cancer. In the modern era of advanced breast cancer therapy it is often unappreciated that steroidal androgens were once the treatment of choice for advanced breast cancer. Fluoxymesterone, danazol, stanozolol and even medroxyprogesterone treatment was associated with 30% response rates, or roughly the same response rates seen following the more contemporary therapies of aromatase inhibition or SERM administration [9–12]. Androgen therapy fell out of favor due in part to the virilizing side effects that have been largely addressed in the clinic with the development of SARMS. However, modern research techniques have resulted in an embroiled controversy surrounding the role of the AR in malignant breast, greatly confusing the choice of an appropriate AR ligand (i.e., agonist or antagonist).

2. AR and ER action in sexually dimorphic tissues The controversy surrounding how best to target the AR in advanced breast cancer is the result of multiple conflicting reports on the role of the AR in the disease. Complex interplay between the AR and other nuclear hormone receptors appear to greatly influence the role of AR signaling in breast cancer models as well as in patients. Homeostasis of critical sex specific tissues requires a balance between estrogen receptor (ER) and AR signaling in the epithelial and stromal compartments with receptors assuming proliferative or anti-proliferative roles in a tissue and disease specific context. As others have noted, informative parallels emerge when considering nuclear hormone receptor action in prostate and breast tissues [13].

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2.1. Prostate Prostate development and homeostasis are unambiguously androgen and AR dependent. It has been recognized for more than a century that castration in male mammals results in rapid and dramatic prostatic atrophy [14]. Likewise, a spectrum of congenital androgen insensitivity syndromes (AIS) have been described whereby patients with key inactivating mutations to the AR present with symptoms ranging from infertility to outwardly female genitalia [15].Targeted inactivation of the AR in mouse knockout models recapitulates human AIS phenotypes confirming the role of the AR [16]. Elucidating the androgen dependence of the normal prostate in turn led to the use of castration as a therapy for prostate cancer. In the 1940’s, Huggins and Hodges’ patients reported almost immediate pain relief from metastatic bone lesions of prostatic origin following androgen ablation via surgical or medical castration [17].The concept of androgen deprivation therapy is employed for non-localized or advanced prostate cancer to this day, more than 70 years later. Despite the overt AR dependence of normal and malignant prostate, the role of androgens in prostate carcinogenesis is less clear. Several studies report no association between circulating androgen levels and prostate cancer risk [18,19]. The lack of association is likely due in part to the differences between systemic androgen levels and local, prostatic androgen load [20]. The latter of which is decidedly more relevant, much harder to quantify and subject to the variable and disease dependent expression of steroidogenic and metabolic enzymes [21]. Animal studies performed in CYP19A1 (aromatase) knockout (ArKO) animals support the irrelevance of systemic androgen load in prostate carcinogenesis. These mice lack the ability to generate 17b-estradiol (E2) from testosterone (T) and spend a lifetime with elevated circulating androgen levels but never develop prostate cancer [22]. Even when challenged with an exogenous androgen, ArKO mice display prostatic hyperplasia but not prostate cancer [23]. Alternatively, when ArKO mice are treated with an estrogen, even transiently as a neonate, the capacity to develop histologically identified pre-neoplastic prostatic lesions is restored [23,24]. When mice are engineered to overexpress aromatase they have increased levels of circulating E2 and greatly reduced levels of T [25]. Owing to insufficient androgen levels these mice develop only rudimentary prostates but also fail to develop neoplastic or pre-neoplastic prostate lesions [26]. These studies clearly suggest the requirement of both androgens and estrogens in prostate carcinogenesis. However, extricating estrogens’ function from the effects of androgens in the prostate is challenging as E2is a not only a metabolite of T but capable of binding to and activating two distinct estrogen receptor isoforms (ERa and ERb). Unlike the AR, the ERs appear to be differentially expressed in the epithelial and stromal compartments of the prostate with ERa residing primarily in the stroma and ERb in the epithelium [27]. In ERa deficient knockout mice, prostates develop normally but are enlarged relative to wild-type (WT) littermates upon aging [28]. Conflicting reports suggest the prostates of ERb knockout mice are either hyperplastic or normal [29,30]. The prostates of both characterized double knockout (ERa and ERb) mice are histologically normal suggesting the particulars of ERb knockout model generation may have played a role in the reported prostatic hyperplasia [31,32]. Ricke et al. utilized selective ERa and ERb knockout mice to tease out the relative contributions of each receptor to composite estrogen signaling in the pathology of the prostate gland [23]. When T and E2 where administered to ERb knockout mice, the rates of prostate inter-epithelial neoplasia (PIN) were similar to WT littermate controls. Similarly treated ERa KO mice developed no PIN strongly implicating stromal ERa in prostate carcinogenesis.

