Emerging data on the efficacy and safety of fulvestrant,a unique antiestrogen therapy for advanced breast cancer

Introduction: Fulvestrant is an antiestrogen therapy with a unique mechanism of action. Unlike the selective estrogen receptor modulator tamoxifen, fulvestrant has no known estrogen agonist activity and is considered a pure antiestrogen. Its primary mechanism of action is thought to result from downregulation of the estrogen receptor (ER). Considerable data have demonstrated the efficacy of fulvestrant in postmenopausal women with ER-positive advanced breast cancer, both in the first-line setting and following disease progression on tamoxifen or aromatase inhibitors. Recent studies report improved benefit with alternative dosing strategies. At all administration schedules, fulvestrant has an excellent safety profile with no significant adverse effects.

Areas covered: This article provides a review of the mechanism of action of fulvestrant and the preclinical and clinical data evaluating its use as a form of endocrine therapy. The reader will gain insight into the pharmacologic properties of the drug and its role in the treatment of advanced hormone receptor-positive breast cancer in postmenopausal women.

Expert opinion: Based on data demonstrating the efficacy of fulvestrant, including prolonged clinical benefit in many patients, this well-tolerated antiestrogen is an important therapy for breast cancer. The optimal position of fulvestrant in the sequence of endocrine therapies for postmenopausal women and its role in combination regimens are not yet resolved.     

An evaluation of fulvestrant for the treatment of metastatic breast cancer

ABSTRACT

Introduction: Fulvestrant is currently the only selective estrogen receptor degrader (SERD) that is approved for clinical use in estrogen receptor (ER) positive advanced breast cancer (ABC). The drug is approved as single-agent therapy in the first and second-line setting of metastatic ER-positive breast cancer.

Areas covered: In this review, the authors review the preclinical studies that were pivotal in the development of fulvestrant, the pharmacologic properties of the drug, and the key clinical trials that resulted in its approval for clinical use. The authors discuss mechanisms of endocrine resistance and potential targets for endocrine refractory disease while highlighting ongoing studies that assess fulvestrant use with novel agents.

Expert opinion: While fulvestrant has limited use in the first-line setting in advanced breast cancer, it is most frequently used in the second line after progression with aromatase inhibitors. The combination of fulvestrant with CDK4/6 inhibitors has shown a clear benefit over monotherapy in patients who progress on prior endocrine therapy. Further study is necessary to assess if patient outcomes can be enhanced by optimizing the sequence of endocrine therapies, targeting resistance pathways with novel agents, and development of new agents in the SERD class.     

Considering the economic principles of pharmaceutical R&D

Importance of the field: Virtual screening (VS) coupled with structural biology is a significantly important approach to increase the number and enhance the success of projects in lead identification stage of drug discovery process. Recent advances and future directions in estrogen therapy have resulted in great demand for identifying the potential estrogen receptor (ER) modulators with more activity and selectivity.

Areas covered in this review: This review presents the current state of the art in VS and structure–activity relationship of ER modulators in recent discovery, and discusses the strengths and weaknesses of the technology.

What the reader will gain: Readers will gain an overview of the current platforms of in silico screening for discovery of ER modulators; they will learn which structural information is significantly correlated with the bioactivity of ER modulators and what novel strategies should be considered for the creation of more effective chemical structures.

Take home message: With the goal of reducing toxicity and/or improving efficacy, challenges to the successful modeling of endocrine agents are proposed, providing new paradigms for the design of ER inhibitors.     

Fulvestrant: a unique antiendocrine agent for estrogen-sensitive breast cancer

Importance of the field: The role of estrogen deprivation for the treatment of breast cancer has been understood since the 1800s. Pharmacologic advances in the field in the past decades, including tamoxifen and the aromatase inhibitors, have contributed significantly to the reduced mortality of estrogen-sensitive breast cancer. However, this subtype of breast cancer still presents with relapses and, once metastatic, progression to hormone-refractory state and loss of disease control remain an expected disease course. Fulvestrant, a pure estrogen receptor downregulator, is a new addition to the antiestrogen therapeutic armamentarium since its FDA approval in 2002. Its unique mechanism of action offers potential advantages over other estrogen targeted therapies.

