optimizing the care of patients with advanced prostate cancer in the uk: current challenges and...

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What ’ s known on the subject? and What does the study add? Treatment options in the UK for men with metastatic castration-resistant prostate cancer (mCRPC) have been limited, and there is no standard approach, particularly in the second-line setting. The absence of a standard approach is further confounded by the differing defi nitions and terminologies still used in clinical practice to describe this group of patients (e.g. androgen-independent prostate cancer, hormone refractory prostate cancer, CRPC). With multiple new treatment options emerging, it will be critical to identify key considerations in our decision-making process and to establish an optimum, standardized approach to treatment so that new therapies can be assimilated into an mCRPC treatment algorithm and our routine clinical practice.

Most UK oncologists consider patients with advanced, symptomatic prostate cancer as eligible for chemotherapy, although a poor performance status, signifi cant co-morbid factors, advancing age, and the presence of asymptomatic disease with slowly rising prostate-specifi c antigen levels would prevent chemotherapy use. The decision to retreat with chemotherapy is largely driven by prior response to fi rst-line chemotherapy. Many UK oncologists feel that UK clinical practice is likely to change over the next 5 years, with abiraterone acetate, MDV3100 and cabazitaxel likely to have the most positive impacts in the treatment of mCRPC.

OBJECTIVES

• To evaluate the current management of patients with advanced prostate cancer by UK oncologists. • To gain insights into the future role of emerging therapies.

MATERIALS AND METHODS

• A semi-structured questionnaire was issued by the British Uro-oncology Group to society members during a closed meeting in September 2010. • Emerging therapies evaluated were: abiraterone acetate, afl ibercept, bevacizumab, cabazitaxel, custirsen, MDV3100, sipuleucel-T and zibotentan.

RESULTS

• Eighty of 98 (82%) surveys were completed. Responders had on average 189 new referrals, and treated 126 patients with advanced prostate cancer each year. • Chemotherapy was used by 86% of responders for patients with symptomatic metastatic castration-resistant prostate cancer (mCRPC), although poor performance status, advancing age and slowly rising prostate-specifi c antigen levels would prevent chemotherapy use.

The decision to retreat with chemotherapy was largely driven by prior response to fi rst-line chemotherapy, with docetaxel preferred for those responding. • Many (78%) felt that UK clinical practice was likely to change over the next 5 years, and that abiraterone acetate, MDV3100 and cabazitaxel would have the most positive impact. • Opinions regarding the future use of afl ibercept and custirsen were mixed. • Few ( ≤ 3%) would use zibotentan or bevacizumab in the future based on recent negative phase III study results, or because of cost and complexity for sipuleucel-T.

CONCLUSIONS

• Although emerging therapies for mCRPC mean that the future is bright, guidelines are needed to ensure optimum use and sequencing of treatments. • Additional costs and anticipated workload associated with new agents will require careful consideration.

KEYWORDS

metastatic castration-resistant prostate cancer , chemotherapy , abiraterone acetate , MDV3100 , cabazitaxel

Study Type – Therapy (quality control) Level of Evidence 4

Optimizing the care of patients with advanced prostate cancer in the UK: current challenges and future opportunities Heather Payne , Amit Bahl * , Malcolm Mason † , Janis Troup ‡ and Johann De Bono § University College Hospital London, London , * University Hospitals Bristol, Bristol , † Cardiff University Department of Oncology and Palliative Medicine, School of Medicine, Velindre Hospital, Cardiff , ‡ British Uro-oncology Group, London , and § Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Sutton, UK Accepted for publication 4 October 2011

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INTRODUCTION

Prostate cancers that are progressing despite castrate hormone levels (i.e. serum testosterone < 50 ng/dL or < 1.7 nmol/L) are considered castration resistant [ 1,2 ] . Unlike hormone refractory prostate cancers (HRPC), which are resistant to all hormonal measures, castration-resistant prostate cancers (CRPC) can remain hormone sensitive, and indeed may be super-sensitive to very low levels of androgen. As such, continued androgen deprivation with a luteinizing hormone releasing hormone (LHRH) agonist, the addition of antiandrogens (combined androgen blockade; CAB), or further hormonal manipulation with antiandrogen withdrawal, oestrogens or corticosteroids, may all be effective treatment strategies [ 1 ] .

