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Keywords:

  • prostate cancer;
  • chemotherapy;
  • urogenital malignancy

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NEW AND EMERGING TREATMENT OPTIONS
  5. CLINICAL ISSUES
  6. CONCLUSION
  7. ACKNOWLEDGEMENT
  8. CONFLICT OF INTEREST
  9. REFERENCES

What's known on the subject? and What does the study add?

Metastatic castrate-resistant prostate cancer (mCRPC) was historically considered to be an aggressive disease resistant to conventional anticancer therapy. Within the last decade the outlook has changed beyond recognition; docetaxel chemotherapy is now firmly established as a well-tolerated treatment with significant survival benefits. Building on this, more recently there have been several landmark developments using various approaches in patients whose disease has progressed despite previous chemotherapy. Cabazitaxel chemotherapy offers survival and health-related quality of life (HRQL) improvements in this setting, as does the CYP inhibitor abiraterone acetate. Significant clinical benefits are also seen with novel radioisotope and immunotherapeutic approaches.

There have been many developments in the management of this condition within the last 2 years, with several landmark studies showing new treatments that offer survival and HRQL benefits even in the setting of advanced disease, which has been heavily pretreated. This review article summarises these important developments and gives the reader an overview of current practice, recent changes and future directions.

  • • 
    With current and forthcoming developments in the treatment of metastatic castrate-resistant prostate cancer (mCRPC) post-docetaxel, we are embarking on an age of potential ‘chronic’ management of this disease.
  • • 
    It is hoped that the survival benefits associated with the various treatments, cytotoxic, hormonal and immunotherapeutic, will prove to be additive, providing a multimodal continuum of care. If so, it will be necessary to determine the optimal sequence and timing of the new treatments.
  • • 
    One key factor in this regard is likely to be the patient's performance status and hence his eligibility for cytotoxic intervention. If chemotherapy is offered early in the post-docetaxel pathway, the patient may still be able to benefit from non-chemotherapeutic options subsequently. However, if this stage of management begins with a non-chemotherapeutic option, there is a risk that the patient's performance status will decline before he has an opportunity to benefit from chemotherapy.
  • • 
    Further studies and ongoing clinical experience are likely to clarify this important issue, and help clinicians to maximise the survival of men with mCRPC post-docetaxel.

Abbreviations
mCRPC

metastatic castrate-resistant prostate cancer

HRQL

health-related quality of life

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NEW AND EMERGING TREATMENT OPTIONS
  5. CLINICAL ISSUES
  6. CONCLUSION
  7. ACKNOWLEDGEMENT
  8. CONFLICT OF INTEREST
  9. REFERENCES

Prostate cancer is the most common male cancer in the UK [1]. However, it still remains a relatively low-profile disease in terms of media coverage and political engagement, compared, for example, with breast cancer. There is no national screening programme, and, until recently, the prognosis for men with metastatic castrate-resistant prostate cancer (mCRPC) was gloomy. While there is still little prospect of population screening on the near horizon in the UK, there is an ongoing transformation in the outlook for long-term management of metastatic prostate cancer. The first step took place in 2004, when Tannock et al. [2] showed that, contrary to decades of previous experience, prostate cancer is a chemo-sensitive disease. The trialists reported that men with metastatic disease that had progressed to become refractory to standard hormone treatment (i.e. mCRPC), could obtain a survival benefit, as well as improvement in health-related quality of life (HRQL), from docetaxel-based chemotherapy [2,3]. These findings changed the paradigm of mCRPC management [4,5]. Not only could survival be improved after a diagnosis of mCRPC, but a patient population previously managed almost exclusively under the auspices of urology was seen to warrant referral to oncology.

For several years, docetaxel-based chemotherapy remained the last bastion of survival-enhancing treatment for mCRPC. Then, in 2010, new treatments emerged from phase III trials, each showing further improvement in survival in men who had progressed after or during docetaxel therapy [6,7]. The treatments in question are from entirely different pharmaceutical classes, one being a chemotherapy agent (cabazitaxel) and the other a novel hormonal intervention (abiraterone). Various other agents showing promise in mCRPC are also being researched, with modes of action that include androgen-receptor antagonism [8] and immunotherapy [9,10].