Areas covered in this review: Published scientific literature, including presented abstracts, on fulvestrant from 1985 to the present were reviewed with selected publications included.

What the reader will gain: This review addresses current issues and therapies for estrogen-sensitive breast cancer, highlights the role of fulvestrant in current treatment guidelines and outlines some of the ongoing investigations of this compound.

Take home message: Fulvestrant is an effective and well-tolerated drug for treatment of metastatic estrogen-sensitive breast cancer. Work is underway to enhance its clinical benefit to patients as a single agent and in combination with other therapies.     

依维莫司联合氟维司群用于激素受体阳性晚期乳腺癌的研究进展

乳腺癌是一种经典的激素依赖性肿瘤,内分泌治疗是激素受体阳性［HR（+）］/人表皮生长因子 2 阴性 ［HER-2（-）］晚期乳腺癌的主要治疗方法。传统的内分泌药物,如他莫昔芬、芳香化酶抑制剂（AI）和氟维司群已被 广泛应用于晚期（局部晚期或转移）绝经后患者。然而,对于这种亚型的乳腺癌患者,在引入靶向药物,如人哺乳动 物雷帕霉素位点（mTOR）抑制剂和细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂后,内分泌治疗的选择已经扩大,出 现了各种靶向药物与内分泌治疗的组合。本文旨在探讨mTOR抑制剂依维莫司联合氟维司群在对AI耐药的雌激素 受体阳性［ER（+）］/HER-2（-）晚期乳腺癌中的应用。     

Abiraterone acetate for castration resistant prostate cancer

Importance of the field: Androgen deprivation therapy has been the standard of care in advanced prostate cancer for >?50 years. Although castration is initially effective, most patients eventually develop progressive disease despite low levels of testosterone (termed castration resistant prostate cancer, CRPC). Intratumor and extra-gonadal androgens (specifically adrenal androgens) represent a means for continued androgen receptor-mediated growth in CRPC and have thus become therapeutic targets. One novel therapeutic is abiraterone acetate (AA): an inhibitor of CYP17, an enzyme that catalyzes two key serial reactions in androgen and estrogen biosynthesis. Data from Phase I and II trials suggest that clinically important antitumor activity is seen in up to 70% of castrate patients with advanced prostate cancer resistant to currently available endocrine therapies. The toxicity profile has also been found to be acceptable. Two large Phase III clinical trials are currently open to accrual and will hopefully validate the impressive Phase II data.

Areas covered in the review: The chemistry, pharmacodynamics, pharmacokinetics, clinical efficacy and safety/tolerability of AA.

What the reader will gain: Readers will understand the function of non-gonadal androgens, the importance of continued androgen deprivation in advanced prostate cancer and the role/clinical efficacy of AA.

Take home message: The recent realization that non-gonadal sources of androgens (adrenal and intracrine de novo synthesis) may be a major mediator of disease progression forms the biological rationale behind the development of abiraterone acetate and related drugs. Abiraterone acetate is an orally administered, specific inhibitor of CYP17A1, a rate-limiting enzyme in androgen biosynthesis. Preliminary data from Phase I and II trials suggest that prostate specific antigen declines occur in a large proportion of patients and that the toxicity profile is acceptable. Two large Phase III clinical trials are currently open to accrual and, if proven to be efficacious, will result in widespread use of a drug specifically developed to suppress adrenal androgens.     

Progression-free survival with endocrine-based therapies following progression on non-steroidal aromatase inhibitor among postmenopausal women with hormone receptor positive,human epidermal growth factor receptor-2 negative metastatic breast cancer: a network meta-analysis

Objective: To quantify the comparative efficacy of currently available endocrine-based therapies (ETs) for postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2?) metastatic breast cancer (mBC) after non-steroidal aromatase inhibitor (NSAI) progression.

Design: Network meta-analysis (NMA).