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These findings are supported by studies in rats administered testosterone alone or in combination with an ERa selective agonist where only the combination resulted in PIN [33]. When an ERb selective agent was administered along with T and the ERa agonist, the onset of PIN was prevented. These animal studies support the utility of ERa selective antagonists and ERb selective agonists in the treatment, or even prevention, of prostate cancer. Though no potent ERb agonist has been evaluated clinically in prostate cancer, the ERa selective antagonist toremifene was evaluated in men with high grade PIN in a Phase II setting with encouraging results [34]. Though the animal data support a protective and anti-proliferative role for ERb in prostate, discovery of multiple ERb isoforms and interrogation of clinical prostate cancer samples suggest a more complex role [35]. 2.2. Breast Much like in prostate, ERa appears to play a proliferative role in female breast development and homeostasis. In fact, full mammary development in mammals is thought to occur due to the dominance of estrogen signaling in females whereas this development does not occur in the male breast owing to androgen dominated signaling. Support for the requirement of ERa in this phenomenon is provided by female ERa knockout mice which fail to develop mature mammary glands where as their male AR deficient counterparts develop mammary tissue closely resembling WT female littermates [28,36]. Similarly, a troublesome side effect of estrogen excess in males is painful, benign breast tissue growth or gynecomastia. So severe is this side effect that men will routinely undergo prophylactic breast tissue irradiation before going on anti-androgen therapy known to result in rebound estrogen production and its associated gynecomastia [37]. Unlike the prostate, ERa is primarily expressed in the epithelial cells that surround the ductal structures within the breast [38]. The breast epithelium of premenopausal women proliferates the most during the luteal phase of the menstrual cycle when the ratio of E2 to T is the highest [39,40]. This proliferation is balanced with the highest rates of apoptosis occurring during the follicular phase when circulating E2 levels are lowest. ERb is also expressed in breast but at much higher levels than ERa and is found in both stromal and epithelial compartments [41,42]. However, ERb knockout female mice have far subtler breast phenotypes than their ERa counterparts and develop glands similar to WT littermates [43]. Much like ERa, AR is expressed primarily in the breast epithelium but appears to play a primarily anti-proliferative role [44]. AR knockout mouse models suggest AR is not required for the development of a functioning mammalian female breast. However, mixed reports of abnormal pubertal histology exist depending on the specifics of the AR knockout model employed [45,46]. Of note, each AR null model has deficiencies in ovarian hormone secretion that trends with the severity of abnormal histology suggesting the impact of AR loss is relative to the amount of circulating estrogens. AR expression in murine breast is known to increase dramatically during adolescence and pharmacologically antagonizing AR action at this time results in marked proliferation of breast tissue [47]. In perhaps the most striking example of the AR’s anti-proliferative role in breast, genetically male (X,Y) sufferers of complete androgen insensitivity syndrome (CAIS) develop full phenotypically female breasts [48]. Whereas antagonizing ER signaling has been the cornerstone of breast cancer therapy for nearly 50 years, the role of AR in breast cancer is yet to be clearly defined. The challenge is due in part to the cellular models available for research and their inherent limitations. A dearth of breast cancer cell lines exist that solely express AR among the relevant sex hormone receptors, and those that do (e.g. MDA-MB-453), have confounding mutations in other tumor

