The legally binding text is the original French version

TRANSPARENCY COMMITTEE

OPINION

29 February 2012

VANTAS 50 mg, implant B/1 implant inside a glass bottle with implantation device (CIP code: 392 600-5)

Applicant: BOUCHARA-RECORDATI

Histrelin (acetate)

ATC code: H01CA03 (gonadotropin-releasing hormones)

List I

Date of Marketing Authorisation (mutual recognition): 15 July 2010

Reason for request : Inclusion on list of products refundable by National Health Insurance and approved for hospital use.

Medical, Economic and Public Health Assessment Division

1/9 1. CHARACTERISTICS OF THE MEDICINAL PRODUCT

1.1. Active ingredient

Histrelin (acetate)

1.2. Indication

“Palliative treatment of advanced prostate cancer.”

1.3. Dosage

“The recommended dose of VANTAS is one implant for 12 months. An average of 50 µg histrelin acetate is delivered daily. The implant is inserted subcutaneously in the inner aspect of the upper arm. Response to VANTAS therapy should be monitored by clinical parameters and by measuring prostate-specific antigen (PSA) serum levels. Clinical studies have shown that serum testosterone concentrations may increase during the first week of treatment (testosterone flare-up). Testosterone concentrations then decreased and reached castrate levels (≤ 50 ng/dl) by Week 4. Once attained, castrate level was maintained as long as VANTAS therapy continued. If a patient's clinical response appears to be sub-optimal, then it would be advisable to confirm that patient's serum testosterone concentration is at castrate level.”

2/9 2. SIMILAR MEDICINAL PRODUCTS

2.1. ATC Classification (2010)

H Systemic hormonal preparations, excl. sex hormones and insulins H01 Pituitary and hypothalamic hormones and analogues H01C Hypothalamic hormones H01CA Gonadotropin-releasing hormones H01CA03 Histrelin

It should be noted that the other GnRH analogues are currently classified under L02AE : L Antineoplastic and immunomodulating agents L02 Endocrine therapy L02A Hormones and related agents L02AE Gonadotropin-releasing hormone analogues It is this class that must be considered for the determination of medicinal products similar to VANTAS, the sole therapeutic indication being prostate cancer.

2.2. Medicines in the same therapeutic category

GnRH analogues indicated in the treatment of advanced-stage prostate cancer:

There are two GnRH analogues with presentations taking the form of biodegradable subcutaneous implants:

- Goserelin : ZOLADEX 3.6 mg and 10.8 mg, implant in prefilled syringe for subcutaneous injection - Buserelin : BIGONIST 6.3 mg, implant in prefilled syringe for subcutaneous injection

There are also GnRH analogues with presentations taking the form of prolonged-release injections:

- Triptorelin : • GONAPEPTYL 3.75 mg, powder and solvent for suspension for prolonged-release injection in prefilled syringes • DECAPEPTYL LP 3 mg, 11.25 mg and 22.5 mg, powder and solvent for suspension for injection (IM)

- Leuprorelin : • ELIGARD 7.5 mg, 22.5 mg and 45 mg, powder and solvent for solution for injection • ENANTONE LP 3.75 mg, 11.25 mg and 30 mg, powder and solvent for suspension for injection

2.3. Medicines with a similar therapeutic aim

GnRH antagonist: FIRMAGON (degarelix)

Antiandrogens: - CASODEX (bicalutamide) - ANANDRONE (nilutamide) - EULEXINE (flutamide) - ANDROCUR (cyproterone)

3/9 3. ANALYSIS OF AVAILABLE DATA

The dossier submitted comprises 3 studies: - a phase II dose-finding study (BAR-002-09591A-USA), which is not analysed in this document. - two phase III studies (study 301, termed the pivotal study, and study 302) analysed below.

3.1. Efficacy

Study 301 Non comparative study evaluating the efficacy and tolerance of VANTAS 50 mg, 1 implant every 12 months in patients with locally-advanced or metastatic prostate cancer requiring androgen suppression therapy.

