Mutual Recognition Procedure. Pamorelin LA 11,25 mg Pamorelin LA 22,5 mg Pamorelin LA 3,75 mg. Marketing Authorisation Holder:

Transcription

1 Mutual Recognition Procedure Type II variation Final Variation Assessment Report Pamorelin LA 11,25 mg Pamorelin LA 22,5 mg Pamorelin LA 3,75 mg (Triptorelin embonate) DE/H/492/01-02/II/33 DE/H/566/01/II/08 Marketing Authorisation Holder: Ipsen Pharma GmbH Einsteinstraße 30 D Ettlingen Date: Pamorelin, DE/H/492/II/33; DE/H/566/II/08 1/38 T ypeii_fvar_rms

2 COVER PAGE Invented name of the pharmaceutical products in the originating Member State Name(s) of the active substances Pharmacotherapeutic classification Pharmaceutical form and strength Pamorelin LA 11,25 mg (DE/H/492/01/II/33) Pamorelin LA 22,5 mg (DE/H/492/02/II/33) Pamorelin LA 3,75 mg (DE/H/566/01/II/08) Triptorelin embonate Hormones and related agents, gonadotropin releasing hormone analogues: ATC code: L02AE04 Powder and solvent for prolonged-release suspension for injection; 11,25 mg, 22,5 mg and 3,75 mg Reference Number for the Mutual DE/H/492/01-02/II/33 Recognition Procedure Member States concerned All AT BE BG CY CZ DE DK EE EL ES FI FR HU IE IS IT LI LT LU LV MT NL NO PL PT RO SE SI SK UK Reference Number for the Mutual DE/H/566/01/II/08 Recognition Procedure Member States concerned All AT BE BG CY CZ DE DK EE EL ES FI FR HU IE IS IT LI LT LU LV MT NL NO PL PT RO SE SI SK UK In the Reference Member State: Marketing authorisation holder's name and address Name and address of manufacturer of the dosage form Date of first authorisation/last update Marketing authorisation number Ipsen Pharma GmbH Einsteinstraße 30 D Ettlingen DE/H/492/01-02/MR DE/H/566/01/MR Date of Assessment Report/Last update Reference Member State Contact Point Name Martin Norta / Roswitha Schabardin Tel: / 3794 Fax: martin.norta@bfarm.de roswitha.schabardin@bfarm.de Assessor(s) Clinical Name Dr. Manfred Hoffmann/ Dr. Frauke Naumann-Winter Tel: /3466 Fax: Pamorelin, DE/H/492/II/33; DE/H/566/II/08 2/38 T ypeii_fvar_rms

3 Start Nature of change requested Addition of a new indication Pamorelin, DE/H/492/II/33; DE/H/566/II/08 3/38 T ypeii_fvar_rms

4 I. RECOMMENDATION Based on the review of the data on safety and efficacy, the RMS considers that the variation applications DE/H/492/01-02/II/33 and DE/H/566/01/II/08 for Pamorelin LA 11,25 mg, Pamorelin LA 22,5 mg and Pamorelin LA 3,75 mg (triptorelin embonate), respectively, in the treatment of locally advanced or metastatic hormone dependant prostate cancer, for the changes concerning concomitant and adjuvant treatment to radiotherapy for locally advanced prostate cancer is approvable. II. EXECUTIVE SUMMARY II.1 Scope of the variation The aim of this Type II variation is to change section 4.1, 4.2 and 5.1 based on clinical data from a study performed by the EORTC (study EORTC 22961). This study compares the combination of radiotherapy plus 6 months of androgen suppression versus combination of radiotherapy plus 3 years of androgen suppression. At the present time, Pamorelin [ ] is indicated for the treatment of locally advanced or metastatic hormone dependant prostate cancer. The applicant requests to extent the indication as follows: Pamorelin [ ] is indicated for the treatment of locally advanced or metastatic, hormonedependent prostate cancer. Pamorelin [ ] is indicated as concomitant to and following radiation therapy in locally advanced hormone-dependent prostate cancer. III. SCIENTIFIC DISCUSSION This discussion should clearly provide the scientific rationale for the recommendation and for the objections and concerns/request for supplementary information listed in section V. III.1 N/A III.2 N/A Quality aspects Non clinical aspects III.3 Clinical aspects III.3.1 Clinical pharmacology No new data have been provided. Assessor s comments: The clinical pharmacology of triptorelin is well-known. Therefore, no new data are required. III.3.2 Clinical efficacy Concerning triptorelin the following data have been provided: - an Interim Analysis Report of study EORTC (dated ) - a Final Analysis Report of study EORTC (dated ) - a Subgroup Analysis Report of study EORTC (dated ). Pamorelin, DE/H/492/II/33; DE/H/566/II/08 4/38 T ypeii_fvar_rms