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suppressors [49,50]. Unlike work with ER antagonists which demonstrated clear anti-proliferative effects across the vast majority of models and conditions, incongruent reports abound for AR agonists and antagonists in breast cancer lines [44,51]. If any pattern has emerged from cellular breast cancer models, it is the importance of ERa in dictating AR response. In cell models that express both ERa and AR (MCF-7, T47D and ZR-751) primarily anti-proliferative responses are reported for androgens [44]. The lowest AR levels are reported in MCF-7 which is accompanied by a near balance of studies reporting androgens’ stimulatory and inhibitory actions [52–55]. Of note, when MCF-7 cells are engineered to overexpress AR, androgens were potent inhibitors of growth [52,56]. Mechanistic studies in MDA-MB-453 [AR(+), ERa( )] cells have demonstrated AR mediated proliferation and importantly cross-talk with human epidermal growth factor receptor II (HER2), a critical oncogenic driver in breast cancer [53,57]. In the absence of ERa, AR:DNA interactions in breast cancer cells closely mimic those of the AR in LNCaP prostate cancer cells. In engineered models, Peters et al. have shown that AR can dosedependently inhibit ERa signaling in breast cancer cells, and that AR can bind to consensus estrogen receptor DNA binding elements [58]. Taken together these studies provide further mechanistic support for the ERa dependent role of AR in breast cancer. Perhaps the best evidence supporting the importance of AR in breast cancer is provided by its prevalence in clinical samples.

3. Androgens and AR in advanced female breast cancer The AR is the most commonly expressed hormone receptor in invasive, metastatic breast cancer. AR has been reported in up to 90% of primary breast cancers and 25% of breast cancer metastases [59–61]. It follows that AR as a prognostic factor has been extensively characterized. In ERa positive disease, AR expression is associated with lower grade disease, reduced invasiveness and longer disease free survival [62–65]. Importantly, improvements in these disease characteristics trend with increased levels of the AR supporting the antagonistic role of AR in ERa(+) disease demonstrated in vitro. AR expression in ERa( ) disease has been studied almost exclusively in the context of triple negative breast cancer (TNBC) which does not express ERa, progesterone receptor (PR) or HER2. TNBC, irrespective of AR status, is well studied and is associated with a generally poor prognosis [66]. AR has been detected in 10–43% of TNBCs, but its utility as a prognostic factor in this population is currently debated [67]. These studies have associated AR with increased mortality, no effect, or even an improved prognosis [68–70]. The confusion surrounding the role of AR in these high risk patients is indicative of both the complexity of AR’s role in advanced breast cancer and the challenge facing the clinician in selecting an appropriate AR ligand (i.e. agonist or antagonist). Androgens have shown efficacy in advanced breast cancer for nearly 70 years, predating the molecular phenotyping at the heart of modern targeted therapy [71–73]. The orally available synthetic androgen fluoxymesterone was championed as a replacement to intra-muscularly administered testosterone propionate therapy by Kennedy et al. in 1956 when they reported objective response rates of 40% [73]. Despite often dose-limiting virilizing side effects, androgens were the therapy of choice in post-menopausal breast cancer patients at that time. SERMs and aromatase inhibitors displaced androgens in the 1970’s as it was increasingly realized that many androgen therapies were readily aromatized to estrogenic compounds and that ER targeted therapies were devoid of virilizing side effects [74–77]. Though the response rates were similar in magnitude, the side effect profiles of the ER targeted agents were preferred and when androgens were added to SERM therapy no improvements were apparent [78].