Methods: Randomized clinical trials of ETs for HR+/HER2? mBC were identified via a systematic literature review using MEDLINE, Embase, Cochrane Library and key conference proceedings. All trials met the following inclusion criteria: (1) included women with HR+/HER2? mBC; (2) previous treatment with ETs or chemotherapy as first-line therapy; (3) treatment with ET as monotherapy or in combination with targeted therapy; (4) progression-free survival (PFS) was reported; and (5) published in 2007 (when HER2 testing became standardized) or later. Regimens were compared using pairwise hazard ratios (HRs) and 95% credible intervals (CrIs) of PFS obtained from a Bayesian NMA. Treatments with different approved dosages were pooled into the same arm; anastrozole and exemestane were pooled as aromatase inhibitors (AIs) due to clinical similarities.

Results: A total of 4 trials and 6 regimens (palbociclib?+?fulvestrant, everolimus?+?fulvestrant, everolimus?+?AI, fulvestrant?+?AI, fulvestrant and AI) were eligible for inclusion. Palbociclib?+?fulvestrant and everolimus?+?AI had 50% and 55% reduced hazard of progression or death vs. AI (95% CrI upper bound ≤1), respectively. Palbociclib?+?fulvestrant, everolimus?+?AI and everolimus?+?fulvestrant had 54%, 58% and 40% reduced hazard vs. fulvestrant (95% CrI upper bound ≤1), while palbociclib?+?fulvestrant and everolimus?+?AI had 52% and 55% reduced hazard vs. fulvestrant?+?AI (95% CrI upper bound ≤1), respectively.

Conclusion: Postmenopausal women with HR+/HER2? mBC who had previously failed an NSAI and received palbociclib?+?fulvestrant, everolimus?+?AI or everolimus?+?fulvestrant had longer PFS compared to those who received fulvestrant or AI alone.     

Selective estrogen receptor modulators in clinical practice: a safety overview

Introduction: Selective estrogen receptor (ER) modulators (SERMs) are a class of nonsteroidal compounds that interact with ERs, each with a distinct tissue-specific profile. Depending upon the degree of ER agonism/antagonism at the target tissue, SERMs show efficacy for various indications including osteoporosis, dyspareunia, and breast cancer, and are associated with safety risks.

Areas covered: This review describes the safety profile of SERMs (tamoxifen, raloxifene, toremifene, bazedoxifene, lasofoxifene, and ospemifene) and fulvestrant (a pure ER antagonist) from Phase III trials, long-term extension studies, and active comparator studies. Tamoxifen, a first-generation SERM, is indicated for breast cancer prevention and treatment but is associated with serious safety concerns including endometrial cancer, venous thromboembolic events (VTE), and stroke. Toremifene, raloxifene, bazedoxifene, lasofoxifene, and ospemifene present generally improved, though distinctly different, safety profiles compared with tamoxifen, especially with endometrial cancer and stroke. However, the risk of VTE remains a concern for most SERMs.

Expert opinion: Each SERM presents a unique risk/benefit profile based on varying indications and tissue-specific ER agonist and antagonist effects, making careful patient selection and ongoing patient monitoring crucial aspects of treatment. Future research may focus on identifying new SERMs for endocrine-resistant and endocrine-responsive cancers and post-menopausal symptoms.     

mTOR inhibition in breast cancer: unraveling the complex mechanisms of mTOR signal transduction and its clinical implications in therapy

Introduction: The mammalian target of rapamycin (mTOR)/PI3K/Akt pathway is altered in breast cancer cells, as demonstrated by mutations in both the upstream and downstream regulators of mTOR, including phosphatase and tensin homolog deleted in chromosome 10 (PTEN) loss or Akt/PI3K activation, and potentially in the mTOR protein itself. This contributes to increased cell proliferation, as well as growth-factor independence and endocrine resistance. Thus, mTOR inhibition holds considerable promise as a rational therapeutic strategy in breast cancer.

Areas covered: This review describes how dysregulation of the mTOR pathway in breast cancer may contribute to breast cancer pathogenesis, as well as discussing preclinical and clinical data that support mTOR inhibitor therapy.