5 Additionally, a clinical overview (including 5 guidelines and 33 publications) has been submitted. Only one of these publications (published results of study EORTC 22961) concerns triptorelin. Main study (Final Analysis Report) Study EORTC was a randomised, multicenter, phase III study comparing the combination of radiotherapy (RT) plus long-term androgen suppression (3 years) with the combination of RT plus short-term androgen suppression (6 months) in patients with locally advanced prostate cancer. Study EORTC was conducted to determine whether overall survival (primary endpoint) after short-term androgen suppression would be inferior to long-term androgen suppression. Assessor s comments In DE, long-term androgen suppression (used as the reference treatment) as well as short-term androgen suppression (the test treatment) has not been licensed for treatment of locally advanced prostate cancer as concomitant and adjuvant to radiotherapy. Thus, both treatment regimens used in study EORTC must be considered experimental. Note: Upon the applicant s request, the underlined terms (i.e. as concomitant and adjuvant to radiotherapy and used in study EORTC ) have been added for clarification, Methods Inclusion criteria: Patients with locally advanced prostate cancer were included. Locally advanced prostate cancer was defined as: - histologically confirmed prostate adenocarcinoma T1c to T2a-b, pathological nodal stage N1 or N2 and no metastatic spread (M0); or - clinical stage T2c to T4, pathological nodal stage N0 to N2 and M0, baseline level of PSA of up to 40 times the upper limit of the normal range. Study design: Patients who had received external-beam radiotherapy plus six months of androgen suppression* and whose disease had not progressed were randomly assigned to receive either no further treatment or to receive further treatment with a LHRH agonist for 2.5 years. Randomisation was performed centrally at the EORTC headquarters with stratification according to clinical stage ( T2b or T2c), nodal stage (N0, N1, or N2), baseline PSA ( 5 times, 5 t0 10 times, or >10 time the ULN), and Gleason score (2 to 7 or 8 to 10). *drugs used for androgen suppression were LHRH agonists (triptorelin (N=672 [62.2%]), goserelin (N=325 [30.1%]), buserelin (N=15 [1.4%]), leuprorelin (N=56 [5.2%]), other (N=10 [0.9%])) and anti-androgens (flutamide (N=254 [23.5%]), bicalutamide (N=763 [70.6%]), nilutamide (N=33 [3.1%]), cyproterone acetate (N=28 [2.6%])) Assessor s comments The study design did not specify which LHRH agonist should be used in study EORTC However, the present application concerns triptorelin, and only 62.2% (N=672/1080) of patients registered for the study received triptorelin. Concerning patients on long-term androgen suppression (N=487), 276 patients (56.7%) received triptorelin and 211 patients (43.3%) received other LHRH (of those 145 received goserelin). Endpoints and sample size: Pamorelin, DE/H/492/II/33; DE/H/566/II/08 5/38 T ypeii_fvar_rms

6 Overall survival was the primary endpoint (defined as the time from randomisation to death from any cause). Secondary endpoints were clinical disease free survival, clinical disease free interval, loco-regional control, acute and late toxicities, QoL and sexual function, cost effectiveness study. Based on the results of a previous trial (study EORTC 22863), the 5-year overall survival in the reference arm (i.e. long-term androgen suppression) was estimated at 80%. Corresponding to a decrease of a 5-year survival rate by at most 6%, from 80 % to 74 %, non-inferiority was defined as a relative risk not greater than Therefore, for overall survival, a hazard ratio of 1.35 or less was used to establish the noninferiority of short-term androgen suppression to long-term androgen suppression. Based on that hypothesis, it was estimated that a total of 275 deaths need to be observed to prove this definition of non-inferiority with a power of 80 %, and a one-sided type I error rate of 5 % (α=0.05). To observe those events, it was projected to randomize a total of 966 patients over a 5-year time period. It was estimated that a follow-up period of 5 years after the last inclusion was required to observe the required number of events. Following an interim analysis, the total number of events required for the final analysis was reevaluated and was increased from 275 in the original protocol to 285 (to maintain the planned statistical power with the reduced final significance level of Assessor s comments Disregarding that the present application concerns triptorelin, endpoints, non-inferiority margin/test hypothesis, and sample size is acceptable with respect to primary objective of study EORTC (i.e. to determine whether overall survival after short-term androgen suppression would be inferior to long-term androgen suppression, without specification of the LHRH agonist to be used). Statistical analysis: All analyses were conducted in accordance with the intent-to-treat principle, with data for all patients who underwent randomisation. The analyses were repeated for the per-protocol population (all patients who underwent randomisation and followed the assigned treatment regimen). Overall survival was also analysed in the per-protocol population who had ct2c-t3 pn0 disease. Results (Final Analysis Report) A total of 1113 men were registered to induction combined androgen blockade plus radiotherapy (CAB), and 970 underwent randomisation (483 to treatment with short-term androgen suppression [short ADT] and 487 to treatment with long-term androgen suppression [long ADT). The median follow-up at the time of the final analysis was 6.4 years from registration. In the final analysis, the number of events was 230 (132 events on short ADT; 98 events on long ADT). This represents 80.7% of the planned total number of events (285). The CAB treatment consisted in most patients in a combination of triptoreline (62.4%) or gosereline (30.1%) with bicalutamide (70.6%) or flutamide (23.5%). The CAB treatment was stopped prematurely in 9.4% of the patients, mostly due to toxicity or refusal to pursue the treatment. Pamorelin, DE/H/492/II/33; DE/H/566/II/08 6/38 T ypeii_fvar_rms