For men with metastatic CRPC (mCRPC), cytotoxic therapy is a treatment option recommended in several guidelines based on the fi ndings from a phase III study which showed that chemotherapy with docetaxel plus prednisone was associated with improved survival, pain response and quality of life compared with mitoxantrone plus prednisone [ 3,4 ] , and this regimen is now a standard fi rst-line treatment option for this group of patients [ 1,5 ] .

The role of second-line chemotherapy is less clear. Docetaxel has shown some effi cacy for those men who have responded to fi rst-line docetaxel [ 1 ] , although there is no level 1 evidence to support this. Moreover, the benefi ts of other chemotherapeutic agents (including mitoxantrone plus prednisone, carboplatin plus etoposide, satraplatin, and pemetrexed) in this setting have been limited [ 6 – 9 ] . As such, the goal of treatment has remained symptom palliation to include analgesics, radiotherapy and bisphosphonates, with treatment choice often tailored to the individual patient [ 1,5 ] . Although some studies have also shown that bisphosphonates reduce the risk of skeletal-related events in men with mCRPC and bone metastases [ 10 – 16 ] , their effi cacy in this setting remains controversial.

Collectively, these data show that treatment options in the UK for men with mCRPC have been limited, and there is a lack of a standard approach, particularly in the second-line setting. Treatment decisions are often based on a patient ’ s response to

previous therapy, number and duration of previous therapies, and speed of progression. This absence of a standard approach is further confounded by the differing defi nitions and terminologies (i.e. androgen-independent prostate cancer [ AIPC ] , HRPC, CRPC) still used in clinical practice to describe this group of patients.

However, with several new agents ( Table 1 ) showing promising activity, the landscape of prostate cancer treatment in the UK is likely to undergo signifi cant change. With state-of-the-art therapies in late-stage clinical development, it is likely that the currently limited treatment options in the UK for men with mCPRC may soon be a thing of the past. However, as we are faced with the reality of an infl ux of multiple new treatment options, it will be critical to identify key considerations in our decision-making process and to establish an optimum, standardized approach to treatment so that new therapies can be assimilated into an mCRPC treatment algorithm and into our routine clinical practice.

Against this background, we conducted a survey among UK-based oncologists to evaluate current management strategies for patients with advanced prostate cancer, to identify key considerations in their decision-making process, and to gain insights into the possible role of emerging therapies in future UK clinical practice.

MATERIALS AND METHODS

A semi-structured questionnaire, comprising 16 questions, was issued by the British Uro-oncology Group (BUG) to society members (see Appendix 1 ), which were completed and returned to the BUG during a closed meeting of society members.

The questionnaire was compiled by the authors and was designed to evaluate current fi rst- and second-line treatment strategies in the UK for patients with advanced CRPC, and to identify key factors thought to infl uence the clinical decision-making process of the treating physician. The survey was also designed to solicit views on the potential impact of emerging state-of-the-art therapies on the clinical management of patients with CRPC over the next 5 years. Therapies included in this evaluation were selected by the authors as

those currently in late-stage clinical development that, in the event of positive phase III data, were likely to have the biggest impact on the management of CRPC in the UK. Therapies selected were: abiraterone acetate, afl ibercept, bevacizumab, cabazitaxel, custirsen, MDV3100, sipuleucel-T and zibotentan.

RESULTS

In September 2010, 98 surveys were distributed to UK-based oncologists and 80 (82%) were completed and returned to the BUG for evaluation. This survey comprised a similar number of participants to previously reported surveys [ 17 ] . The authors believe that the sample size included most prostate cancer oncologists in the UK and hence the fi ndings are of clinical relevance and refl ective of current practice of the management of advanced mCRPC. Initial questions, designed to establish the number of referrals and patients treated each year, showed that responding oncologists in the UK had an average of 189 new referrals for prostate cancer each year, with 24% reporting > 200 new referrals annually ( Fig. 1A ). Responding oncologists also

FIG. 1. ( A ) Number of new referrals for prostate cancer and ( B ) number of patients treated for advanced prostate cancer each year by UK oncologists.

