Targeting the androgen receptor signalling axis in castration‐resistant prostate cancer (CRPC)

What's known on the subject? and What does the study add? Castration resistance has been appreciated for decades, and several mechanisms theorising on this effect have been proposed. A rich pipeline of novel agents, including abiraterone and MDV3100, have provided proof of principle that novel agents targeting the AR signalling pathway with superior selectivity and activity than predecessors have yielded significant clinical benefit for patients with metastatic castration‐resistant prostate cancer. Our review provides an update in the development of several novel agents targeting the AR signalling pathway now in clinical testing, as well as review novel therapies in development with distinct mechanisms of action showing promising preclinical activity.

• ? Despite undergoing local therapy with curative intent, 20–30% of patients with prostate cancer will ultimately development metastatic disease, leading to morbidity and mortality.
• ? Androgen‐deprivation therapy (ADT) for men with metastatic prostate cancer results in transient clinical benefit, but ultimately, cancers progress despite castrate levels of serum testosterone, a clinical state classically referred to as ‘hormone refractory’ disease.
• ? In this review, we examine mechanisms of resistance to ADT that have redefined our understanding of the more appropriately termed ‘castration resistant’ disease, and have paved the way for a new generation of therapeutics targeting the androgen signalling axis in advanced prostate cancer.

     

Quality of life and pain relief in men with metastatic castration‐resistant prostate cancer on cabazitaxel: the non‐interventional ‘QoLiTime’ study

Female urologists represent an ever‐increasing percentage of the work force; more and more of our colleagues will be working through pregnancy. There is a lack of clear and concise advice for pregnant urologists about occupational risks during pregnancy. Urology exposes expectant mothers to potential risks from radiation, teratogenic and cytotoxic drugs, iodine hand scrub, infections, and long working hours. We aim to provide a review of the current evidence and guidance to aid expectant mothers in their decision making. Relevant research articles and up‐to‐date guidance were reviewed. The millisevert (the average accumulated background radiation dose to an individual for 1 year, exclusive of radon) was used as the main unit of radiation dose. There is no published evidence to date in pregnant clinicians that shows a received radiation dose of more than the recommended dose for a pregnant lady, and no data showing an increased risk of foetal abnormalities in clinicians who continue to screen during pregnancy; however, the data are from small studies. There is strong advice suggesting avoidance of contact with crushed or broken 5α‐reductase inhibitor tablets (finasteride and dutasteride), mitomycin and other cytotoxic drugs during pregnancy. Pregnant surgeons should avoid frequent use of iodine hand wash. Good hygiene precautions will protect from many infections along with up‐to‐date immunisations and use of personal protective equipment for certain cases.     

Alternative antiandrogen therapy in patients with castration‐resistant prostate cancer: A single‐center experience

Outcomes of alternative (second‐line) antiandrogen therapy in 112 patients with relapsing prostate cancer after first‐line hormonal therapy were analyzed. A good response (prostate‐specific antigen [PSA] decrease ≥50%) and a partial response (PSA decrease of 0–50%) by switching from bicalutamide (BCL) to flutamide (FLT) and from FLT to BCL were achieved in 35.4% (28/79) and 30.4% (24/79), and in 45.0% (9/20) and 20.0% (4/20) of cases, respectively. A good response and a partial response with the change from chlormadinone acetate (CMA) to a non‐steroidal antiandrogen (FLT or BCL) and from a non‐steroidal antiandrogen to CMA were obtained in 25.0% (2/8) and 37.5% (3/8), and in 20.0% (1/5) and 0% (0/5) of cases, respectively. In multivariate analyses, a second‐line good response was significantly predictive of cause‐specific survival from first therapy relapse to cancer death in all patients. Patients (52/112, 46.4%) with ≥30% decrease in PSA levels were associated with significantly better cause‐specific survival as measured from the start of first‐line treatment and first‐line relapse.     