Recent studies of androgen action in breast cancer suggest that molecular phenotyping of tumors is crucial, and as with most transformed cellular models, extrapolating clinical relevance from in vitro data should be done with caution. The balance of data suggest that in AR(+)/ERa(+) disease an AR agonist could be of therapeutic benefit whereas in AR(+)/ER( ) molecular apocrine disease an antagonist might be more appropriate [44]. Given the clinical success of existing therapies in ER(+) disease and the drawbacks of existing steroidal androgens (aromatization, virilization, etc.) recent clinical efforts have focused primarily on high risk ERa( ) disease and the use of AR antagonists. 4. Recent AR targeted therapy in advanced breast cancer Gucalp et al. hypothesized that an anti-androgen may have efficacy in AR(+), ER( )/PR( ) disease based on the aforementioned preclinical evidence of androgen dependent growth in ER( )/ PR( ) breast cancer cells [79,80]. Though few studies on AR(+), ER( )/PR( ) subsets of breast cancer have been reported, these patients are a sub-strata of more widely recognized TNBC. TNBC does not typically respond to hormonal therapy, thus primarily palliative treatment is limited to chemotherapeutics. Representing roughly 15 to 20% of all breast cancers, TNBC is a large unmet medical need [81]. As such, clinicians and patients are earnest to evaluate any option to cytotoxic chemotherapy despite the lack of efficacy demonstrated by anti-androgen (flutamide) administration in women with breast cancers of unknown ER, PR or AR status in the late 1980’s [82,83]. Buoyed by bicalutamide’s clinical experience in women suffering from less serious endocrine diseases, Gucalp et al. administered 150 mg of the anti-androgen to women whose breast cancer was histologically confirmed ER( ), PR( ) and AR(+). In the population screened at this single site study, only 51 of 424(12%) of ER( )/ PR( ) were determined to have AR(+) disease. This differs from a recent survey of more than 7500 patients where 31.8% of ER( ) cancers expressed AR(+) and studies using similar methodology that report AR prevalence in TNBC closer to 50% [84–86]. Of the 26 patients with evaluable data, 5 were determined to have stable disease after 6 months of bicalutamide therapy with no complete or partial responses reported. Of note, the patient with the longest response (231 + weeks of therapy) had the lowest reported AR expression (10–20%). The study’s authors did not comment on this apparent disconnect between AR levels and response. Unphased by these modest results, as of the writing of this manuscript, Medivation Inc. was enrolling patients with incurable breast cancer of any histology to receive their third generation anti-androgen enzalutamide (NCT01597193) with similar trials reported for the androgen synthesis inhibitor abiraterone acetate as well (NCT00755885). 5. Enobosarm in advanced breast cancer Key features of an androgen agonist to be utilized in an advanced breast cancer population are zero estrogenic capacity, either through receptor cross reactivity or metabolism to an ERbinding ligand, and reduced capacity for androgenization or virilization. The most advanced SARM to date, GTx-024 or enobosarm, has no characterized estrogenic activity either inherent to its parent form or via any described metabolite. The virilizing effects of traditional steroidal androgens are primarily associated with androgen action in tissues expressing high levels of 5a-reductase (hair and skin) and thus typically ascribed to the actions of the most potent endogenous androgen 5a-dihydrotestosterone (DHT). Enobosarm is not subject to 5a-reduction or the AR signal amplification that results in local production of an androgen with 10-fold increased potency, and is therefore expected to have

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C.C. Coss et al. / Steroids 90 (2014) 94–100 Table 1 Sebum tape scores in healthy elderly women following enobosarm therapy. Percent change from baseline day 30 Treatment (N = 12)

Active-placebo (SE)

c

All placebo Enobosarm Enobosarm Enobosarm Enobosarm a b c

a

p-Value

85.5 83.2 34.0 50.1 26.3

0.1 mg 0.3 mg 1 mg 3 mg

Percent change from baseline day 84 b

Active-placebo (SE)

– 0.097 0.495 0.338 0.605

a

p-Valueb

39.6 0.9 93.7 39.9 78.6

– 0.988 0.102 0.505 0.180

Difference between least squares means active – placebo. ANOVA. Placebo values presented as least squares mean percent change from baseline only in both male and females.