This expanding array of active therapies, for what was once a poor prognosis cancer, will raise several important questions for patients, healthcare professionals and healthcare commissioners. Given the diverging range of potential treatment mechanisms, it will be essential to consider the best ways of sequencing or combining the various options to maximise the survival and HRQL benefits for patients. New treatment pathways will have to be developed, with an emphasis on timely referral and good communication between the different members of the multidisciplinary team, and between primary and secondary care. Patients who would once have been candidates for only palliative care look likely to enter a period of ‘chronic’ disease management, and hence may face associated survivorship issues [11]. New treatments can be expected to have implications for healthcare spending in the next few years. Also, after so many years of relative absence from the media, we may see greater public debate over prostate cancer and its optimal management.

NEW AND EMERGING TREATMENT OPTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NEW AND EMERGING TREATMENT OPTIONS
  5. CLINICAL ISSUES
  6. CONCLUSION
  7. ACKNOWLEDGEMENT
  8. CONFLICT OF INTEREST
  9. REFERENCES

CHEMOTHERAPY AGENTS

The first treatment to obtain European and USA licences for use in mCRPC that progressed post-docetaxel was cabazitaxel, after the publication of findings from the international phase III TROPIC trial, showing that it improved overall survival vs mitoxantrone (both used combined with prednisone; Fig. 1) [6]. Further analysis showed that the benefit of cabazitaxel over mitoxantrone was maintained across a variety of pre-planned patient subgroups, including those who had previously been heavily treated with docetaxel (Fig. 2) [6].

image

Figure 1. Kaplan–Meier estimates of the probability of survival in patients treated with cabazitaxel plus prednisone, or mitoxantrone plus prednisone [6].

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image

Figure 2. Intention-to-treat analysis of overall survival in pre-planned subgroups [6].

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The clinically significant side-effects of cabazitaxel included febrile neutropenia (8%), grade 3+ diarrhoea (47%), nausea (34%) and vomiting (23%). There were seven neutropenic deaths in cabazitaxel recipients, compared with one in the mitoxantrone group [6]. However, no neutropenic deaths were reported after a trial protocol amendment requiring use of granulocyte colony-stimulating factor (G-CSF) plus cabazitaxel dose reduction where judged appropriate [12]. It has also been pointed out that variation in the pattern of febrile neutropenia management across the countries involved in the trial may have had a bearing on the neutropenic deaths before the protocol amendment [13,14]. It is recommended, therefore, that the management of patients receiving cabazitaxel includes a strategy of appropriate preventive and supportive patient care [13–15]. Patient selection is also an important issue, with pre-treatment performance status being a key factor.

Of note, although cabazitaxel is, like docetaxel, a member of the taxane family, it does not exhibit the taxane resistance seen with others in this class, and is effective in cells lines resistant to paclitaxel and docetaxel [16–18].

So far, cabazitaxel remains the only chemotherapy agent to benefit survival in mCRPC post-docetaxel. Data on its effects on HRQL is likely to be published in due course, after the completion of an international expanded-access programme in late 2011.

After preliminary evidence that some patients remain sensitive to docetaxel after completion of the recommended 10-cycle docetaxel course, there has been some interest in further use of this agent in the second-line chemotherapy setting [19]. However, given the well documented problem of taxane resistance [19], and lack of evidence about this strategy from any robust randomised controlled trial, there is a risk that patients will simply endure the side-effects of further docetaxel without reaping any survival benefit. Furthermore, while time is spent on such an unproven strategy, the opportunity to try evidence-based treatments is likely to be delayed, or even missed altogether.

A phase III, placebo-controlled trial of satraplatin in the second-line setting has shown no difference in overall survival [20], and there is no evidence that mitoxantrone produces a survival benefit in mCRPC. However, there have been some encouraging results from phase II trials of two epothilone agents, ixabepilone [21] and patupilone [22], in patients with mCRPC who have received docetaxel and further data on these agents and others in their class is awaited with interest.

