Stakeholder Insight Prostate Cancer Hormonerefractory patients still waiting for treatment breakthroughs

CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of the analysis 3
Datamonitor insight into the prostate cancer market 3
Contributing experts 5
Related reports 5
Upcoming reports 5
CHAPTER 2 INTRODUCTION AND SCOPE 8
Introduction 8
Coverage of the Stakeholder Insight Survey 8
Disease definition and epidemiology 8
Patient segmentation 8
Drug therapy for prostate cancer 8
Recurrent prostate cancer 9
Hormone-refractory prostate cancer 9
Pipeline products for hormone-refractory prostate cancer 9
CHAPTER 3 COUNTRY TREATMENT TREES 11
Introduction 11
Country treatment trees 12
US 12
Japan 16
France 20
Germany 24
Italy 28
Spain 32
UK 36
CHAPTER 4 DISEASE DEFINITION AND EPIDEMIOLOGY 40
Definition of prostate cancer 40
Prostate cancer 40
The most common cancer type and second leading cause of cancer-related death in males 40
Histology 40
The majority of prostate tumors are adenocarcinomas 40
Risk factors 41
Older age 41
Race 41
Family history 42
Hormones 42
Dietary factors 42
Symptoms 43
Symptoms frequently occur only at an advanced stage of prostate cancer 43
Screening and diagnosis 43
Measurement of PSA has proved fairly useful in the detection of prostate cancer, however, several issues need to be resolved 43
A widespread screening program exists in the US... 44
...however, in Europe, results from the ERSPC trial are necessary before screening programs can be considered 44
Though PSA screening has been shown useful in Japan, the practice is not widespread 44
Staging 45
Prostate cancer is staged using the TNM system and a histologically-based Gleason score 45
Epidemiology of prostate cancer 46
Incidence of prostate cancer 46
Prostate cancer is a tumor associated with older men, therefore incidence is rising in line with the ageing population 46
Mortality from prostate cancer 47
Potentially asymptomatic disease and a high rate of fatality from co-morbidities mean mortality from prostate cancer is not especially high 47
Prevalence of prostate cancer 49
Prevalence is high given the tendency for early diagnosis and low mortality 49
CHAPTER 5 PATIENT SEGMENTATION 51
Introduction 51
Staging of prostate cancer 51
Staging at diagnosis 51
Around half of all prostate cancer cases are diagnosed at a localized stage 51
Staging at the time of survey 53
A greater proportion have advanced-stage prostate cancer if patients at the time of survey are examined 53
One-quarter of all prostate cancer patients have hormone-refractory disease 55
Differences in staging 55
Urologists encounter more early-stage patients, while medical oncologists typically treat advanced disease... 55
...however, the difference is minimal in Japan due to its structure of medical practice 59
CHAPTER 6 INITIAL DRUG THERAPY FOR PROSTATE CANCER 60
Introduction 60
Overview of initial therapy for prostate cancer 60
Localized prostate cancer patients can undergo watchful waiting or radical prostatectomy 60
Initial treatment of locally advanced and metastatic prostate cancer constitutes androgen deprivation therapy 61
Initial treatment of prostate cancer 62
Initial use of drug therapy 62
As expected, use of initial drug therapy increases with an advancing stage of prostate cancer 64
However, a higher than expected proportion of localized stage patients appear to receive drug therapy 64
A lower proportion than average of locally advanced and metastatic prostate cancer patients receive initial drug therapy in the US 65
Specific initial drug therapy of prostate cancer 66
Across all stages of prostate cancer 66
LHRH agonist monotherapy and total androgen blockade are the favored drug regimens used in the initial treatment of prostate cancer 66
Localized prostate cancer 68
LHRH agonist monotherapy is generally sufficient given that an aggressive approach is not needed while the tumor is localized... 69
...however, in Spain and Japan, total androgen blockade is the favored initial treatment approach for localized prostate cancer 69
Anti-androgen monotherapy is the third most frequently used drug regimen for localized tumors due to its lower efficacy than medical castration 70
Use of cytotoxics with or without antihormonal therapy is very low in the initial treatment of localized prostate cancer 70
Locally advanced prostate cancer 72
On average, similar trends are seen in the initial treatment of locally advanced prostate cancer as for localized 73
More locally advanced patients receive TAB than localized patients, at the expense of use of anti-androgen monotherapy 74