reduced effects in these tissues. To this end, enobosarm’s capacity for virilization has been extensively characterized in the clinic. 5.1. Skin and hair effects Androgen excess in pilosebaceous units of the face, neck and upper trunk is associated with increased gland volume and sebum production often leading to acne vulgaris [87]. In a Phase II study of healthy elderly women over the age of sixty, daily doses of enobosarm (placebo, 0.1 mg, 0.3 mg, 1 mg or 3 mg, n = 12 per treatment arm) were administered for 3 months [5]. Sebum content of the forehead was assessed at baseline and Days 30 and 86 using sebum tape methodology. Changes in sebum levels were variable across treatment groups with significant differences apparent between enobosarm and placebo treated controls (Table 1). Another marker of androgenization in women is excessive terminal hair growth or hirsutism [88]. In the same patient population hair on the upper lip, chin, chest, upper abdomen, upper arm and upper back were assessed using a modified Ferriman–Gallwey scale at baseline and Day 86 [89] (Table 2). Most patients had no changes or decreased hair growth with only a single patient reporting an increase in hair growth at the 1 mg level. In a separate Phase II study, healthy post-menopausal women were administered 3 mg enobosarm (n = 25) or placebo (n = 23) daily for 3 months. In this study, sebum excretion rates were assessed using bentonite clay patches applied to the forehead at baseline and after 12 weeks of therapy (Table 3). Using this methodology, enobosarm therapy resulted in a mean 1.25-fold increase in sebum production from baseline and 1.5-fold increase compared to placebo after 12 weeks of therapy. Though this change was statistically significant, the placebo treated patients had reduced

Table 4 Change from baseline in total sebaceous gland volume in postmenopausal women following 84 days of enobosarm therapy. Treatment(N)

Mean (95% CI)a

Placebo (23) Enobosarm 3 mg (25)

13.03 ( 8.42, 34.49) 13.44 ( 6.53, 33.42) 6

Mean Difference (95% CI)b

p-value

0.41 ( 28.48, 29.29)

0.978

3

Volumes are expressed in the multiple of 10 lM . a Means are least squares estimates from a cLDA model. b Mean difference between active drug and placebo after 12 weeks of treatment.

Table 5 10 Day ProveraÒ challenge in postmenopausal women following 84 days of daily dosing with enobosarm. Treatment

Placebo Enobosarm 3 mg

Any Bleeding

Total

Yes Frequency (%)

No Frequency (%)

Frequency (%)

4 (19.0) 1 (4.0)

17 (81.0) 24 (96.0)

21 (100.0) 25 (100.0)

sebum production (0.84-fold versus baseline) during the 12 week study and skin based adverse events were balanced between the two treatment groups (7 per treatment arm). A histological analysis of sebaceous gland volume was also performed on 5-mm skin punch biopsies obtained at baseline and after 12 weeks of therapy (Table 4). No treatment mediated differences were apparent in glandular volume (Table 5).

5.2. Endometrial effects Table 2 Number of postmenopausal women with a change from baseline in the modified Ferriman–Gallwey score following 84 days of enobosarm therapy. Dose (N = 12)

Decrease from baseline (N)

Increase from baseline (N)

Placebo Enobosarm 0.1 mg Enobosarm 0.3 mg Enobosarm 1 mg Enobosarm 3 mg

1 2 0 0 4

0 0 0 1 0

To assess any potential estrogenic effects of enobosarm treatment in post-menopausal women, a sensitive medroxyprogesterone acetate (MPA) challenge was administered to subjects following 12 weeks of therapy (Table 6). At the conclusion of enobosarm treatment, a ten day course of 10 mg/day ProveraÒ was administered to trigger withdrawal bleeding. Any menstrual spotting was recorded using a 30-day bleeding diary. The frequency of bleeding in enobosarm treated patients was reduced compared to placebo suggesting enobosarm is devoid of estrogenic effects.

Table 3 Change from Baseline in Sebum Excretion Rate in Postmenopausal Women Following 84 days of GTx-024 Therapy. a

Treatment (N)

GM (95% CI)

Placebo (23) Enobosarm 3 mg (25)

0.84 (0.66, 1.07) 1.25 (1.00, 1.58)

GMR (active vs. placebo) (95% CI)b

p-Value

1.50 (1.10, 2.03)

0.010

Fold change analysis performed on log scale. GM: geometric mean, GMR: geometric mean ratio. a Geometric Means (GM) are least squares estimates from a cLDA model. b Geometric Mean Ratio (GMR) for fold change between active drug and placebo after 12 weeks of treatment.