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treated an average of 126 patients with advanced prostate cancer each year ( Fig. 1B ). More than half (55%) treated between 21 and 100 patients, 17% treated 101 – 250 patients, and 8% treated 251 – 1000 patients with advanced prostate cancer annually, suggesting that some of our responding oncologists are based

in specialized oncology units, that are associated with a high patient throughput.

Question 3 of the survey asked participants what defi nition they used (HRPC, CRPC, both, other) when referring to men with metastatic prostate cancer, and how they

would defi ne CRPC in clinical practice. Although almost half (45%) used the term CRPC, 33% referred to this patient group as HRPC, and 20% used both terms (2% did not respond). The defi nitions used for CRPC were wide-ranging, and included disease progression; disease progression after CAB, after orchidectomy and an LHRH agonist,

TABLE 1 Overview of key phase III studies of state-of-the-art therapies in metastatic castration-resistant prostate cancer

AgentPivotal phase III study

Prior docetaxel

Estimated enrolment

Primary endpoint Secondary endpoints

Outcome for primary effi cacy endpoint (where known)

Estimated completion date

Cabazitaxel + prednisone

TROPIC Yes 755 OS PFS, overall tumour response, TTP, time to PSA progression, PSA response, time to pain progression, pain response

2.4-month improvement in median OS vs mitoxantrone (HR 0.70; 95% CI 0.59 – 0.83, P < 0.001) [ 21 ]

September 2009NCT00417079

Sipuleucel-T IMPACT Yes * 512 OS Time to objective disease progression 4.1-month improvement in median OS vs placebo (HR 0.78; 95% CI 0.61 – 0.98, P = 0.030) [ 50 ]

January 2009NCT00065442

Afl ibercept + docetaxel/prednisone

VENICE No 1200 OS PSA, pain, SREs NA June 2012

NCT00519285

Bevacizumab + docetaxel/prednisone

CALGB 90401 No 1020 OS PFS, PSA PFS, proportion of patients with a 50% post-treatment PSA decline from baseline, toxicity

No improvement in OS December 2007NCT00110214 Median OS: 22.6 (CP + B) vs 21.5

(DP) months (HR 0.91; 95% CI 0.78 – 1.05, P = 0.181) [ 41 ]

Zibotentan + docetaxel

ENTHUSE M1C No 1445 OS PFS, tolerability, SREs, time to PSA progression, time to pain progression, pain response, HRQoL, PSA response

NA May 2011

NCT00617669

Zibotentan ENTHUSE M1 No 848 OS PFS, tolerability, time to opiate use, SREs, bone metastasis formation, HRQoL, time to PSA progression, time to pain progression, time to initiation of chemotherapy, PK

No signifi cant improvement in OS [ 36 ]

July 2010

NCT00554229

Abiraterone acetate + prednisone

COU-AA-301 Yes 1158 OS Proportion of patients achieving a PSA decline of ≥ 50% according to PSAWG criteria

3.9-month improvement in median OS vs placebo (HR 0.65; 95% CI 0.54 – 0.77, P < 0.001) [ 28 ]

June 2011

NCT00638690

Abiraterone acetate + prednisone

COU-AA-302 No 1000 OS, PFS – NA April 2011

NCT00887198

Custirsen + docetaxel/prednisone

NCT01083615 Yes 292 Proportion of patients with durable pain palliation

Time to pain progression, safety NA December 2012

Custirsen + docetaxel/prednisone

SYNERGY No 800 OS PFS at days 140 and 255, safety, PSA NA December 2013NCT01188187

MDV3100 AFFIRM Yes NA OS NA NA NA

NCT00974311

MDV3100 PREVAIL No 1680 OS and PFS SREs, time to initiation of cytotoxic chemotherapy

NA September 2014NCT01212991

* Prior chemotherapy was permitted, and 15.5% of the patients randomized to sipuleucel-T had received prior docetaxel. CI, confi dence interval; HR, hazard ratio; HRQoL, health-related quality of life; NA, not available; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetic; PSA, prostate-specifi c antigen; PSAWG, Prostate Specifi c Antigen Working Group; SRE, skeletal-related events; TTP, time to progression.

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after androgen deprivation therapy, or after all appropriate lines of hormone therapy, including steroids and diethylstilboestrol.