7 Major deviations from the recommended 6 months induction treatment were documented in 199 patients (17.9%), which consisted mostly in failure to continue the anti-androgen, adjunction of one extra injection of LH-RH or a >1 month delay between the end of the 6 months CAB and the randomization. 454 of the 487 patients allocated the long term ADT have been documented to have finished treatment. For 33 patients, the documentation of the end of the treatment is missing. 112 patients (23.0%) stopped the long term ADT earlier than planned by protocol (main reasons: refusal [42], toxicity [23], disease progression [10] or death [20]). The intent-to-treat analysis of the overall survival shows 82.6% survival at 5 years on the long term ADT arm and 78.8% on the short term ADT arm, with an estimated hazard ratio of 1.42 (95.71% CI: ), indicating that the short ADT treatment is inferior to the long term ADT treatment. The per-protocol analysis confirms the results with a hazard ratio of 1.47 (95.71% CI: ). The clinical progression-free survival data indicate a 5-year event free rate of 80.5% on the long term ADT arm, and 68.7% on the short term ADT arm, with a hazard ratio of 1.77 that indicates a shorter clinical progression-free survival with short term ADT. The biochemical progression-free survival data point in the same direction with 77.7% event free survival at 5 years on the long term ADT versus 56.8% on the short term ADT (HR=2.22). Assessor s comments A total of 1113 men were registered to CAB and 970 were randomised to short ADT (N=483) or long ADT (N=487), respectively. 454 of the 487 patients allocated to long term ADT have been documented to have finished treatment (documentation missing for 33 patients), of whom 112 patients (23.0%) stopped treatment earlier than planned by protocol. The intent-to-treat analysis of the primary endpoint (overall survival) with an estimated hazard ratio of 1.42 indicates that short ADT is inferior to long term ADT. The per-protocol analysis confirms the results with a hazard ratio of Results (Subgroup Analysis Report) For the subgroup analysis, the dataset was separated between patients who received only triptorelin for the LHRH treatment (574 patients: 298 on short term ADT and 276 on long term ADT) and patients who received other LHRH (goserelin, buserelin, leuprorelin, other ) or a mixture of triptorelin and other treatment (396 patients: 185 on short term ADT and 211 on long term ADT). Drugs and regimen used for short term CAB for patients with documented induction CAB Missing (N=129) SADT triptorelin (N=298) SADT other LHRH (N=175) LADT triptorelin (N=276) LADT other LHRH (N=202) Total (N=1080) N (%) N (%) N (%) N (%) N (%) N (%) no 2 (1.6) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (0.2) goserelin 36 (27.9) 0 (0.0) 139 (79.4) 0 (0.0) 150 (74.3) 325 (30.1) buserelin 2 (1.6) 0 (0.0) 6 (3.4) 0 (0.0) 7 (3.5) 15 (1.4) triptorelin 79 (61.2) 298 (100.0) 0 (0.0) 276 (100.0) 19* (9.4) 672 (62.2) leuprorelin 8 (6.2) 0 (0.0) 24 (13.7) 0 (0.0) 24 (11.9) 56 (5.2) Pamorelin, DE/H/492/II/33; DE/H/566/II/08 7/38 T ypeii_fvar_rms

8 other 2 (1.6) 0 (0.0) 6 (3.4) 0 (0.0) 2 (1.0) 10 (0.9) Patients did not have triptorelin during the w hole long term ADT Drugs used for long term ADT LADT triptorelin (N=276) LADT other LHRH (N=211) Total (N=487) N (%) N (%) N (%) no 0 (0.0) 15 ( (3.1) goserelin 0 (0.0) 145 (68.7) 145 (29.8) buserelin 0 (0.0) 7 (3.3) 7 (1.4) triptorelin 276 (100.0) 21 (10.0) 297 (61.0) leuprorelin 0 (0.0) 17 (8.1) 17 (3.5) other 0 (0.0) 1 (0.5) 1 (0.2) Missing 0 (0.0) 5 (2.4) 5 (1.0) The median follow-up was 6.1 years in the triptorelin subgroup and 7.1 years in the other LHRH subgroup. Concerning patients receiving triptorelin, the intent-to-treat analysis of the overall survival shows 84.6% survival at 5 years on the long term ADT arm and 83.5% on the short term ADT arm, with an estimated hazard ratio of 1.28 (95.71% CI: ), indicating that the short term ADT treatment is not inferior to the long term ADT treatment. Whereas for patients receiving other LHRH agonists, the intent-to-treat analysis of the overall survival shows 85.1% survival at 5 years on the long term ADT arm and 76.6% on the short term ADT arm, with an estimated hazard ratio of 1.66 (95.71% CI: ), indicating that the short term ADT treatment is inferior to the long term ADT treatment. The per-protocol analysis confirms the results with a hazard ratio of 1.31 (95.71% CI: ) for patients receiving triptorelin, and a hazard ratio of 1.73 (95.71% CI: ) for patients receiving other LHRH agonists. Concerning patients receiving triptorelin, the clinical progression-free survival data indicate a 5- year event free rate of 79.4% on the long term ADT arm, for 69.9% on the short term ADT arm, with a hazard ratio of 1.71 that indicates a significantly shorter clinical progression-free survival with short term ADT. The biochemical progression-free survival data point in the same direction with 77.1% event free survival at 5 years on the long term ADT versus 57.4% on the short term ADT (HR=2.29). The authors concluded: - that the subgroup analysis shows that there is no difference of treatment effects between the two subgroups. - that, due to the fact that the number of events observed in each subgroup is under 130 (the number of events planned for the final analysis was 285), there is a lack of power to show a significant result for the primary endpoint especially in the triptorelin subgroup. Assessor s comments For the subgroup of patients receiving triptorelin, overall survival in the short term ADT arm was not inferior when compared to the long term ADT arm (ITT analysis: HR 1.28 [95.71% CI: ]), whereas for the subgroup of patients receiving other LHRH agonists, overall survival in the short term ADT arm was inferior when compared to the long term ADT arm (ITT analysis: HR 1.66 [95.71% CI: ]). Pamorelin, DE/H/492/II/33; DE/H/566/II/08 8/38 T ypeii_fvar_rms