Expert opinion: Direct blockade of the mTOR pathway is a new and intriguing area in breast cancer therapy, with the potential to modulate growth-factor and estrogen-dependent and -independent pathways, that contribute to the pathogenesis and progression of breast tumors. mTOR inhibitors demonstrate significant biologic activity with manageable toxicities, in combination with hormonal therapy and chemotherapy, in both the neoadjuvant and metastatic breast cancer settings.     

Current status and future perspectives in the endocrine treatment of postmenopausal,hormone receptor-positive metastatic breast cancer

Introduction: Endocrine therapy is a fundamental component of the therapeutic repertoire for treatment of metastatic, hormone receptor-positive breast cancer. Inevitably, however, tumors develop resistance to these compounds, and overcoming this phenomenon is a key motivator of research in this field.

Areas covered: This review summarizes the current status of endocrine therapy for the treatment of metastatic disease, with a main focus on postmenopausal patients. Furthermore, strategies that could potentially sustain endocrine resistance and future perspectives in this direction are also to be described. Relevant references were identified by PubMed searches and from the abstract books of the annual meetings of The European Society of Clinical Oncology (ESMO), The American Society of Clinical Oncology (ASCO) and from the San Antonio Breast Cancer Symposia.

Expert opinion: Combinations of endocrine therapy with HER2 targeting agents, as well as with compounds that can interfere with PI3K/Akt/mTOR signaling, are two promising strategies for delaying or overcoming endocrine resistance, mediated by these relevant biological pathways. Due to increased costs and the burden of toxicity associated with these combination therapies, compared to endocrine therapy alone, it is imperative to concentrate efforts on establishing biomarkers that can predict efficacy.     

Efficacy of fulvestrant 500 mg in Japanese postmenopausal advanced/recurrent breast cancer patients and factors associated with prolonged time-to-treatment failure

Objective: We aimed to confirm the efficacy of fulvestrant in Japanese postmenopausal advanced/recurrent breast cancer (ABC) patients, and investigate factors contributing to time-to-treatment failure (TTF) prolongation.

Research design and methods: This retrospective study included 194 ABC patients who received fulvestrant (500 mg) from January 2012 to December 2014.

Main outcome measures: TTF (efficacy measure), overall survival (OS), factors prolonging TTF and adverse events were evaluated.

Results: The median age was 65 (42 – 90) years. Overall, TTF was 5.48 months. In patients without prior chemotherapy (n = 59), OS was significantly longer (p = 0.0131) than in patients with prior chemotherapy (n = 135). There was no strong correlation between TTF with fulvestrant and other endocrine therapies, total duration of endocrine therapy and maximum duration of endocrine therapy. TTF was significantly longer in patients with less than two prior chemotherapy regimens (p = 0.0093), de novo metastatic disease (p = 0.0124) and without liver metastasis (p = 0.0024). We observed one case each of pulmonary infarction and psychiatric disorder.

Conclusions: Fulvestrant is effective for ABC patients and may show greater efficacy in patients with few prior chemotherapy regimens, de novo metastatic disease and absence of liver metastasis. Prior endocrine therapy duration might not be a predictive factor for fulvestrant TTF in heavily treated ABC patients.     

Investigational PI3K/AKT/mTOR inhibitors in development for endometrial cancer

Introduction: Endometrial cancer (EC) is the most common neoplasm of the female genital tract in developed countries. Despite the progress in early detection and treatment, a significant number of cases of advanced ECs are still diagnosed. These patients have few treatment options and a poor prognosis. Our understanding of EC pathogenesis and progression has been enhanced by recent genomic studies. Among the relevant biological pathways, phosphatidylinositol 3-kinase/AKT (PIK3/AKT)-mammalian target of rapamycin (mTOR) signaling is frequently upregulated in this cancer.

Areas covered: This review covers investigational EC therapeutics acting on the PI3K/AKT/mTOR pathway. The authors review the results of clinical studies and highlight ongoing trials.

Expert opinion: Several new agents are under evaluation for treating patients with metastatic, recurrent, and persistent EC. Clinical trials investigating PI3K/AKT/mTOR inhibitors have yielded controversial results. In the near future, new studies with dual inhibitors or multi-pathways inhibitors as mono or combination therapies with conventional chemotherapy (CT) or other targeted drugs may provide more promising data. Moreover, the evaluation of new serum and histological biomarkers is an attractive strategy for patient selection.     