Questions 4 to 13 of the survey focused on assessing the use of chemotherapy for patients with advanced prostate cancer in the UK, and key factors infl uencing the oncologists ’ decision to treat with both fi rst-line and second-line chemotherapy.

On average, oncologists participating in the survey treated 28 patients with advanced prostate cancer with chemotherapy each year. For those who use chemotherapy, 90% advised that they would treat with docetaxel in the fi rst-line setting (other chemotherapy regimens used were mitoxantrone, 5-fl uorouracil [ 5-FU ] and cyclophosphamide). When asked which types of patients they would consider treating with chemotherapy in the fi rst-line setting, most (86%) considered those with advanced, symptomatic disease as eligible. However, fewer reported that they would use chemotherapy to treat asymptomatic patients with clinical progression (66%), radiological progression (49%) or PSA progression (34%) ( Fig. 2 ). Patients considered ineligible for chemotherapy included those with a poor performance status, signifi cant co-morbid factors, the elderly and asymptomatic patients with a slowly rising PSA level. Patient preference was also identifi ed as a key consideration.

In the second-line setting, participants treated an average of nine patients with advanced prostate cancer with chemotherapy each year; mitoxantrone was used by 48% of participants compared with 39% who used docetaxel. Other chemotherapy regimens used in this setting were 5-FU, cyclophosphamide and carboplatin/etoposide; chemotherapy as part of a clinical trial was also listed as an option. A previous response to docetaxel appeared to be a key factor infl uencing the decision to retreat with docetaxel in the second-line setting, whereas the decision to treat with mitoxantrone second-line was more common for patients who had not responded to fi rst-line docetaxel ( Fig. 3 ). Other factors infl uencing the oncologists ’ decision to treat with second-line chemotherapy were the presence of progressive symptoms (81%), tolerance of previous chemotherapy (77%), radiological progression (49%) and biochemical

progression (38%). The most important endpoints infl uencing the oncologists ’ choice of second-line chemotherapy agent were overall quality of life (63%), pain response (46%) and toxicity (40%) ( Fig. 4 ).

Patients that oncologists would consider ineligible for second-line chemotherapy were similar to those identifi ed in the fi rst-line setting. However, additional factors included a poor/no response to fi rst-line

FIG. 2. UK oncologists ’ views on the types of patients with advanced prostate cancer who should be treated with chemotherapy in the fi rst-line setting. CRPC, castration-resistant prostate cancer; PSA, prostate-specifi c antigen.

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FIG. 3. Infl uence of prior response to fi rst-line docetaxel on the oncologists ’ decisions to treat with second-line docetaxel or mitoxantrone for patients with advanced prostate cancer in the UK.

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FIG. 4. UK oncologists ’ views on the most important endpoints infl uencing the oncologists ’ choice of second-line chemotherapy agent. OS, overall survival; PFS, progression-free survival; PSA, prostate-specifi c antigen; QoL, quality of life.

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chemotherapy, and patients with rapid clinical deterioration and/or short life expectancy.

Questions 14 to 16 of the survey were designed to assess opinions regarding the likelihood of changes in clinical practice over the next 5 years for the treatment of advanced prostate cancer in the UK, and the impact that emerging state-of-the-art therapies were likely to have.

Most (78%) oncologists felt that their current clinical practice was likely to change over the next 5 years. When asked about the eight agents currently in late-stage clinical development, 71% felt that they were very likely to be using abiraterone acetate in their clinical practice within the next 5 years ( Fig. 5 ). Similarly, 31% felt that they were very likely to be using, and a further 35% felt that they would possibly be using, MDV3100 in their practice in the future. Both abiraterone acetate and MDV3100 were described as ‘ very promising ’ and likely to ‘ make a big impact ’ , with some survey responders indicating that their thoughts were based on their clinical trial experience of these two agents, as well as reports in the scientifi c literature.

Forty-four percent of oncologists felt that they were very likely to be using cabazitaxel in their clinical practice within the next 5 years, with a further 35% stating that this was a possibility. Reasons for this included prior approval of cabazitaxel, improvement in overall survival, and the fact that the effi cacy of cabazitaxel shown in the

second-line setting is superior to that seen for any of the currently available treatment options for patients with advanced mCRPC. However, cost and funding approval were listed as potential limiting factors for the future use of cabazitaxel, as well as abiraterone acetate and MDV3100.