9 It cannot be excluded that results concerning overall survival of all randomised patients (receiving triptorelin or other LHRH) showing that short term ADT was inferior compared to long term ADT have been negatively biased by the subgroup receiving other LHRH agonists. However, due to the fact that there is a lack of power to show a significant result for the primary endpoint, results from the subgroup analysis are inconclusive. III.3.3 Clinical safety Patient exposure A total of 1113 patients were registered, of whom 970 patients underwent randomisation. Of those, 487 were exposed to long-term androgen suppression (long ADT), and 483 to short-term androgen suppression (short ADT). Adverse events Adverse reactions to induction CAB Short ADT N=473 N (%) 150 (31.7%) 118 (24.9%) Long ADT N=478 N (%) 150 (31.4%) 147 (30.8%) Hot flushes <3x a day >3x a day Gynecomastia 32 (6.8%) 35 (7.3%) Elevation of ASAT/ALAT Grade 1 17 (3.6%) 25 (5.2%) Grade 2 6 (1.3%) 3 (0.6%) Grade 3 2 (0.4%) 2 (0.4%) Grade 4 0 (0%) 1 (0.2%) Diarrhea Grade 1 Grade 2 Grade 3 Grade 4 96 (20.3%) 32 (6.8%) 8 (1.7%) 3 (0.6%) 91 (19.0%) 36 (7.5%) 5 (1.0%) 2 (0.4%) Incontinence 54 (11.4%) 38 (7.8%) Potency 26 (5.5%) 29 (6.1%) Fatigue 25 (5.3%) 11 (2.3%) Proctitis 1(0.2%) 3 (0.6%) Headache 1 (0.2%) 3 (0.6%) Skin 5 (1.1%) 1 (0.2%) Pain 9 (1.9%) 12 (2.5%) Other 352 (74.4%) 381 (79.7%) Adverse reactions to long ADT Long ADT N=487 N (%) Hot flushes <3x a day 156 (32.0%) >3x a day 191 (39.2%) Gynecomastia 88 (18.1%) Other AEs* 241 (49.5%) *not specified Pamorelin, DE/H/492/II/33; DE/H/566/II/08 9/38 T ypeii_fvar_rms

10 Assessor s comments Concerning overall adverse events, only a few information is available, which do not allow any conclusion concerning the safety of long ADT and long term treatment with triptorelin, respectively, in patients with locally advanced prostate cancer. QoL results The number of patients with QoL forms (i.e. at least 1 form) was 473 (97.9%) and 479 (98.4%) for patients exposed to short ADT and long ADT, respectively. Quality of Life Long-Term Results for Patients Who Underwent Randomization.* Variable Mean Score at 1.5 Yr for STAS (1 y r after end of STAS) Mean Score at 1.5 Yr for LTAS (at 1.5 yr of LTAS) Ov erall P Value for LTAS v s. STAS EORTC QLQ-C30 function scales Ф Global health status and quality of life 74.9± ± Phy sical functioning 80.7± ± For matier t: F ranzösisch (Frankreich) For matier t: F ranzösisch (Frankreich) Cognitiv e functioning 84.2± ± Emotional functioning 84.7± ± Role f unctioning 81.8± ± Social f unctioning 87.9± ± EORTC QLQ-C30 symptom scales Appetite loss 4.2± ± For matier t: F ranzösisch (Frankreich) Constipation 7.2± ± Diarrhea 10.4± ± Dy spnea 17.7± ± Fatigue 21.9± ± Nausea or vomiting 1.7± ± Pain 11.2± ± Insomnia 18.0± ± Ad hoc questions Θ Hot flushes 12.6± ±1.60 <0.001 Enlarged nipples or breasts 5.7± ± Swelling of legs 8.5± ± Problems passing urine 12.6± ± Reduced interest in sex 58.5± ±2.15 <0.001 Reduced sexual activity 69.8± ±2.03 <0.001 * Plus minus values are means ±SD. EORTC denotes European Organization for Research and Treatment of Cancer, LTAS long-term androgen suppression, and STAS short-term androgen suppression. P v alues are based on linear mixed-effects models and Student s t-test. Because of multiple comparisons, a P value of less than 0.01 was considered to indicate statistical significance. Ф For the EORTC Quality-of -Life Questionnaire C30 (QLQ-C30) function scales, 0 indicates the lowest function and 100 the best. For the EORTC Quality-of-Life Questionnaire C30 (QLQ-C30) symptom scales, 0 indicates the fewest symptoms and 100 the most. Θ For the ad hoc questions, 0 indicates the fewest symptoms and 100 the most. Assessor s comments QoL results show that at 5 years, insomnia, hot flushes, enlarged nipples or breasts (i.e. gynecomastia), reduced interest in sex and reduced sexual activity was significantly more frequent Pamorelin, DE/H/492/II/33; DE/H/566/II/08 10/38 T ypeii_fvar_rms

11 for long ADT when compared to short ADT. Otherwise, QoL did not differ significantly between the two groups. However, since patients randomised to long ADT received various LHRH agonists (triptorelin, goserelin, buserelin, leuprorelin, other [not specified] ), QoL results are considered not meaningful with respect to the safety of triptorelin. Serious adverse events and deaths After a median follow-up of 6.4 years, 132 patients receiving short ADT and 98 receiving long ADT had died; prostate cancer was the cause of death in 47 and 28 patients, respectively, and cardiac events in 31 and 25, respectively. The cumulative incidence of fatal cardiac events at 5 years was not significantly different (4% on short ADT and 3% on long ADT). Assessor s comments The cumulative incidence of fatal cardiac events at 5 years seems to be in line with the incidence reported in recent studies. However, it might reasonably have been expected that cumulative incidence of fatal cardiac events at 5 years would be higher for patients on long ADT than on short ADT. As already mentioned above, since various LHRH agonists have been used, the results are considered not meaningful with respect to the safety of triptorelin. Laboratory findings For patients receiving induction CAB, elevation of ASAT/ALAT has been reported (see table Adverse reactions to induction CAB above). Assessor s comments No information is available concerning patients receiving long ADT. Safety in special populations N/A IV. OVERALL CONCLUSION Based on the data provided by the applicant, efficacy and safety of long-term treatment with triptorelin in patients with locally advanced prostate cancer have not been sufficiently established (see section V). It is well known that LHRH agonists are used as adjuvant treatment to radiotherapy. However, at present, data showing a significant improvement in clinical meaningful endpoints (e.g. overall survival, disease free survival) are only available for goserelin. Therefore, before authorisation can be granted, a clinical study is required showing that long-term adjuvant treatment with triptorelin monotherapy in patients with locally advanced prostate cancer improves clinical meaningful endpoints. Pamorelin, DE/H/492/II/33; DE/H/566/II/08 11/38 T ypeii_fvar_rms