The original study protocol had planned a comparison versus leuprorelin 22.5 mg, one prolonged-release injection every 3 months. A modification to the protocol of this study was made following a change of marketing authorisation holder. Recruitment to the leuprorelin group was stopped after 35 patients had been included.

The inclusion criteria were as follows: - patients aged 45 years and over with stage III or IV prostate cancer (AJCC classification) or in treatment failure with a rise in PSA, - blood testosterone ≥ 150 ng/dl, - life expectancy more than 1 year.

The primary efficacy endpoint was : achievement of a blood testosterone level ≤ 50 ng/dl from week 4 onwards and maintaining it until week 52.

Secondary endpoints were : PSA level, LH level, disease progression, response to treatment based on PSA level (two consecutive values two weeks apart of less than 4 ng/ml or showing a decrease of 50% since inclusion), WHO status, pain, quality of life.

Results: Of the 138 patients treated with VANTAS, 111 (80%) had blood testosterone levels ≤ 50 ng/dl from week 4 onwards which remained below this level until week 52 (primary efficacy endpoint). A decrease in PSA below 1 ng/ml was observed in 66.6% (92 of the 138 patients included). At week 60, 87 patients had shown a full response, with 12 showing progression. For the remaining patients (n = 39), no data on these criteria are provided in the dossier submitted by the company.

Study 302 Non comparative study evaluating the efficacy and tolerance of VANTAS 50 mg, 1 implant every 12 months in patients with metastatic prostate cancer requiring androgen suppression therapy.

The original study protocol had planned a comparison versus goserelin 10.8 mg, 1 implant every 3 months. A modification to the protocol of this study was made following a change of marketing authorisation holder. Recruitment to this study was stopped after 59 patients had been included.

4/9 The inclusion criteria were as follows: - patients aged 45 years and over with metastatic prostate cancer (M1) or in treatment failure with a rise in PSA, - PSA ≥ 5 ng/ml, - blood testosterone ≥ 150 ng/dl, - life expectancy more than 1 year.

The primary efficacy endpoint was : achievement of a blood testosterone level ≤ 50 ng/dl from week 4 onwards and maintaining it until week 52.

Secondary endpoints were: PSA level, LH level, disease progression, response to treatment based on PSA (two consecutive values two weeks apart of less than 4 ng/ml or showing a decrease of at least at least 50% since inclusion), WHO status, pain, quality of life.

Results: Of the 59 patients included, 33 were treated with VANTAS, of whom 25 completed the study. Blood testosterone ≤ 50 ng/dl from week 4 onwards, with this maintained until week 52 (primary efficacy endpoint), was achieved in 31 of the 33 patients treated with VANTAS. No numerical data on the secondary endpoints are provided in the dossier submitted by the company.

3.2. Adverse effects

A total of 134 patients were exposed to treatment for at least 1 year in the two phase III studies. Practically all patients reported adverse events, with serious ones reported by 24%. Discontinuation of treatment was not, however, necessary. The adverse events attributable to the treatment, none of which were serious, and reported in at least 2% of patients were events associated with hormonal suppression, in particular hot flushes (65.5%), fatigue (10%) and reactions at the implantation site (5.8%). As regards local problems at the implant insertion site in particular, some expulsions (n = 10) occurred at the start of the clinical studies. The problem was solved, on two occasions, by changing the insertion device. The cumulative number of expulsions since initial marketing authorisation (2004) is 343 for 88,954 implants (0.4%).

3.3. Conclusion

The efficacy and tolerance data for VANTAS are taken from two non comparative studies with a small number of patients: a total of 144 patients included, of whom 134 were exposed for at least 1 year of treatment. The study, termed the pivotal study, in which the study population consisted of around one hundred patients, showed that VANTAS caused medical castration, i.e. blood testosterone ≤ 50 ng/dl from about week 4 of treatment onwards, maintaining it below this level until week 52 (primary efficacy endpoint) in 80% of patients treated. A PSA level below 1 ng/ml was observed in 66.6% of patients. At week 60, 87 patients had shown a full response, with 12 showing progression. For the remaining patients (n = 39, i.e. 28% of the study population), no data on these criteria are provided in the dossier submitted by the company. Quantification of the therapeutic benefit of VANTAS in prostate cancer is difficult, given the absence of comparisons with GnRH analogues, active treatments which have been available for a number of decades.