Opinions regarding the future use of afl ibercept and custirsen were mixed. Although only 2% of survey responders felt that they were very likely to be using either of these agents in the next 5 years, 20% (afl ibercept) and 11% (custirsen) felt that they were unlikely to be using these agents, and a further 30% (afl ibercept) and 44% (custirsen) were undecided. Reasons behind this included their clinical trial experience (afl ibercept), and current lack of clinical evidence.

Despite its US licence, only 3% of oncologists felt that they would be likely to be using sipuleucel-T in their practice within the next 5 years; reasons for this included the complexity of the procedure and the high cost. In addition, only 2% of oncologists felt that they were likely to be using either zibotentan or bevacizumab in their practice within the next 5 years, with recent negative phase III study results listed as the reason for this.

DISCUSSION

Treatment options in the UK for men with mCRPC have historically been limited, and there is a lack of a standard approach that is further confounded by the differing

defi nitions and terminologies (i.e. AIPC, HRPC, CRPC) still used in clinical practice to describe this group of patients. However, as several new agents have now entered late-stage clinical development, it will be critical to ensure consistent use of accurate terminology and to identify key considerations in our decision-making process to establish an optimum and standardized approach to treatment so that these new therapies can be assimilated into an mCRPC treatment algorithm. As such, we conducted a survey of UK-based oncologists to assess current defi nitions and terminologies used in this setting, to evaluate current management strategies and key considerations, and to gain insights into the possible role of emerging therapies for the future treatment of mCRPC in UK clinical practice.

Findings from this survey indicate that the terminology currently used by UK oncologists to describe men with metastatic prostate cancer is inconsistent, with 45% using the term CRPC, 33% using HRPC and 20% of responders using both terms. The defi nitions used for CRPC were also broad ranging. As with any condition, it is important to have consistency and to ensure that the most accurate terminology is used to describe a specifi c group of patients. Accordingly, current European Association of Urology (EAU) guidelines state that CRPC should be used to describe those patients with progressive disease despite castrate hormonal levels and who may retain some sensitivity to hormonal manipulation, with HRPC reserved only for those patients who are truly resistant to all hormonal manipulation [ 1 ] . However, as prostate tumours are rarely totally androgen independent [ 18 ] , CRPC appears to be the most accurate term to describe this group of patients. It is therefore suggested that CRPC is used in this setting and that earlier terminologies are avoided because they may be misleading and could even result in patients being offered suboptimal therapy. It is also worth noting that although some currently available therapies still use the term mHRPC for their licensed indication, as this was the term used at the time of the study design, in modern parlance these agents should be considered for the treatment of men with mCRPC.

Regarding patient eligibility to receive fi rst-line chemotherapy for CRPC, fi ndings

FIG. 5. UK oncologists ’ views on the likelihood that they will be using currently emerging therapies in their clinical practice within the next 5 years.

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from our survey indicate that UK oncologists consider patients with advanced, symptomatic disease as eligible, and those with a poor performance status, signifi cant co-morbid factors, the elderly, or those with asymptomatic disease and a slowly rising PSA level as ineligible. These opinions are largely consistent with EAU guidelines, which recommend chemotherapy for patients with symptomatic advanced disease who are considered well enough to tolerate treatment, although there is no clear guidance regarding the optimum timing of treatment [ 1 ] . However, one notable difference is that, although EAU guidelines do not list advanced age as an ineligibility criterion for chemotherapy, our fi ndings suggest that many elderly patients with advanced prostate cancer in the UK do not receive chemotherapy, even with docetaxel, for which a signifi cant survival benefi t has been shown [ 3,4 ] . Moreover, as subgroup analyses have shown that the benefi ts of docetaxel [ 19 ] and cabazitaxel [ 20 ] are just as signifi cant in the elderly, the decision not to treat with chemotherapy based on age alone appears to be unwarranted. Interestingly, these fi ndings are also in contrast to the situation for advanced breast cancer, where oncologists are much more likely to administer chemotherapy, even with those regimens for which there is no proven overall survival benefi t. However, reasons behind these apparent differences in clinical practice are unclear.