Use of cytotoxics with or without antihormonal therapy is still low 74
Advanced prostate cancer 74
On average, the majority of advanced prostate cancer patients appear to receive the more aggressive total androgen blockade regimen as initial treatment, although this observation is deceptive 75
More advanced disease which may require more aggressive treatment means the combination of cytotoxics and antihormonal therapy is the third preferred initial regimen 76
Use of cytotoxics in the initial treatment of prostate cancer is relatively high across all stages in Germany 78
LHRH agonist monotherapy 78
Use of anti-androgens to counter testosterone flare 78
Use of anti-androgens to prevent testosterone flare from LHRH agonists increases with a more advanced stage of prostate cancer 78
Use of temporary anti-androgen therapy is, surprisingly, lowest in the US and Germany, and highest in the UK 80
Use of specific LHRH agonists as monotherapy 83
Leuprolide is the favored LHRH agonist for use as monotherapy across all stages of prostate cancer due to its availability in a variety of depot formulations 83
Goserelin is the second preferred LHRH agonist monotherapy across all stages of prostate cancer 85
Use of the various LHRH agonists varies greatly between countries, with use of leuprolide highest in the US and use of goserelin highest in the UK 85
Anti-androgen monotherapy 89
Use of specific anti-androgens as monotherapy 89
Bicalutamide, in varying dosing formulations, is the leading anti-androgen for use as monotherapy across all stage of prostate cancer 89
Despite being the only branded product in a heavily genericized market, Casodex (bicalutamide) remains the leader due to a number of advantages over its competition 91
Casodex is by far the preferred anti-androgen for use as monotherapy in each of the seven major pharmaceutical markets 91
Casodex 150mg has had a tumultuous regulatory pathway to date 94
The EPC trial showed that 150mg Casodex daily is suitable for treatment of locally advanced prostate cancer, but not localized disease 94
Casodex 150mg is still used in localized prostate cancer, according to surveyed physicians 95
In Japan, only 80mg Casodex is available, while in the US, only 50mg Casodex is available 95
In the EU, use of Casodex is more fragmented between the 50mg and 150mg formulations 95
Use of flutamide is highest in the US 96
Use of cyproterone and nilutamide are highest in the EU 96
Total androgen blockade 97
Use of specific total androgen blockade regimens 97
A combination of leuprolide and bicalutamide is the top TAB regimen across all stages of prostate cancer 97
No specific recommendations for TAB regimen are made, therefore the choice of agents is most likely due to physician preference or cost 98
In the US and Japan, the top three TAB regimens do not vary by stage, with the leading combination constituting leuprolide and bicalutamide 99
More variation is seen in the top three TAB regimens used in each of the five European countries, although leuprolide or goserelin with bicalutamide still emerge as the first or second preferred regimen in all markets 101
Use of specific formulations of LHRH agonists 107
Use of specific formulations as monotherapy or as part of combination regimens 107
On average across the seven major markets, the three-month depot version of leuprolide is the leading formulation of LHRH agonist 107
Three-month goserelin emerges as the second preferred formulation of LHRH agonist 108
Three-month formulations of LHRH agonist are deemed to offer the most convenience and flexibility to patients 109
In the US, use of alternative leuprolide formulations is favored 110
Triptorelin and buserelin formulations appear in the top three preferred LHRH agonist formulations only in four of the EU countries 110
CHAPTER 7 RECURRENT PROSTATE CANCER 111
Introduction 111
Overview of therapy for recurrent prostate cancer 111
Treatment of recurrent prostate cancer typically involves further lines of antihormonal therapy 111
Remission rates 112
Remission rates by stage of disease 112
Remission rates are surprisingly high in the more advanced stages of prostate cancer, indicating that systemic therapy may offer sufficient disease control 112
High use of TAB to treat localized disease in Japan may result in a significantly higher remission rate in these patients 114
Duration of remission 114
Duration of remission is longest in localized prostate cancer patients and shortest in advanced patients 114