Docetaxel reintroduction in patients with metastatic castration‐resistant docetaxel‐sensitive prostate cancer: a retrospective multicentre study

OBJECTIVE

To investigate the potential benefit of reintroducing docetaxel chemotherapy in patients with progressive metastatic castration‐resistant prostate cancer (mCRPC) who had initially responded to first‐line docetaxel‐based regimen.

PATIENTS AND METHODS

Records were evaluated retrospectively from French patients with mCRPC who had been included in seven controlled clinical studies of docetaxel as first‐line treatment. We identified patients who were confirmed as responders to first‐line treatment, discontinued for reasons other than disease progression or unacceptable toxicity, and who received further docetaxel chemotherapy for disease progression. The primary objective was to assess efficacy in terms of the prostate‐specific antigen (PSA) response after resuming a docetaxel‐based chemotherapy. Secondary objectives were overall survival and tolerance.

RESULTS

Of the 148 patients who responded to first‐line docetaxel, 50 received further therapy with docetaxel and were analysed. The median (range) response duration to first‐line docetaxel was 10.3 (4.6–45.7) months and the median docetaxel‐free interval was 18.4 (5.0–46.7) months. Docetaxel was reintroduced as second‐line therapy in 52% of patients and as further lines in 48%. After docetaxel reintroduction, 24 patients (48%) had a 50% decrease in PSA level (95% confidence interval, CI, 34.1–61.8%). The median (95% CI) overall survival from docetaxel reintroduction was 16 (13–20) months. Re‐treatment was well tolerated (6% of grade 3–4 haemotoxicity).

CONCLUSION

Docetaxel reintroduction appears to be effective, with favourable tolerance profiles, in patients with mCRPC having responded to first‐line docetaxel, and should be prospectively assessed in clinical trials against alternative therapies or investigational agents given alone or in combination, to define further management.     

Phase II study of docetaxel re‐treatment in docetaxel‐pretreated castration‐resistant prostate cancer

Study Type – Therapy (cohort)
Level of Evidence 2b What’s known on the subject? and What does the study add? We show that (i) docetaxel re‐treatment, after a treatment‐free interval, preserves activity; (ii) the treatment is especially well tolerated in patients who were effectively pretreated with docetaxel; and (iii) it could be speculated that combining docetaxel with other agents in this setting might be safe and result in greater activity.

OBJECTIVE

To determine the activity and tolerability of docetaxel re‐treatment after first‐line therapy with docetaxel in castration‐resistant prostate cancer (CRPC).

PATIENTS AND METHODS

Between November 2005 and January 2009, 45 patients initially responding to docetaxel and then experiencing disease progression after a period of biochemical remission of at least 5 months were enrolled in a prospective multicenter study and re‐treated with docetaxel. The primary endpoint was the biochemical response (biochemical partial response defined as >50% prostate‐specific antigen [PSA] decline); secondary endpoints were objective response, toxicity, progression‐free survival (PFS) and overall survival (OS).

RESULTS

Partial PSA responses were observed in 11 patients (24.5%), 4 (25%) of whom also had an objective response. The treatment was well tolerated, with grade 1–2 neutropenia, thrombocytopenia, vomiting and peripheral neuropathy noted in 18 (40%), 11 (24.5%), 8 (17.8%), and 6 (13.3%) patients, respectively. The most common grade 3 toxicity was neutropenia, which was observed in 8 patients (17.8%). Median PFS was 5 months and median OS was 13 months.

CONCLUSIONS

Docetaxel re‐treatment preserves anti‐tumour activity and is well tolerated in a selected population of pretreated patients with CRPC. Further randomized trials are needed to confirm our preliminary results.     

Final analysis of a phase II trial using sorafenib for metastatic castration‐resistant prostate cancer

OBJECTIVE

To determine if sorafenib is associated with an improved 4‐month probability of progression‐free survival, using radiographic and clinical criteria alone, in patients with metastatic castration‐resistant prostate cancer. Secondary endpoints included pharmacokinetics, toxicity analysis and overall survival.