Regarding the choice of chemotherapy, 44% of oncologists included in our survey felt that they were very likely to be using cabazitaxel in their clinical practice within the next 5 years, with a further 35% stating that this was a possibility. These fi ndings are unsurprising given the impressive phase III study data reported for this agent, which showed that treatment with cabazitaxel was associated with a signifi cant improvement in overall survival (hazard ratio [ HR ] 0.70, 95% confi dence interval [ CI ] 0.59 – 0.83, P < 0.001) and progression-free survival (HR 0.74, 95% CI 0.64 – 0.86, P < 0.001) compared with mitoxantrone in men with mCRPC whose disease had progressed during or after docetaxel-based therapy [ 21 ] . Moreover, as cabazitaxel is already licensed for mCRPC in the USA [ 20 ] and has received European Union licence approval [ 22 ] , it is very likely that cabazitaxel will become the standard second-line chemotherapy option in the UK for patients with mCRPC.

Other agents identifi ed in our survey as likely to have a big impact on UK clinical practice over the next 5 years were abiraterone acetate and MDV3100.

Abiraterone acetate is a non-steroidal ester that selectively and irreversibly inhibits both 17 α -hydroxylase and the C17,20-lyase function of CYP17A1, a cytochrome involved in the production of dehydroepiandrosterone and androstenedione (precursors of testosterone) [ 23 ] . Encouraging anti-tumour activity has been reported with abiraterone acetate at a dose of 1000 mg/day in various CRPC populations across several phase II studies [ 24 – 27 ] . More recently, fi ndings from a phase III study showed that abiraterone acetate plus low-dose prednisone signifi cantly improved overall survival (HR 0.65, 95% CI 0.54 – 0.77, P < 0.001), time to PSA progression (HR 0.58, 95% CI 0.46 – 0.73, P < 0.001), progression-free survival (HR 0.67, 95% CI 0.58 – 0.78, P < 0.001) and PSA response ( P < 0.001) compared with placebo in men with mCRPC who had progressed after docetaxel-based therapy [ 28 ] . Based on these data, abiraterone acetate recently received US Food and Drug Administration approval for use in combination with prednisone for the treatment of patients with mCRPC who have received prior chemotherapy containing docetaxel [ 29 ] . Abiraterone has now received a European License approval from the EMA [ 30 ] . In addition, a second phase III study of abiraterone acetate plus low-dose prednisone in chemotherapy-naive men with mCRPC is ongoing [ 31 ] . Hence, it is likely that, once available, there will be a signifi cant and rapid uptake in the use of abiraterone acetate in the UK, in patients who have previously received chemotherapy and pending licence approvals in the future, also in chemotherapy-naive patients.

Although MDV3100 is at a slightly earlier stage of clinical development compared with abiraterone acetate, available data are promising and suggest that this agent is also likely to have a signifi cant impact on UK clinical practice within the next 5 years. MDV3100 is an androgen receptor antagonist that lacks agonist activity and works by preventing nuclear translocation of the androgen receptor and its binding to DNA [ 23 ] . A phase I – II dose escalation study, conducted in 140 men with progressive mCRPC, showed that MDV3100 was well tolerated up to a dose of 240 mg, with

encouraging anti-tumour activity indicated [ 32 ] . As a result, MDV3100 at a dose of 160 mg/day is being evaluated in a phase III study in men with mCRPC who have previously received docetaxel-based therapy [ 33 ] . A second phase III study in chemotherapy-naive men with progressive mCRPC is also ongoing, with results anticipated in September 2014 [ 34 ] . However, there may be potential challenges in interpreting fi ndings from this study because of the possibility of the placebo arm crossing over to receive abiraterone acetate in the future.