HORMONAL AGENTS

Despite being classified as castrate-resistant, there is evidence that men with mCRPC may retain active androgen receptor-dependent signalling pathways, suggesting a potential hormonal target for ongoing therapy [23]. Abiraterone, an inhibitor of androgen production, is one such candidate. The international, phase III COU-AA-301 study reported in 2010 that abiraterone improves overall survival (vs placebo) in mCRPC that progresses post-docetaxel (Fig. 3) [7]. Abiraterone is currently undergoing another phase III trial (COU-AA-302) to investigate its efficacy in chemotherapy-naive patients. The common side-effects of abiraterone include fatigue (44% of patients), fluid retention (31%) and hypokalaemia (17%).

image

Figure 3. Kaplan–Meier estimates of overall survival for abiraterone vs placebo [7].

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Phase III data are also awaited on the activity of an androgen receptor antagonist currently named MDV3100 [8], which is under investigation in men who have already received chemotherapy and in the pre-chemotherapy setting. Ketoconazole, another inhibitor of androgen production, has shown efficacy against advanced prostate cancer [24,25], although it has a more unfavourable side-effect profile, and there may be a continuing role for corticosteroids and oestrogens in mCRPC post-docetaxel.

IMMUNOTHERAPY

Tumour-targeted immunotherapy is attracting research interest across various cancers. The sipuleucel-T vaccine is licensed in the USA for the treatment of mCRPC in men with no or minimal symptoms. A phase III trial of sipuleucel-T in men with CRPC (15.5% of whom had previously received docetaxel) has shown a survival advantage for the vaccine vs placebo [9]. The antitumour antigen, Ipilimumab, has shown efficacy in prostate cancer in a phase II trial [10], and is under phase III investigation in men with mCRPC after docetaxel.

CLUSTERIN TARGETING

It has been shown that when custirsen, an antisense oligonucleotide that inhibits production of the cell-survival protein clusterin, is added to docetaxel therapy, it improves survival compared with docetaxel alone [26]. The effect is now being investigated in a phase III study in the post-docetaxel setting.

OTHER APPROACHES

There are preliminary data on the use of tyrosine kinase inhibition [26–27] and poly(ADP-ribose) polymerase (PARP) inhibition [28] in advanced prostate cancer. Of note, the phase III SUN trial of sunitinib in mCRPC was stopped by the Independent Data Monitoring Committee, and data presented to the American Society of Clinical Oncology in 2011 showed no survival benefit.

CLINICAL ISSUES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NEW AND EMERGING TREATMENT OPTIONS
  5. CLINICAL ISSUES
  6. CONCLUSION
  7. ACKNOWLEDGEMENT
  8. CONFLICT OF INTEREST
  9. REFERENCES

TREATMENT SEQUENCING

Even if only a handful of the agents currently under investigation are successful in the management of mCRPC in the post-docetaxel setting, clinicians and patients will face a new challenge, i.e. how to make best use of the full range of active treatments in a context where palliation and support were previously the only management options. Guidance on the optimal use of such agents may well emerge from future research. Meanwhile, it will be important to consider the question from the point of view of each individual patient.

Initially at least, the post-docetaxel treatment pathway is likely to include cabazitaxel and abiraterone. These two agents have very different modes of action and side-effect profiles, and there is no reason to assume that a given patient can receive only one or the other. If, as is hoped, patients are able to accrue the survival benefits of both cabazitaxel and abiraterone, either fully or in part, the priority may be to ensure that as many as possible do in fact have the opportunity to use both agents. In this setting, the side-effect profile may prove to be a key factor. As a cytotoxic agent, cabazitaxel is likely to be better tolerated by patients with a good performance status, than by those whose condition has deteriorated. Abiraterone, with its more favourable toxicity profile, is likely to remain appropriate for use as performance status declines. It has already been argued in the literature that patients who are judged on assessment to be fit to receive chemotherapy, and are ready and willing to do so, should probably commence their second-line management with cabazitaxel, leaving the abiraterone step available for use subsequently [29]. As other agents enter the clinical arena, men with mCRPC may be candidates for a continuum of active management, based on the characteristics of their disease and their underlying fitness.