A high proportion of localized patients are initially treated with drug therapy in Spain, thereby resulting in a higher duration of remission 116
Relapse rates 116
Patients who relapse following remission 116
As expected, relapse rates are highest among advanced prostate cancer patients and lowest in localized disease 116
Highest relapse rates in Spain, albeit for no apparent reason 117
Stage of disease present at relapse 118
Due to enhanced detection of rising PSA levels, relapsed disease can be identified while still at a localized stage 118
Hormone-refractory disease at relapse 120
Patients with more advanced disease may have more aggressive tumors, potentially placing them at a higher risk of developing hormone-refractory disease more quickly at relapse 120
Drug therapy for recurrent prostate cancer 122
Use of drug therapy for relapse 122
The majority of prostate cancer patients who relapse go on to receive further antihormonal and/or cytotoxic therapy 122
Surprisingly, drug therapy for relapsed disease is highest in the Japan and lowest in the US 123
Specific drug regimens used to treat recurrent prostate cancer 124
Drug therapy following LHRH agonist monotherapy 124
In accordance with treatment guidelines, the majority of patients receive TAB for relapsed disease after undergoing LHRH agonist monotherapy as initial therapy 124
Cytotoxic-based regimens are the second preference after LHRH agonist monotherapy, most likely for those patients with HRPC at relapse 125
Third choice varies between anti-androgen monotherapy or LHRH agonist monotherapy depending on the country 126
Drug therapy following anti-androgen monotherapy 126
TAB appears the favored regimen to follow initial anti-androgen monotherapy 126
On average, LHRH agonist monotherapy appears the second preferred treatment approach following initial anti-androgen monotherapy, although in some countries use is equivalent to that of cytotoxic-based regimens 128
The seven-market average dictates that cytotoxic-based regimens are the third preferred treatment option following initial anti-androgen monotherapy 129
Anti-androgen monotherapy in both the initial and second-line treatment settings has been clinically proven to offer few benefits 129
Drug therapy following total androgen blockade 130
Cytotoxic-based regimens are administered to the majority of patients who receive initial therapy with TAB 130
Continued TAB appears to be the second most popular approach following initial TAB therapy, possibly as part of an intermittent dosing regimen 131
On average, the third favored approach following initial TAB is LHRH agonist monotherapy, although significant differences occur between individual countries 132
Drug therapy following cytotoxic-based regimens with or without antihormonal therapy 133
Cytotoxic-based regimens are not typically used as initial therapy, therefore second-line treatment is highly fragmented between countries 133
CHAPTER 8 HORMONE-REFRACTORY PROSTATE CANCER 135
Introduction 135
Overview of therapy for hormone-refractory prostate cancer 135
Taxotere-based chemotherapy forms the first-line standard of care for HRPC patients 135
Bisphosphonates can be used to prevent the formation of bone metastases and to alleviate bone pain 136
Optimal second-line therapy for HRPC is yet to be defined 136
Progression to hormone-refractory prostate cancer 137
Patients who progress to hormone-refractory prostate cancer 137
Patients diagnosed with advanced prostate cancer are more likely to progress to HRPC than earlier-stage patients 137
Duration of antihormonal therapy prior to progression to HRPC 138
Localized patients undergo a longer duration of hormonal therapy prior to development of HRPC, while advanced patients progress more quickly 138
Drug therapy for hormone-refractory prostate cancer 140
Use of drug therapy for HRPC 140
Given the aggressive nature of HRPC, approximately three-quarters of patients receive drug therapy as treatment 140
Highest use of initial drug therapy for HRPC seen in Japan, lowest use seen in the US 142
First-line drug therapy 142
First-line drug regimens used to treat HRPC 142
Taxotere-based chemotherapy regimens are used heavily across all seven major pharmaceutical markets in the first-line treatment of HRPC 142
The leading seven-market first-line regimen is Taxotere and prednisone, which is expected given that this combination has regulatory approval for treatment of HRPC in the US and EU 144