5/9 Tolerance data are limited. Out of a total of 134 patients exposed for at least 1 year to VANTAS, the following events associated with hormonal suppression were reported: hot flushes (65.5%), fatigue (10%), reactions at the implantation site (5.8%). In addition, some expulsions of the implant (n = 10) occurred at the start of the clinical studies.

VANTAS implant must be inserted by a doctor and not by a nurse, under local anaesthesia. An incision must be made, followed where necessary by closure with a stitch. Morbidity due to the procedure is thus much greater than with other substances in this therapeutic class. For it to be removed, it must be possible to locate the implant by cutaneous palpation, otherwise ultrasonography, CT or MRI may be necessary in order to locate it. For removal of the implant, a fresh incision in the skin must be made to open the tissue pseudocapsule surrounding this implant. The low level of evidence for the therapeutic benefit of VANTAS (absence of comparison and missing data in each of the two studies) and the complex and time-consuming procedure necessary for its insertion and removal cast doubt on its usefulness in the therapeutic arsenal.

6/9 4. TRANSPARENCY COMMITTEE CONCLUSIONS

4.1. Actual benefit

Prostate cancer is a life-threatening disease. These proprietary medicinal products fall under the category of palliative treatment. The efficacy/adverse effects ratio is modest. This medicinal product is a first-line therapy. Alternative medicinal products exist.

Public health benefit : Prostate cancer is the most common of all cancers. In terms of mortality, it is the third most common cause of death from cancer in humans. The burden represented by prostate cancer is considerable. The burden of the disease for the population covered by the therapeutic indication of VANTAS (hormone-dependent advanced prostate cancer) is moderate. Improvement in the treatment of cancer is a public health need which is an established priority (French 2004 Law on Public Health). However, the proprietary medicinal product VANTAS does not make any additional contribution towards meeting a public health need over and above the strategy currently used. On the basis of the available clinical data, in particular the absence of comparative data, and because of the difficult handling of the product associated with its mode of administration, the proprietary medicinal product VANTAS is not expected to have a positive impact on morbidity/mortality and quality of life. A positive impact on the organisation of care cannot be expected, given the need for implantation/removal to be carried out by a doctor. Consequently, the proprietary medicinal product VANTAS is not expected to benefit public health.

Given the low level of evidence (absence of comparison with the available drugs and missing data in each of the two studies), the Committee considers that, based on the current state of the dossier, the actual benefit of VANTAS is moderate.

4.2. Improvement in actual benefit (IAB)

VANTAS does not offer any improvement in actual benefit (level V) in the management of metastatic prostate cancer.

4.3. Therapeutic use 1

“Locally advanced cancer (T3/T4, N0-x, M0) The standard treatment for locally advanced cancers (T3/T4, N0-x, M0) consists of conformational radiotherapy of the prostate bed extended to pelvic lymph nodes with or without intensity modulation plus hormone therapy for 3 years. For a restricted group of patients (T3, young men, functional urinary symptoms, at low risk of metastatic spread), extended radical prostatectomy without preservation of the erectile bands is an option. It must meet strict quality criteria and be preceded by lymph node dissection. There is no benefit in carrying out hormone therapy prior to radical prostatectomy. The patient is informed of the possibility of complementary adjuvant therapy (radiotherapy and/or hormone therapy) depending on the results of the histopathological examination of the excised tissue.