Collectively, these data support the fi ndings from our survey and suggest that both abiraterone acetate and MDV3100 are likely to have a signifi cant impact on UK clinical practice within the next 5 years. However, given this likely infl ux of new agents for CRPC in the near future, it will be important that oncologists work closely with urologists to further study the optimal sequencing of all treatments for mCRPC patients. Indeed, further effi cacy and safety data from ongoing phase III studies of abiraterone acetate and MDV3100 will likely determine the extent of use of these agents and their position in the sequencing of therapies in the future, and will also help to establish which patients will be treated with these agents and which will receive docetaxel. It is also worth noting that, once available, these new therapies should be administered in dedicated uro-oncology clinics so that responses can be monitored accurately and the sequencing of these agents can continue to be monitored and optimized.

There was consensus among UK oncologists that the specifi c endothelin-A receptor antagonist, zibotentan, and the anti-vascular endothelial growth factor (VEGF) monoclonal antibody, bevacizumab, would not have an impact on the management of mCRPC in the future, with recent negative phase III study results identifi ed as the reason for this. Indeed, although fi ndings from a phase II study indicated that zibotentan is associated with improved overall survival (but not improved time-to-progression) compared with placebo in men with mCRPC [ 35,36 ] , fi ndings from a similar phase III study of zibotentan verses placebo failed to show a signifi cant improvement in the primary endpoint of overall survival in men with mCRPC [ 37 ] . Another phase III study


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has also recently been halted based on an early effi cacy review by the Independent Data Monitoring Committee while indicated that zibotentan was unlikely to meet its primary effi cacy endpoints (progression-free survival and overall survival) in men with non-metastatic CRPC [ 38 ] . A third phase III study of zibotentan in combination with docetaxel in chemotherapy-naive patients with mCRPC is still ongoing and results are expected later this year, but with two failed phase III studies, the future of zibotentan as a treatment option in CRPC appears bleak. Similarly, despite data from three phase II studies all suggesting that bevacizumab plus docetaxel is associated with encouraging anti-tumour activity in men with CRPC [ 39 – 41 ] , results from a recent phase III study of bevacizumab plus docetaxel and prednisone showed that the addition of bevacizumab did not improve overall survival in men with mCRPC and was associated with increased morbidity and mortality [ 42 ] .

There were mixed views among UK oncologists regarding the future roles of custirsen and afl ibercept for the treatment of CRPC.

Custirsen (OGX-011) is an antisensense oligonucleotide that inhibits clusterin, a chaperone protein that protects cells from apoptosis-inducing stressors, including cytotoxic chemotherapy, and also inhibits mitochondrial apoptosis [ 23 ] . A phase II randomized study showed that the addition of custirsen to docetaxel and prednisone was associated with improved overall survival and a favourable tolerability profi le in men with mCRPC [ 43 ] , and two phase III studies evaluating custirsen in combination with docetaxel and prednisone for the fi rst-line and second-line treatment of men with mCRPC are ongoing, with results anticipated in December 2013 and December 2012, respectively [ 44,45 ] . Thus, despite the encouraging phase II data reported to date, it is possible that the mixed opinions revealed in our survey are the result of the current lack of available evidence from phase III studies. Moreover, it is possible that the opinions of some UK oncologists may have been negatively infl uenced by the eventual outcomes of zibotentan and bevacizumab, both of which also reported positive phase II data and subsequent negative phase III study data.

Afl ibercept (VEGF trap) is a soluble fusion protein, comprising human VEGF receptor 1 (VEGFR1) and VEGFR2 extracellular domains fused to the Fc portion of human immunoglobulin 1 (IgG1), and functions as a decoy by binding to VEGF-A isoforms to prevent VEGF-induced angiogenesis [ 46 ] . Phase I/II studies have shown that 3-week cycles of afl ibercept 6 mg/kg in combination with docetaxel 75 mg/m 2 can be safely administered in patients with solid tumours [ 46,47 ] , and this regimen is being evaluated in a phase III, placebo-controlled study as a fi rst-line treatment for men with mCRPC [ 48 ] . Similar to custirsen, it is possible that the mixed views regarding the potential future role of afl ibercept in CRPC were affected by the observed outcomes of zibotentan and bevacizumab. Indeed, given that afl ibercept shares the same target as bevacizumab (VEGF), the negative overall survival results from the phase III bevacizumab study have probably dampened enthusiasm for this drug. The lack of clinical data in prostate cancer with afl ibercept (as phase I/II studies were in solid tumours) may also have contributed towards the negative opinion among some UK oncologists.