PATIENTS AND METHODS

The study was an open‐label, phase II, two‐stage design, focusing on the results from the second stage, as criteria for progression were modified after completing the first stage. Sorafenib was given at a dose of 400 mg orally twice daily in 28‐day cycles. Clinical and laboratory assessments were done every 4 weeks, and radiographic scans were obtained every 8 weeks.

RESULTS

Twenty‐four patients were accrued in the second stage; the median (range) age was 66 (49–85) years, the on‐study prostate‐specific antigen level was 68.45 (5.8–995) ng/mL, the Gleason score 8 (6–9) and Eastern Cooperative Oncology Group status 1 (in 17 patients). Of the 24 patients, 21 had previous chemotherapy with docetaxel. All patients had bony metastases, either alone (in 11) or with soft‐tissue disease (in 13). One patient had a partial response; 10 patients had stable disease (median duration 18 weeks, range 15–48). At a median potential follow‐up of 27.2 months, the median progression‐free survival was 3.7 months and the median overall survival was 18.0 months. For the whole trial of 46 patients the median survival was 18.3 months. Most frequent toxicities included hand‐foot skin reaction (grade 2 in nine patients, grade 3 in three), rash, abnormalities in liver function tests, and fatigue.

CONCLUSIONS

Sorafenib has moderate activity as a second‐line treatment for metastatic castration‐resistant prostate cancer.     

Activity of ketoconazole after taxane‐based chemotherapy in castration‐resistant prostate cancer

Study Type – Therapy (case series)Level of Evidence 4

OBJECTIVE

To assess the efficacy of the androgen‐synthesis inhibitor ketoconazole as a secondary hormonal therapy in patients with castration‐resistant prostate cancer (CRPC) previously treated with chemotherapy, as persistent androgens appear to play a role in the development and maintenance of CRPC.

PATIENTS AND METHODS

We retrospectively identified 34 patients with CRPC who were treated with ketoconazole as a secondary hormonal therapy after paclitaxel‐ or docetaxel‐based chemotherapy for CRPC. They were treated with ketoconazole 200–400 mg three times daily with or without hydrocortisone. Patients with previous use of ketoconazole were excluded. Half the patients had received estramustine as part of their chemotherapy regimen. The primary endpoint was the proportion of patients with a decline of ≥50% in their prostate‐specific antigen (PSA) level. PSA progression was defined by the PSA Working Group 1 Criteria.

RESULTS

Eight of the 32 evaluable patients (25%) had a PSA decline of ≥50%. The median time to progression (TTP) was 3 months (95% confidence interval, 1.2–5.4). A history of previous response to taxane‐based chemotherapy was not associated with the response to ketoconazole. However, previous use of oestrogens for CRPC was significantly associated with a shorter TTP on ketoconazole (1.5 vs 10.2 months; P = 0.03).

CONCLUSIONS

Ketoconazole has moderate activity as secondary hormonal therapy in patients with CRPC previously treated with taxane‐based chemotherapy, although the TTP was short. Previous treatment with oestrogenic therapy is associated with a shorter TTP.     

Phase II trial of RAD001 and bicalutamide for castration‐resistant prostate cancer

Study Type – Therapy (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Despite expanding treatment options for castration‐resistant prostate cancer (CRPC), therapies with long response duration remain intangible due to prostate cancer cells’ natural ability to develop iterative resistance. Androgen receptor (AR) signaling has been shown to play a critical role in CRPC and its expression is regulated by the PI3K‐Akt pathway. Thus inhibition of AR signalling and PI3K‐Akt‐mTOR (a downstream mediator of the PI3K‐Akt pathway) pathway is a logical combination in CRPC and we report a phase II trial of RAD001 and bicalutamide. Our study is the first clinical trial report of an AR inhibitor of PI3K‐Akt‐mTOR. The AR pathway and the PI3K‐Akt‐mTOR pathway are two of the most relevant growth pathway for CRPC. Despite low efficacy results from our trial there will be significant interest in the field for these data (dose, schedule, response, toxicity, trial design) as newer generations of both AR inhibitors and PI3K‐Akt‐mTOR inhibitors are in development and likely will be tested in combination in CRPC.