Whatever the order of use of current and forthcoming treatments, careful management of side effects, and appropriate education and support of patients in this regard, will also be a key facet of continuing care.

EFFECTIVE REFERRAL

To benefit from the current and forthcoming range of second-line treatments for mCRPC, it will be essential to ensure that patients move along the therapeutic pathway in a timely fashion, starting with the delivery of first-line chemotherapy. If there is delay in referral to oncology for consideration of docetaxel, there is a risk that the patient's condition may decline before he can receive further treatment options including cytotoxic interventions, e.g. cabazitaxel, and the continuum of care for this individual will therefore be shortened.

Similarly, there will be a need for close monitoring of patients during and after docetaxel chemotherapy to ensure that the early signs of disease progression are detected, possibly before the patient declines clinically. In areas where local protocol requires the return of patients to primary care management after first-line docetaxel, it will be particularly important to ensure good systems are in place for patient monitoring and timely referral back to oncology.

Sharing of information and treatment pathways between primary and secondary care and within the multidisciplinary team will be fundamental to the effective ongoing management of mCRPC. There is likely to be a need for education and support for patients, explaining the survival implications of a multimodal continuum of care. A chronic disease management strategy for mCRPC will also require careful consideration at commissioning level.

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NEW AND EMERGING TREATMENT OPTIONS
  5. CLINICAL ISSUES
  6. CONCLUSION
  7. ACKNOWLEDGEMENT
  8. CONFLICT OF INTEREST
  9. REFERENCES

mCRPC, once a disease of poor prognosis and low public/political profile, is moving into a new age of active management, with an array of recently developed and emerging novel therapies offering a potential survival benefit post-docetaxel. It is hoped that patients will eventually have access to a multimodal continuum of care, conferring additive survival benefits. In the short term, the challenge will be how to obtain the maximum benefit from two agents, cabazitaxel and abiraterone, which differ widely in their mode of action and side-effect profile.

The optimal treatment sequence will be one key consideration. In practice, cytotoxic agents, e.g. cabazitaxel, may warrant an early introduction into the treatment pathway, at a time when the patient is sufficiently fit and well to cope with the side-effects of this approach. If interventions with a gentler side-effect profile, e.g. abiraterone, are used first, it will be very important to ensure that patients who are showing signs/symptoms of disease progression are offered the option of chemotherapy before their performance status has deteriorated to a point where chemotherapy would not be a feasible option.

Another key issue will be timely referral, both within the multidisciplinary team and between primary and secondary care. The emphasis on timeliness will begin with referral for first-line docetaxel, with a long-term view to maximising the patient's chance of receiving all/most of the array of treatments available further along the pathway.

Looking forward, prostate cancer looks set to be a disease with multiple treatment options offering a chronic style of disease management, comparable to that seen in breast cancer.

ACKNOWLEDGEMENT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NEW AND EMERGING TREATMENT OPTIONS
  5. CLINICAL ISSUES
  6. CONCLUSION
  7. ACKNOWLEDGEMENT
  8. CONFLICT OF INTEREST
  9. REFERENCES

Editorial support in the preparation of this manuscript was provided by Succinct Healthcare Communications, and funded by Sanofi. All opinions expressed are those of the author, and Sanofi had no input into or influence over the content of the article.

CONFLICT OF INTEREST

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NEW AND EMERGING TREATMENT OPTIONS
  5. CLINICAL ISSUES
  6. CONCLUSION
  7. ACKNOWLEDGEMENT
  8. CONFLICT OF INTEREST
  9. REFERENCES

Susan Masson has received honoraria from Sanofi. Amit Bahl has served on advisory boards for Sanofi, Novartis, Amgen and Janssen.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NEW AND EMERGING TREATMENT OPTIONS
  5. CLINICAL ISSUES
  6. CONCLUSION
  7. ACKNOWLEDGEMENT
  8. CONFLICT OF INTEREST
  9. REFERENCES