Targeted therapy in sarcomas: mammalian target of rapamycin inhibitors from bench to bedside

Introduction: Sarcomas are rare heterogeneous malignancies of mesenchymal origin relatively common during childhood. Disruption of the mammalian target of rapamycin (mTOR) pathway is a very common event during the tumorigenesis of several types of cancer. In particular, strong preclinical evidences suggest pivotal roles of this pathway during the sarcomagenesis. Therefore, the inhibition of mTOR via rapamycin, rapamycin analogs (rapalogs) and ATP-competitive inhibitors seems to be a promising path to follow for a fully tailored therapy.

Areas covered: The aim of the present review is to summarize the available data about the mechanisms of mTOR pathway, its biological implications and its possible role in the pathogenesis of soft tissue sarcoma. Moreover, preclinical and clinical evidences of different mTOR inhibitors in the treatment of sarcomas are reported.

Expert opinion: Early studies with mTOR inhibitors have demonstrated promising antitumor activity in patients with metastatic sarcoma who have failed standard treatments: that is why mTOR inhibitors represents today a promising chance to improve the prognosis of those patients affected by these rare disease, which is today still extremely poor.     

Ixabepilone for the treatment of endometrial cancer

Introduction: Endometrial cancer (EC) is the most common gynaecological cancer. Despite significant progress in the multimodality treatment approach, the prognosis remains poor for patients with advanced disease. Thus, there is the necessity of more effective strategies.

The microtubule-stabilizing agent ixabepilone is the first drug in this new class of agents that has been approved for metastatic breast cancer treatment. Based on empiric data and on the clinical efficacy demonstrated in breast cancer, several clinical trials were proposed to define its role in EC.

The aim of this review is to determine whether ixabepilone improved the clinical outcome in patients with locally advanced, recurrent or metastatic EC.

Areas covered: Preclinical and clinical studies of ixabepilone in endometrial cancer were analyzed and discussed. Data were obtained by searching for English peer-reviewed articles on PubMed, phase I and II studies registered on clincaltrials.gov, and related abstracts recently presented at major international congresses.

Expert opinion: Advanced or recurrent EC still represents a challenge and an unmet need in the panorama of gynaecological malignancies. Ixabepilone’s future therapeutic role in EC remains ill defined. Nevertheless, despite its limited efficacy in EC, clinicians treating gynaecological tumours should be aware of its main aspects.     

Paliperidone extended-release: a review of efficacy and tolerability in schizophrenia,schizoaffective disorder and bipolar mania

Importance of the field: Paliperidone extended-release (ER), a once-daily, oral, atypical antipsychotic, has been available in the USA and the EU for the treatment of schizophrenia for more than 2 years and was recently (July 2009) approved in the USA for treatment of schizoaffective disorder. Additional data on its efficacy and safety, including that for additional indications, is emerging.

Areas covered in this review: This review provides a background on the compound and summarizes recent data available on treatment of schizophrenia, including comparative data with other antipsychotics, and efficacy and safety data from clinical trials in schizoaffective and bipolar disorders.

What the reader will gain: The reader will gain knowledge of the compound and the existing clinical data so far for paliperidone ER.

Take home message: Paliperidone ER is effective for the treatment of schizophrenia and is at present the only antipsychotic approved in the USA for treatment of schizoaffective disorder. Its efficacy and tolerability profile in treating patients with schizophrenia or schizoaffective disorder indicates that paliperidone ER offers an important treatment option among atypical antipsychotic therapy for these patients.     

Estrogen receptor ligands: a patent review update

Introduction: The role of estrogens is mostly mediated by two nuclear receptors (ERα and ERβ) and a membrane-associated G-protein (GPR30 or GPER), and it is not limited to reproduction, but it extends to the skeletal, cardiovascular and central nervous systems. Various pathologies such as cancer, inflammatory, neurodegenerative and metabolic diseases are often associated with dysfunctions of the estrogenic system. Therapeutic interventions by agents that affect the estrogenic signaling pathway might be useful in the treatment of many dissimilar diseases.