12 V. REQUEST FOR SUPPLEMENTARY INFORMATION AS PROPOSED BY THE RMS V.1 Potential serious risks to public health <V.1.1 Quality aspects> <V.1.2 Non clinical aspects> V.1.3 Clinical efficacy and safety For the following (main) reasons, the RMS is of the opinion that there are Potential serious risks to public health, precluding a recommendation to the variation to the term of the marketing authorisation: Question 1 (RMS DE) In DE, long-term androgen suppression (used as the reference treatment) as well as short-term androgen suppression (the test treatment) has not been licensed for treatment of locally advanced prostate cancer as concomitant and adjuvant to radiotherapy. Thus, both treatment regimens used in study EORTC must be considered experimental. Note: Upon the applicant s request, the underlined terms (i.e. as concomitant and adjuvant to radiotherapy and used in study EORTC ) have been added for clarification. Applicant s Response (Q1) The Applicant considers that the proposed labelling should not be considered as an extension of the indication but rather as providing additional information surrounding the current indication wording based on the existence of clinical data on triptorelin within the radiotherapy treatment setting. The proposed change does not modify the target patient population; it is a revision/scientific update of the approved indication, by adding this combination treatment, which is the current standard of care. The indication already approved in Germany for Pamorelin is the treatment of locally advanced or metastatic, hormone-dependent prostate cancer. The approach to treatment of prostate cancer depends on clinical assessment, tolerance of therapy, expected life span, the stage of the disease and the extent of metastatic spread. Current therapeutic options for prostate cancer mainly include active surveillance or watchful waiting, surgery (radical prostatectomy or palliative transurethral resection of the prostate [TURP]), radiation therapy, hormonal manipulation therapy, cytotoxic chemotherapy, immunotherapy, new hormonal therapy or a combination of these treatments. The combination of treatments (hormonotherapy and radiotherapy) is in the current medical recommendations/guidance: Local guidance: German guidelines stipulate that for treatment of locally advanced prostate cancer it is recommended to prescribe on top of radiotherapy a neoadjuvant or adjuvant hormonal treatment (5.64, recommendation A and 5.65, recommendation O). International guidance s: The European Association of Urology (EAU) guidance [1] (summary table of the guidance is provided hereafter under Table 1) recommends the use of combination therapy (hormonal and radiotherapy) for the treatment of stage T3 and T4 prostate cancer as highlighted below. Pamorelin, DE/H/492/II/33; DE/H/566/II/08 12/38 T ypeii_fvar_rms

13 Guidelines on the evaluation of anticancer medicinal products in man [2]. Under section 8 of the condition specific guidance, subsection 8.2 Prostate cancer (line 1298, page 26/34) there is the following recommendation: adjuvant treatment using hormones has proven effective in patients receiving radiotherapy or surgery in terms of improved progression free survival. As detailed in the submitted clinical overview, in the early 90s data was already available suggesting that long term androgen deprivation therapy (ADT) improves outcomes when combined with radiotherapy (RT) in localised prostate cancer [3, 4, 5]. The combination of RT and ADT in locally- advanced prostate cancer has become the standard of care, although the optimal duration of ADT remains to be determined [6]. The EORTC study (22961) submitted aims to determine whether short-term ADT (i.e. 6M) would preserve the same quality of life (QoL) and overall survival as obtained with long term ADT (i.e. 3 years). Recently, at the American Society of Clinical Oncology (ASCO) 2012 session, the Southwest Oncology Group (SWOG) presented their updated results, which indicated that the addition of RT to ADT significantly reduced the risk of death (Hazard Ratio 0.70, 95% CI , p=0.001), (10 Pamorelin, DE/H/492/II/33; DE/H/566/II/08 13/38 T ypeii_fvar_rms

14 year cumulative disease specific death rates 15% with ADT+ RT, 26% with ADT alone, p<0.0001) [7]. In order to revise the present indication, due to current clinical knowledge and practice, the Applicant cannot envisage the conduct of a clinical study to update the indication in It would be unethical to not use combined therapy in patients for which this treatment is recommended, as described in international and national guidance, in order to improve overall survival. RMS comments on Applicants Response (Q1) The RMS agrees that the combination of radiation therapy with long-term androgen suppression is considered as standard of care for locally advanced prostate cancer. Androgen suppression is achieved by either orchiectomy or by treating patients with GnRH agonists, the latter being preferred by the majority of patients in view of the irreversibility of orchiectomy. No interactions of GnRH agonists with radiotherapy are expected which would have an impact on the safety of the medicinal product used. There is consensus of international treatment guidelines concerning the combination of radiotherapy with long-term androgen suppression. The optimal timing and duration of androgen suppression, however, is not known. The successful achievement and maintenance of a castration level of serum testosterone is critical for licensing of GnRH agonists. In view of the long experience of radiotherapy combined with and followed by androgen suppression, a variation based on the review of important clinical studies in the field and further supportive studies using the active ingredient in question could be accepted. Based on the responses provided, the RMS follows the company in its assessment of the EORTC study as supportive for approval of adding radiotherapy into the wording of the incidation. Issue resolved. Question 2 (RMS DE) The present application concerns triptorelin, and only 62.2% (N=672/1080) of patients registered for the study received triptorelin. Concerning patients on long-term androgen suppression (N=487), 276 patients (56.7%) received triptorelin and 211 patients (43.3%) received other LHRH (of those 145 received goserelin). The RMS is of the opinion that data obtained from a study evaluating efficacy and safety of longterm treatment with various LHRH agonists (including 56.7% receiving triptorelin) cannot be extrapolated to triptorelin. Applicant s Response (Q2) All GnRH agonists available on the market (triptorelin, leuprorelin, and goserelin) are decapeptides derived from GnRH whose differences are due to substitution and modification of an amino-acid residue at position 6. This substitution affects their half-lives and potencies. Triptorelin has a 100-fold higher relative potency compared with GnRH, while goserelin and leuprorelin are only 50 times more potent. Their mechanism of action is similar and result in decreased serum testosterone concentrations to castration levels (< 50 ng/ml), decreased PSA levels, and a positive influence on disease control and the survival of prostate cancer patients [8, 9, 10]. The EORTC study concluded that 6 months of androgen suppression in combination with radiotherapy did not improve the overall survival or the biochemical progression free survival. The results were similar for all GnRH agonists. It should be noted that the forest plot, which graphically Pamorelin, DE/H/492/II/33; DE/H/566/II/08 14/38 T ypeii_fvar_rms