OBJECTIVES

• ? To determine best overall response and duration of response of RAD001, a selective inhibitor of mammalian target of rapamycin, in combination with bicalutamide in castration‐resistant prostate cancer (CRPC).
• ? To characterize the toxicity profile of RAD001 in combination with bicalutamide in patients with CRPC.

PATIENTS AND METHODS

• ? A phase II study was conducted to explore the efficacy and tolerability of RAD001 (10 mg daily) in combination with bicalutamide (50 mg daily) in men with progressive CRPC.
• ? The primary endpoint was a composite of prostate‐specific antigen (PSA) level and measurable disease response by standard criteria.
• ? This single‐stage trial with a sample size of 38 eligible patients provided 90% power to differentiate a response rate of ≥40% from a response rate of ≤20%, as expected for bicalutamide alone (α= 0.10, power = 0.90).

RESULTS

• ? In total, 36 men were enrolled, with a median (range) age of 68 (60–72) years and median (range) baseline PSA level of 22.2 (8.4–121.3) ng/mL, and 89% had metastatic disease.
• ? There were 31 (86%) patients had previously used bicalutamide for a median duration of 7.4 months.
• ? There were two patients with a confirmed PSA level decline ≥50%.
• ? The median (interquartile range) time to progression was 8.7 (7.9–15.9) weeks.
• ? The most common toxicity was grade 1/2 mucositis, which was observed in 20 (56%) patients.

CONCLUSION

• ? The combination of RAD001 and bicalutamide in men with CRPC was well tolerated but had low activity and failed to achieve the primary endpoint of improved response compared to the results previously achieved for bicalutamide alone in this population.

     

Final safety and efficacy analysis of the specific endothelin A receptor antagonist zibotentan (ZD4054) in patients with metastatic castration‐resistant prostate cancer and bone metastases who were pain‐free or mildly symptomatic for pain: a double‐blind,placebo‐controlled,randomized Phase II trial

Study Type – Therapy (RCT)
Level of Evidence 1b

OBJECTIVES

To report the final analysis of a Phase II trial, which investigated the safety and efficacy of the specific endothelin A receptor antagonist zibotentan (AstraZeneca, Macclesfield, UK) in patients with metastatic castration‐resistant prostate cancer (CRPC).

PATIENTS AND METHODS

Patients with CRPC and bone metastases who were pain free or mildly symptomatic for pain were randomized to receive once‐daily oral tablets of zibotentan 10 mg, 15 mg or placebo. The primary endpoint was the time to progression and secondary endpoints included overall survival, change in the number of bone metastases, and safety.

RESULTS

In total, 312 patients were randomized (placebo, n= 107; zibotentan 10 mg, n= 107; zibotentan 15 mg, n= 98). The median duration of study treatment and median follow‐up time were 4 and 22 months, respectively. At the final analysis, there were no statistical differences of the primary outcome of time to progression between treatment groups, although an improvement in overall survival was observed in the zibotentan groups compared to placebo. Consistent with the previous analyses for overall survival, hazard ratios (HRs) of less than one were sustained for both zibotentan 15 mg (HR, 0.76; 80% CI, 0.61–0.94; P= 0.103) and 10 mg (HR, 0.83; 80% CI, 0.67–1.02; P= 0.254). The most commonly reported adverse events considered to be related to zibotentan treatment were peripheral oedema, headache and nasal congestion.

CONCLUSIONS

The results obtained in the present study support endothelin A receptor antagonism as an approach for treating patients with CRPC. To confirm the survival signal observed in the present study, zibotentan is being investigated further in the ENdoTHelin A USE (ENTHUSE) Phase III clinical trial programme.     