Areas covered: The massive chemodiversity of ER ligands, limited to patented small molecules, is herein reviewed. The reported compounds are classified on the basis of their chemical structures. Non-steroidal derivatives, which mostly consist of diphenolic compounds, are further segregated into chemical classes based on their central scaffold.

Expert opinion: Estrogens have been used for almost a century and their earlier applications have concerned interventions in the female reproductive functions, as well as the treatment of some estrogen-dependent cancers and osteoporosis. Since the discovery of ERβ in 1996, the patent literature has started to pay a progressively increasing attention to this newer receptor subtype, which holds promise as a target for new indications, most of which still need to be clinically validated.     

Comparison of palbociclib in combination with letrozole or fulvestrant with endocrine therapies for advanced/metastatic breast cancer: network meta-analysis

Background: Palbociclib is the first cyclin-dependent kinase 4/6 inhibitor approved in the United States for HR+/HER2- advanced/metastatic breast cancer, in combination with letrozole as initial endocrine-based therapy in postmenopausal women or with fulvestrant in women with disease progression following endocrine therapy. We compared progression-free survival (PFS) and discontinuations due to adverse events for palbociclib combinations against other endocrine therapies using a mixed-treatment comparison meta-analysis of randomized, controlled trials.

Methods: A systematic literature review identified relevant trials. Separate analyses were conducted for each palbociclib combination using a Bayesian approach. Treatment rankings were established using the surface under the cumulative ranking curve (SUCRA).

Results: Sixty-five unique studies met inclusion criteria. Palbociclib plus letrozole had the highest SUCRA value (99.9%) and was associated with significantly longer PFS than all comparators in treatment-naïve patients (hazard ratios [HRs] ranged from 0.41 to 0.58). Palbociclib plus fulvestrant had the second highest SUCRA value (93.9%) and, in previously treated patients, yielded significantly longer PFS than most comparators (HRs ranged from 0.26 to 0.46); the exception was everolimus plus exemestane, with similar PFS (HR, 1.04; 95% credible interval [CrI], 0.58–1.76). Palbociclib plus fulvestrant was associated with significantly lower odds of discontinuation due to adverse events than everolimus plus exemestane (odds ratio, 0.14; 95% CrI, 0.05–0.39).

Conclusions: The results suggest that the two palbociclib combinations yielded significantly greater PFS than endocrine therapy in treatment-naïve and previously treated patients with advanced/metastatic breast cancer. Palbociclib plus fulvestrant was associated with significantly less toxicity than everolimus plus exemestane.     

New inhibitors of the mammalian target of rapamycin signaling pathway for cancer

Importance of the field: Contrasting with the broad activation of the PI3K/AKT/mammalian target of rapamycin (mTOR) survival pathway in most cancer, activity of rapalogues appears to be restricted to a few tumor types.

Areas covered in this review: The analysis of molecular activity of the PI3K/AKT/mTOR pathway and resistance mechanisms of rapamycin and rapalogues led to the development of several inhibitory molecules.

What the reader will gain: New anticancer agents including PI3K inhibitors, dual PI3K/mTOR inhibitors, specific mTOR inhibitors, and AKT inhibitors may have direct inhibitory effects on targets by competing with ATP or may be non-ATP-competitive allosteric modulators of protein functions. In addition, another way of blocking the abnormal activation of the PI3K/AKT/mTOR pathway may be achieved by using HSP90 inhibitors. In this paper we review novel drugs inhibiting the mTOR signaling pathway.

Take home message: Several trials are ongoing with novel drugs targeting key kinases involved in the mTOR pathway. Benchmarking those agents with rapalogues in rationally designed preclinical models and conceiving clinical trials in everolimus/temsirolimus-sensitive tumor types may help to identify drugs with a real clinical potential. Understanding mechanisms associated with primary and acquired resistance to rapalogues may help to enlarge indications and provide a rationale for designing combinations that will minimize the risk of developing resistance to rapalogues.