15 represents the heterogeneity of treatment effects between the two subgroups, did not show a significant difference between the two groups in terms of treatment effects. Therefore, it is the Applicant s view that the data available from the EORTC study can be extrapolated to the triptorelin subgroup. A summary of GnRH agonist development has been provided in Module 2.5 of the variation. In conclusion due to the known mechanism of action of GnRH agonists, the Applicant s view is that it is reasonable to use these data to update the triptorelin SmPC even if only 62% of patients were treated with triptorelin. Based on the available study data and supportive literature references, it can be concluded that goserelin, leuprorelin, and triptorelin all decrease serum testosterone to castration levels. Khun et al reported that leuprorelin and triptorelin show a comparable effect in terms of castration [11]. If triptorelin was not as effective as other GnRH agonists, the clinical benefit observed in the EORTC study would not be as great, given that 62% of patients received triptorelin. Based on this, the Applicant s view is that the proposed change in the triptorelin SmPC could be acceptable. The goserelin and triptorelin SmPCs of some EU countries already include the use of these products as adjuvant treatment to radiotherapy. RMS comments on Applicants Response (Q2) The long-standing experience with this class of agents with an identical mode of action (suppression of serum testosterone levels below castration level), allows some extrapolation of results gained from individual class members within the class of GnRH agonists. Up to now, there is no indication that any of the member within this class differs with respect to efficacy and safety. While subgroup analyses and cross-trial comparisons are generally problematic, both the results of the supportive study itself and their consistency with the overall body of evidence on androgen suppression adjuvant to radiotherapy are reassuring: The RMS agrees that the overall effect of the supportive study is likely to be driven by the triptorelin subgroup (62% of patients). Reviewing trials on androgen suppression adjuvant to radiotherapy, it appears that overall, long term androgen suppression results in superior outcome compared to no or to short androgen suppression. In addition, no interaction of GnRH agonists with radiotherapy are expected which would have an impact on the safety of the medicinal product. Taken together, the RMS can follow the reasoning of the applicant and considers the update of the indication as acceptable. However, in view of the extrapolations performed, the recommendation for a long-term treatment should be provided in section 4.2 with reference to current treatment guidelines and a cautious note of the ongoing debate (see also SPC). Point resolved. Question 3 (RMS DE) Intent-to-treat analysis of the primary endpoint (overall survival) indicates that short ADT is inferior to long term ADT (HR 1.42). Disregarding that the present application concerns triptorelin, and that study results have been obtained from long-term treatment with various LHRH agonists (triptorelin, goserelin, buserelin, leuprorelin, other [not specified] ), inferiority of short ADT does not imply superiority of long term ADT. Applicant s Response (Q3) Pamorelin, DE/H/492/II/33; DE/H/566/II/08 15/38 T ypeii_fvar_rms

16 The Applicant agrees with this comment and has modified the first paragraph in Section 5.1 of SmPC in order to clarify this point. Current proposal: A randomized phase III study of 970 patients with prostate cancer locally advanced (T2c-T4) has investigated whether radiation therapy associated with short term androgen deprivation therapy (6 months, n = 483) was non-inferior to radiotherapy associated with long term androgen deprivation therapy (3 years, n = 487). Revised proposal: In a phase III randomized clinical trial including 970 patients with locally advanced prostate cancer (T2c-T4) on whom 483 were assigned to short term androgen suppression (6 months) in combination with radiation therapy and 487 to long-term therapy (3 years), a noninferiority analysis compared the short-term to long-term concomitant and following hormonal treatment with triptorelin (62.2%) and goserelin (30.1%). The Applicant consider that a statistical significant difference using 2-sided testing for difference was observed between short-term and long-term ADT with short-term treatment being less favourable as compared with long-term treatment for the total study population of EORTC (table in the summary of clinical efficacy). Therefore the Applicant believes that the revised text proposed for Section 5.1 of the SmPC addresses BfArM s comment above, incorporates the NL assessor s comment (see Response 9) and is consistent with the EORTC Study Report conclusion. RMS comments on Applicants Response (Q3) in case of authorisation of variation DE/492/II/33 and DE/566/II/8, the RMS would agree with the applicant s revised proposal. However, for clarification, the following should then be added: In a phase III randomized clinical trial to long-term therapy androgen suppression (3 years) in combination with radiation therapy. EORTC failed to demonstrate non-inferiority of a short treatment with GnHR agonists compared to a long-term treatment. The results have to be interpreted taking account of other clinical studies (mainly performed using Goserelin) which aimed at determining the optimal timing and duration of treatment with GnRH agonists after radiotherapy. The RMS supports the conclusion that the failed non-inferiority of the short treatment arm indicates that the long term treatment should be preferred. Recommendation for a long-term treatment should be provided in section 4.2 with reference to current treatment guidelines and a cautious note of the ongoing debate. Point resolved. Question 4 (RMS DE) Subgroup analysis of patients receiving triptorelin indicates that overall survival in the short term ADT arm was not inferior when compared to the long term ADT arm (HR 1.28). However, due to the fact that there is a lack of power to show a significant result for the primary endpoint, results from the subgroup analysis are inconclusive. Applicant s Response (Q4) Pamorelin, DE/H/492/II/33; DE/H/566/II/08 16/38 T ypeii_fvar_rms