Molecular modelling of the androgen receptor axis: rational basis for androgen receptor intervention in androgen-independent prostate cancer

Androgen depletion in combination with antiandrogenic agents is initially highly effective for treating prostate cancer, and is the recommended treatment for more advanced or higher-grade tumours. However, many tumours eventually become insensitive to androgens, even though the androgen receptor (AR) continues to be expressed. Computational chemistry combined with structural analysis of nuclear receptors and determination of binding affinities of natural and designed coregulators (coactivators and corepressors) provides the theoretical framework for the rational design of novel therapeutic agents directed at the AR. Adding alternative groups to various sites throughout the receptor can alter the conformation of the molecule and its functional binding with coactivators or corepressors. Possible molecules can be identified thoroughly and systematically using intelligent high-throughput screening and FASTrack chemistry (three-dimensional crystallography). Applying these techniques should eventually result in therapeutic agents for androgen-independent prostate cancer that can block binding of AR coactivators while simultaneously increasing binding of AR corepressors.     

恩杂鲁胺在晚期前列腺癌患者中的应用

通过搜索Pubmed以及ClinicalTrials.gov数据库,包括ASCO会议摘要,回顾恩杂鲁胺的前瞻性临床试验及其结果:恩杂鲁胺对于去势抵抗性前列腺癌是一种有效的口服药,在化疗前和化疗后患者中均生存期获益,毒性温和,并获得NICE最终指南推荐用于治疗多西他赛化疗后的转移性去势抵抗性前列腺癌(mCRPC)患者。本文就其有关方面情况作一综述。     

Key targets of hormonal treatment of prostate cancer. Part 1: the androgen receptor and steroidogenic pathways

OBJECTIVE

Knowledge of the molecular and cellular changes that occur during the transition of hormone‐naïve to castration‐resistant prostate cancer (CRPC) is increasing rapidly. This might provide a window of opportunity for (future) drug development, and for treating patients with these potential devastating states of disease. The objective of this review is to provide an understanding of the mechanisms that prostate cancer cells use to bypass androgen‐deprived conditions.

METHODS

We searched PubMed for experimental and clinical studies that describe the molecular changes that lead to CRPC.

RESULTS

CRPC remains dependent on a functional androgen receptor (AR), AR‐mediated processes, and on the availability of intraprostatic intracellular androgens. CRPCs might acquire different (molecular) mechanisms that enable them to use intracellular androgens more efficiently (AR amplification, AR protein overexpression, AR hypersensitivity), use alternative splice variants of the AR protein to mediate androgen‐independent AR functioning, and have altered co‐activator and co‐repressor gene and protein expression. Furthermore, CRPCs might have the ability to synthesise androgens de novo from available precursors through a renewed and up‐regulated synthesis of steroid‐hormone converting enzymes. Blocking of enzymes key to de novo androgen synthesis could be an alternative means to treat patients with advanced and/or metastatic disease.

CONCLUSION

In CRPC, prostate cancer cells still rely on intracellular androgens and on an active AR for growth and survival. CRPCs have gained mechanisms that enable them to use steroids from the circulation more efficiently through altered gene expression, and through a renewed and up‐regulated synthesis of steroid hormone‐converting enzymes. Additionally, CRPCs might synthesise AR isoforms that enable AR mediated processes independent from available androgens.     

New developments in the treatment of castration resistant prostate cancer

In the past 5 years, the treatment and understanding of metastatic castrate resistant prostate cancer （CRPC） have improved dramatically. Our understanding of the mechanisms of castration resistance has allowed for the development of new drugs to target prostate cancer, and our understanding of genetic mutations may give us new tools with which to more accurately diagnose and be able to predict the course of this heterogeneous disease. This article summarizes the recent advances in the understanding of the development of CRPC, as well as the new drugs and targets, which have evolved from this basic research.