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.