17 Indeed we agree that due to the lack of power (around 55%) for the subgroup analysis based on triptorelin subjects, non-inferiority testing cannot be fully interpreted. Accordingly no conclusions could be drawn between short term and long term triptorelin treatment. However, when examining overall survival with triptorelin treatment in long and short term treatment groups (84.6% and 83.5% respectively), it can be noticed that rates were very similar to the overall ITT population (84.8%) for long term ADT treatment. As this subgroup represents more than the half of the study population (574 of 970 patients) the analysis could have some medical relevance even if statistically inconclusive. Based on the agency comment, the Applicant proposes to revise the section 5.1 of SmPC to avoid any reference to the overall survival data form subgroup analysis. The comment of the NL assessor will also be taken into account (removal of the paragraph provided data in post hoc analysis) (see the revised text for SmPC at the end of these responses). RMS comments on Applicants Response (Q4) Subgroup analyses in non-inferiority trials certainly lack the power to allow firm conclusions and should therefore not be included into section 5.1. of the SPC. Point resolved. Question 5 (RMS DE) Only a few information is available on overall adverse events, not allowing any conclusion concerning the safety of long ADT and long term treatment with triptorelin, respectively. Applicant s Response (Q5) The proposed variation is intended to provide additional clarification within the currently approved indication setting predominantly based on international and national guidance on the treatment of prostate cancer (see clinical overview and Response to Question 1 above). The results from the EORTC study are provided as supportive information. The Applicant s view is that the EORTC report provides a reliable assessment of safety and demonstrates that the safety data provided in the EORTC report are consistent with the known safety profile provided in marketing application (MA) files, periodic safety update reports (PSURs) and approved SmPCs. A listing with the detail of other adverse effects during ADT therapy (not provided in the EORTC Study Report previously submitted) is provided in Appendix 1 of these responses. The safety data from EORTC study are consistent with known safety profile of triptorelin and GnRH agonists. Safety of Triptorelin Triptorelin has been marketed since 1986 and its safety profile and that of other GnRH agonists is well established. The safety profile is directly linked to the pharmacological effects (castration). The triptorelin safety profile has been reviewed in 2009 in the context of the PSUR working sharing procedure (WSP; WSP procedure number DE/H/PSUR/0038/001, Germany as RMS). This has allowed the harmonisation of the safety information provided for different triptorelin formulations and with goserelin. As a result of this, a Core Safety Profile (CSP) for triptorelin formulations has been defined and agreed by the European Authorities (PSUR WSP Final Assessment Report dated 25 February 2010). The SmPC variations to implement the agreed CSP have been approved in August 2011 for the triptorelin 1-, 3- and 6-month Debiopharm formulations. In May 2012, the Applicant has submitted again the triptorelin PSURs for Ipsen formulations and the PSUR for Pamorelin, DE/H/492/II/33; DE/H/566/II/08 17/38 T ypeii_fvar_rms

18 Debio formulations via WSP with Germany as RMS (procedure number DE/H/PSUR/0038/02 with Day 0 1 July 2012). This will allow a full assessment of safety information by EU authorities. The agreed CSP takes into account Adverse Drug Reactions (ADRs) of more than twenty clinical studies in patients with prostate cancer treated with the different Ipsen and Debiopharm formulations of triptorelin. The majority of patients are treated during 9 months, 12 months or more than one year. Post marketing exposure since the first marketing administration approval of triptorelin is in the region of 30 million treatment months across all populations and all indications. GnRH agonist class effect safety Since goserelin and triptorelin belong to the same class of drugs, there has also been alignment between goserelin and triptorelin in the CSP for some class effects, such as metabolic changes or increased risk of cardiovascular disease, described in the SmPCs. Prospective data has not confirmed the link between treatment with GnRH analogues and an increase in cardiovascular mortality [12, 13, 14, 15, 16, 17, 18, 19]. The agreed triptorelin CSP additionally includes a class effect warning on the adverse effects of long-term androgen deprivation which reads as follows: In addition, from epidemiological data, it has been observed that patients may experience metabolic changes (e.g., glucose intolerance), or an increased risk of cardiovascular disease during androgen deprivation therapy. However, prospective data did not confirm the link between treatment with GnRH analogues and an increase in cardiovascular mortality. Patients at high risk for metabolic or cardiovascular diseases should be carefully assessed before commencing treatment and adequately monitored during androgen deprivation therapy. Conclusion The safety profile of triptorelin is well known and is linked to the pharmacological effect of GnRH analogues. The EORTC data shows a safety profile consistent with the known safety profile of GnRH analogies in that most adverse reactions are expected with testosterone suppression (hot flushes, erectile dysfunction and loss of libido). RMS comments on Applicants Response (Q5) The RMS agrees that the safety profile of triptorelin and other GnRH agonists is well known and primarily linked to their pharmacodynamic action. A relevant interaction of GnRH agonists, e.g. triptorelin with radiation is unlikely Extrapolation of safety experience from other GnRH agonists combined with radiation to triptorelin is acceptable. The limited information from the supportive trial is therefore acceptable. Point resolved. Question 6 (RMS DE) At 5 years, only insomnia, hot flushes, gynecomastia, reduced interest in sex and reduced sexual activity have been reported to be significantly more frequent for long ADT when compared to short ADT. Additionally, the cumulative incidence of fatal cardiac events at 5 years was not significantly different (4% on short ADT and 3% on long ADT). However, since patients randomised to long ADT received various LHRH agonists, these results are considered not meaningful with respect to the safety of triptorelin. Applicant s Response (Q6) Pamorelin, DE/H/492/II/33; DE/H/566/II/08 18/38 T ypeii_fvar_rms