Single-agent estramustine and single-agent Taxotere see equal use in the first-line treatment of HRPC when the seven-market average is examined despite a lack of robust supporting clinical data 145
Greater evidence exists supporting the first-line use of a Taxotere and estramustine combination in comparison to either agent as monotherapy 146
Use of secondary hormonal therapy as first-line treatment for HRPC may still be appropriate in those cases where androgen receptors are still active 147
Second-line drug therapy 147
Progression from first-line to second-line therapy 147
The majority of HRPC patients progress to second-line therapy, although variation is shown across the seven major markets 147
Second-line drug regimens used to treat HRPC 149
Use of Taxotere-based regimens is still high in the second-line treatment of HRPC, although mitoxantrone is also used frequently at this stage 149
The leading seven-market second-line regimens are single-agent mitoxantrone and a combination of Taxotere and prednisone, both administered to equal proportions of HRPC patients 151
Single-agent Taxotere is the third leading second-line regimen for the treatment of HRPC, most likely due to a lack of other approved agents 152
Use of single-agent estramustine is still high in the second-line treatment of HRPC in Japan, as well as in France, Italy and Spain 152
Continued use of a combination of Taxotere and estramustine is seen in the second-line treatment of HRPC in Japan 152
In Germany, a combination of vinorelbine and estramustine appears in the top three second-line regimens, most likely due to vinorelbine's milder toxicities 153
Secondary hormonal therapy is used in the second-line treatment of HRPC in Italy and the UK, which is somewhat surprising at this late stage 153
Key prescribing influences 153
Key prescribing influences for drug therapy of HRPC 153
The ability to improve overall survival, symptoms and quality of life are the leading two influences on prescribing for treatment of HRPC 153
The third leading prescribing influence concerns side-effect profiles, which is obviously of significance following improvements to survival and quality of life 156
The importance of remaining key prescribing influences vary depending on country-specific issues, with cost issues, method and frequency of administration and physician product familiarity more or less of similar weight 156
Relatively high importance of cost issues is expected in the more cost-conservative UK, but not in the US 156
Method of administration, frequency of dosing and physician product familiarity are all of similar relevance in each of the seven markets 156
Pharmaceutical company marketing and services appears to be the least important key prescribing influence across the seven major markets 157
CHAPTER 9 PIPELINE PRODUCTS FOR HORMONE-REFRACTORY PROSTATE CANCER 158
Introduction 158
Prostate cancer pipeline overview 158
Key pipeline product profiles 164
Abbott's Xinlay (atrasentan) 165
Spectrum Pharmaceuticals/GPC Biotech's Orplatna (satraplatin) 166
Dendreon's Provenge (sipuleucel-T) 167
Cell Genesys's GVAX 169
Novacea/Schering-Plough's Asentar (calcitriol, DN-101) 170
Northwest Biotherapeutics' DCVax-Prostate 172
Genentech/Roche's Avastin (bevacizumab) 172
Key attributes 174
Key attributes for HRPC pipeline products 174
As expected, the top desired attributes in a pipeline drug for HRPC is to prolong overall survival duration and improve quality of life 174
Superiority over the current first-line standard 176
Clinical improvements required for a pipeline drug to be used ahead of the current first-line standard, Taxotere plus prednisone 176
In order for a pipeline drug to be used in combination with Taxotere over the current first-line standard, relatively large improvements in clinical benefits would need to be shown 176
Acceptable price increase for a pipeline drug to be used in advance of the current first-line standard, Taxotere plus prednisone 177
Physicians speculate that payers are prepared to pay nearly 20% more for a pipeline drug if survival is increased, even at the expense of increased toxicity 177
Predicted performance of late-phase pipeline products 178
Pipeline drugs are predicted to have some advantages over the current standard 178
Taxotere-based regimens are ranked highest in terms of overall survival and symptom/quality of life improvements, which is expected given the solid clinical evidence available 180
In terms of side-effect profile, method of administration and frequency of dosing, pipeline products are all ranked ahead of the standard Taxotere-based regimen, which i