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Table 6 Summary of endometrial thickness (mm) by TVU in postmenopausal women following 84 days of daily dosing with enobosarm. Treatment (N)

Placebo (23) Enobosarm 3 mg (25) a b

Time point

Predose Week 12 Predose Week 12

Change from baselinea

Value Mean

SE

2.40 2.52 2.73 3.08

0.25 0.29 0.21 0.23

Nb

Mean

19

0.09

0.34

20

0.29

0.23

SE

Prestudy measurement serves as baseline; analysis performed on raw scale. Actual sample size.

Postmenopausal women on hormone replacement therapy are at greater risk for endometrial hyperplasia and endometrial carcinoma [90]. Though estrogens’ role in uterine proliferation is well known and enobosarm therapy is associated with no estrogenic risk, the role of androgens in uterine proliferation, if any, is less well understood. The uterine wall contains a myometrial layer which expresses the AR and pre-clinical evidence has demonstrated proliferative capacity in response to exogenous androgen administration [91]. However, the relationship between myometrial hyperplasia and endometrial disease is unclear as is the ligand dependence of the AR’s effects in myometrium [90,92]. Transvaginal ultrasound (TVU) is a widely accepted measure of the uterine cavity and women with an echo thickness of 65-mm without bleeding have low likelihood of presenting with endometrial cancer [93,94]. TVUs were performed on healthy post-menopausal women at baseline and after 12 weeks of 3 mg enobosarm daily. Any woman with >5-mm thickness at baseline was excluded from the analysis. There were no clinically or statistically significant differences between the 3 mg dose of enobosarm and placebo in the change from baseline effects on endometrial thickness suggesting enobosarm therapy possess minimal endometrial or myometrial risk (Table 6).

efficacy of androgens in these patients was never in question. Modern research techniques suggest that if given to a properly selected group of patients [ER(+), AR(+)], response rates to an androgen agonist might even improve beyond the historical ceiling of 20–30% for hormonal manipulation in this disease. SARMs have shown that it is possible to develop safe, orally available, potent androgens devoid of estrogenic and virilizing side-effects. Despite promising preliminary results, the clinical efficacy of non-steroidal androgens like enobosarm in breast cancer is yet to be demonstrated. Should such agents reproduce the historical efficacies associated with androgen therapy, clinicians will again be forced to weigh side effect profiles. The use of SERMs and aromatase inhibitors in postmenopausal women is associated with thromboembolic events, endometrial carcinoma and bone fractures [98]. It also is estimated that arthralgia and muscle stiffness contribute greatly to the 20% of non-compliant patients on aromatase inhibitor therapy [99]. These side effects are not expected from exogenous androgen administration following SARM administration in postmenopausal women. SARMs appear to have successfully addressed the critical limitations of androgen therapy in advanced breast cancer patients and returned a proven hormonal therapy to the clinician’s arsenal.

5.3. Clinical evaluation of enobosarm in advanced breast cancer patients

References

In early 2012, GTx Inc. began a Phase II evaluation of enobosarm in ER(+) metastatic breast cancer patients who had a history of prolonged response of their localized disease to hormonal therapy or recent responses to hormonal treatment of their metastatic disease(NCT01616758). Due to the high correspondence of AR(+) and ER(+) disease and little consensus on histological determination of AR status in this population, only the presence of ER was required for enrollment [95–97]. The primary efficacy measure was overall clinical benefit [complete response(CR), partial response(PR) or stable disease (SD)] as determined by RECIST criteria following 6 months of daily 9 mg enobosarm therapy. Other key endpoints included clinical response in AR(+) patients, progression free survival, PSA response and assessments of skeletal related events and bone turnover markers. The trial was fully enrolled by the end of 2013 with 22 women (mean age 63.2). 17 of 19 patients with evaluable samples metastatic leions were histologically determined to be AR(+) and 8 subjects presented with detectable baseline PSA (serum values P0.01 ng/dL). As of the drafting of this manuscript, 9 mg enobosarm therapy continues to be well tolerated and 6 of 17 AR(+) have demonstrated clinical benefit. All subjects are expected to conclude the planned six months of therapy in early 2014 with topline results available in a similar time frame. 6. Conclusions Androgen therapy in breast cancer was replaced by SERMs and aromatase inhibitors due to an unfavorable side effect profile. The

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