19 The safety of triptorelin is linked with its pharmacological action (castration) and is consistent across the drug class (see Response to Question 5). Based on this rationale, class effect harmonisation has been requested by agencies. As such, the safety data observed in EORTC study which is linked to castration could be relevant for triptorelin despite the fact that only 62.2 % of patients were treated with triptorelin. The Applicant s view is that the safety of long-term ADT is known due to the 26 years postmarketing experience of triptorelin and other GnRH agonists. The ADRs table reported in the SmPC (from more than 20 clinical studies and post marketing experience) provides the safety profile of the product which is consistent with safety reported in the EORTC 22961study. Post marketing exposure since the first marketing administration approval of triptorelin is in the region of 30 million treatment months across all populations and all indications. The cumulative incidence of cardiac events at 5 years is not significantly different to that seen with short-term treatment (4% on short-term ADT and 3 % on long-term ADT) and is consistent with epidemiological data where patients have experienced metabolic changes (e.g. glucose intolerance) or an increased risk of cardiovascular disease during ADT. Prospective data did not confirm a link between treatment with GnRH analogues and an increase in cardiovascular mortality. This information is already contained within SmPCs of triptorelin in Section 4.4 Special warnings and precautions for use (was requested by BfArM during a prior procedure) and reads as follows: In addition, from epidemiological data, it has been observed that patients may experience metabolic changes (e.g. glucose intolerance), or an increased risk of cardiovascular disease during androgen deprivation therapy. However, prospective data did not confirm the link between treatment with GnRH analogues and an increase in cardiovascular mortality. Patients at high risk for metabolic or cardiovascular diseases should be carefully assessed before commencing treatment and adequately monitored during androgen deprivation therapy. The above is consistent with EAU guidance (1) and with a recent publication from Von Poppel and Tombal [20]. The publication advises that before initiation and during ADT treatment, men with prostate cancer should be periodically checked for potential metabolic effects by their physician. At the time of registration of the triptorelin 6-month formulation in 2010, the Applicant has provided responses to questions from BfArM on the cardiovascular risks (see below for convenience a copy of response provided during the triptorelin 6 M procedure). Response to question during the Triptorelin 22.5 mg registration: Pamorelin, DE/H/492/II/33; DE/H/566/II/08 19/38 T ypeii_fvar_rms

20 RMS comments on Applicants Response (Q6) The RMS agrees that the safety profile of triptorelin and other GnRH agonists is well known and primarily linked to their pharmacodynamic action. A number of class effects have been observed which are included in the core safety profiles of several GnRH agonists, as e.g. the warning in section 4.4 on cardiovascular adverse events. In order to be in line with other members of the class of GnRH, e.g. Zoladex, cardiovascular adverse events should be included in section 4.8 of the SPC. The applicant is asked to implement changes to the safety sections of the SmPC in the course of the ongoing PSUR Worksharing Procedure (DE/H/PSUR/0038/002). A relevant interaction of GnRH agonists, e.g. triptorelin with radiation is unlikely. Extrapolation of safety experience from other GnRH agonists combined with radiation to triptorelin is acceptable. Point resolved. Question 7 (RMS DE) For patients receiving induction CAB (combined androgen blockage), elevation of ASAT/ALAT has been reported ( ). No information is available concerning patients receiving long ADT. Note: The a.m. comment only describes a minor concern in study EORTC and has not been listed in the RMS list of question. Applicant s Response (Q7) In Table 2 provided below (p.9/15 of the DE - PVAR) there is information on the elevation of the aspartate transaminase (ASAT)/alanine transaminase (ALAT) in patients treated with short ADT (second column) and with long ADT (last column) during the 6 first month of the study (called induction CAB). The Applicant has attached Table 2 for convenience with the correction as explained in response to Question 10 highlighted. Pamorelin, DE/H/492/II/33; DE/H/566/II/08 20/38 T ypeii_fvar_rms

21 The Applicant agrees that in the EORTC Final Report there is no information on the ASAT/ALAT elevation during ADT (during the 2.5 year following the induction of CAB) as it was not specifically requested within the EORTC protocol. As explained in Response to Question 5 above, the listing of the other adverse events provided in Appendix 1 of these responses showed no elevation of ASAT/ALAT as other adverse events during ADT. In the current SmPCs, there are lists of ADRs based on more than 20 clinical studies in patients with prostate cancer treated with the different Ipsen and Debiopharm formulations of triptorelin. In addition, post marketing exposure since the first marketing administration approval of triptorelin is in the region of 30 million treatment months across all populations and all indications. Clinical data generated by the EORTC study showed safety profile comparable to those described in the approved SmPC with the most common adverse events being related to the suppression of testosterone levels, which is due to the intended pharmacological action of the drug. Some events reported in EORTC study were solicited and this could explain some minor differences of frequencies versus those of the current SmPC. Under the system organ class (SOC) Investigations of the ADR table provided in Section 4.8 of the SmPCs of the 1-, 3- and 6-month formulations of triptorelin, there is information on ASAT/ALAT increase. A copy of the table is provided below for convenience (Table 4). Pamorelin, DE/H/492/II/33; DE/H/566/II/08 21/38 T ypeii_fvar_rms

22 Pamorelin, DE/H/492/II/33; DE/H/566/II/08 22/38 T ypeii_fvar_rms