Finally, despite its US licence [ 49 ] , UK oncologists felt that sipuleucel-T would not have an impact on prostate cancer management in the UK in the next 5 years. Sipuleucel-T is a dendritic cell-based vaccine designed to stimulate the patient ’ s own immune system to target cancer cells. Peripheral blood mononuclear cells are induced ex vivo to turn into antigen-presenting cells, which are pulsed with PA2024, a recombinant fusion protein that contains prostate antigen, prostatic acid phosphatase and granulocyte – macrophage colony-stimulating factor. The effi cacy of sipuleucel-T has been shown in three phase III studies [ 50 – 52 ] . In the pivotal Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) study, conducted in 512 men with asymptomatic or minimally symptomatic mCRPC, sipuleucel-T was associated with a reduction in the risk of death by 22% and an improvement in median overall survival of 4.1 month vs placebo [ 51 ] . Based on these data, sipuleucel-T is indicated for the treatment of asymptomatic or minimally symptomatic mCRPC in the USA [ 49 ] , but European Union approval is not expected until 2013 [ 53 ] . The known high cost

($93 000 for a full course of treatment; $31 000 per infusion) [ 54 ] and the complexity of sipuleucel-T administration were identifi ed as the main reasons why UK oncologists felt that they would not be using this agent within the next 5 years. However, if the costs were to fall, this would be an attractive drug because it has low toxicity. Despite these drawbacks, the results obtained with sipuleucel-T represent an encouraging advance for the potential role of immunotherapy in prostate cancer in general, and clinicians need to embrace this concept as an advance in the management of mCRPC. Indeed, there are many other immunotherapy agents currently under clinical evaluation, including ProstVac, ipilumumab, and anti-PD1 antibody, and results from these trials are awaited with considerable interest.

Collectively, fi ndings from our survey together with currently available scientifi c evidence suggest that the forthcoming introduction of novel therapies for mCRPC will have a positive impact on the future management of our patients. However, our fi ndings also reinforce the need for clear guidelines to ensure best use and sequencing of treatments to optimize outcomes. In addition, the higher costs and anticipated increase in workload associated with the use of these new agents will require careful consideration.

ACKNOWLEDGEMENTS

Sanofi Aventis provided an educational grant towards the costs associated with the implementation of this survey. Sanofi Aventis had no infl uence over the content or fi ndings from the survey or the content of this manuscript. Angela Corstorphine of Kstorfi n Medical Communications Ltd provided medical writing support with the preparation of this manuscript. This support was funded by the British Uro-oncology Group. Heather Payne ’ s work was supported by the UCLH/UCL Comprehensive Biomedical Research Centre.

CONFLICT OF INTEREST

Heather Payne has attended and received honorarium for advisory boards and served as a consultant for Astra Zeneca, Janssen, Johnson and Johnson, Sanofi Aventis, Ferring and Novartis. Amit Bahl has

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attended and received honorarium for advisory boards for Janssen, Johnson and Johnson and Sanofi -Aventis. Malcolm Mason has attended and received honorarium for advisory boards for abiraterone and cabazitaxel. Johann de Bono was the Chief Investigator of the abiraterone acetate and cabazitaxel phase III trials and has served as a consultant for multiple organizations including Cougar, Johnson & Johnson, sanofi -aventis, Medivation, Astellas, Dendreon, Pfi zer, Novartis, GSK and AstraZeneca. He is a paid employee of The Institute of Cancer Research, which has a commercial interest in abiraterone acetate.

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Correspondence: Heather Payne, Consultant in Clinical Oncology, University College Hospital London, First Floor Central, 250 Euston Road, London NW1 2PG, UK. e-mail: [email protected]

Abbreviations : 5-FU , 5-fl uorouracil ; AIPC , androgen-independent prostate cancer ; BUG , British Uro-oncology Group ; CAB , combined androgen blockade ; CI , confi dence interval ; EAU , European Association of Urology ; HR , hazard ratio ; HRPC , hormone

refractory prostate cancer ; IgG1 , immunoglobulin 1 ; LHRH , luteinizing hormone releasing hormone ; mCRPC , metastatic castration-resistant prostate cancer ; VEGF , vascular endothelial growth factor.

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