1 LTC guide “Prostate cancer”: www.has-sante.fr. September 2008

7/9 Prostate cancer with pelvic lymph node involvement (all T, cN1/pN1, M0) Early, long-term hormone therapy is the standard treatment. Radical prostatectomy is considered if lymphatic involvement extends to max. 2 nodes and is microscopic. External radiotherapy of the prostate bed and pelvis can be proposed. The principle of watchful waiting is to defer hormone therapy until the development of urinary and bone symptoms or a rapid rise in total PSA. This is possible with hormone therapy (or combined hormone therapy/radiotherapy) deferred in the case of asymptomatic patients whose life expectancy (taking into account age and individual comorbidities) is estimated at less than 10 years.

Metastatic prostate cancer Hormone therapy is the standard treatment as set out below: - early initiation - combination of GnRH analogue and antiandrogens for the first month, - then recommended monotherapy with GnRH analogue or surgical castration. The long-term benefit of complete androgen blockade is unproven. Intermittent hormone therapy and combined hormone therapy/chemotherapy are currently undergoing evaluation. Hormone-resistant forms may respond to hormonal manipulation (modification of hormone treatment) or to treatment with chemotherapy on the onset of metastatic bone pain or a downturn in general condition, or if rapid progression criteria apply. Intravenous bisphosphonates are part of protocols for the prevention of bone complications (pathological fractures, spinal cord compression, bone irradiation or surgery, tumour-induced hypercalcaemia) in some advanced-stage malignant tumours (including prostate cancer) with bone involvement. Watchful waiting is possible in asymptomatic patients whose life expectancy (taking into account age and individual comorbidities) is estimated at less than 10 years. Deferred hormonal treatment is commenced in the event of significant clinical or biological progression.” In the absence of comparative data versus other GnRH analogues, the status of VANTAS in the therapeutic strategy remains unclear. However, it’s more complicated (quasi-surgical procedure) and laborious handling for the doctor casts doubt on its usefulness in the therapeutic arsenal and means that the patient must be informed of these constraints.

4.4. Target population

The target population of VANTAS is represented by patients with locally advanced (T3 and T4) or metastatic (at the time of diagnosis or after progression from a localised stage) prostate cancer requiring androgen suppression therapy. 2 In France, the incidence of prostate cancer is estimated at 71,577 new cases per year. According to a study on prostate cancer provided for the French parliamentary office for the assessment of health policy (OPEPS) 3, the estimated distribution of its diagnostic stages is: - 84% for localised stages; - 3% for locally advanced stages, i.e. 2,147; - 10% for metastatic stages, i.e. 7,157.

2 INCA. The cancer situation in France. November 2010 – http://www.ecancer.fr/component/docman/doc_download/6035-la-situation-du-cancer-en-france-en- 2010 3 M. Bernard Debré, Député. Report on prostate cancer screening and treatment. Conclusion and study carried out for OPEPS (French parliamentary office for the assessment of health policy) in 2008 (FRANCIM-InVS 2001 cohort). 2009: 154-172.

8/9 The percentage progression at five years is 5% for the prostate-localised stage and between 22 and 32% for the capsular invasion stage (T2 in the TNM clinical staging system). 4 Based on the distribution of clinical stages T1 (27%) and T2 (58%) in the OPEPS study, the percentage progression of the localised stage to the metastatic stage can be put at about 20%. The number of prostate cancer patients diagnosed at the localised stage and progressing towards a metastatic stage is estimated to be 12,030.

It is not known what proportion of these patients are eligible for hormone therapy on its own.

In total, the target population of VANTAS is of the order of 21,500 patients per year.

4.5. Transparency Committee recommendations

The transparency Committee recommends inclusion on the list of medicines refundable by National Health Insurance and on the list of medicines approved for hospital use and various public services in the indication and at the dosage in the Marketing Authorisation.

4.5.1 Packaging : Appropriate for the prescription conditions.

4.5.2 Reimbursement rate : 100%

4 Avancès C. Cancer de la prostate: la maladie localisée [Prostate cancer: localised disease]. Médecine Nucléaire. 2008; 32: 46-50.

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