פ א ר מ ה P H A R x M A

פ א ר מ ה P H A R x M A הביטאון לענייני תרופות ותראפיה ISRAEL DRUG BULLETIN Vol. 19, Bulletin No. 107 June-July 2012 Also in the Bulletin: Degarelix for Advanced Hormone-Dependent Prostate Cancer NEW TREATMENT OPTIONS FOR METASTATIC PROSTATE CANCER: Cabazitaxel and Abiraterone Cabazitaxel, like docetaxel, is a taxane derivative that interferes with cell mitosis and replication. Cabazitaxel is the first drug licensed for the treatment of metastatic hormone-refractory prostate cancer that has progressed during or after treatment with docetaxel. The approval is based on a pivotal study which showed that it may prolong overall survival when compared to mitoxantrone. Adverse effects of cabazitaxel, such as neutropenia, can be severe. Abiraterone is a potent inhibitor of the CYP17 enzyme, an enzyme involved in testosterone synthesis. It blocks androgen synthesis by the adrenal glands and testes and within the prostate tumour itself. Abiraterone is an oral drug that can extend survival in patients with metastatic castrationresistant prostate cancer previously treated with docetaxel. It is the first oral drug approved for this indication. How it compares with other drugs for this indication remains to be determined. Abiraterone offers an alternative orally administered hormone treatment option to IV chemotherapy regimens and is better tolerated with a different safety profile. It is not possible to identify patients who are more likely to respond to the drug. According to the Israel Ministry of Health (MoH), there has been a marked increase (46.2%) from 1999 to 2008 in the number of patients found to have prostate cancer. There has also been a slight decline in the mortality rate from the disease which in 2008 was 8.2%. The MoH has recently approved two new treatments for hormone-refractory or castration-resistant prostate cancer. The first is cabazitaxel (Jevtana; Sanofi-Aventis), approved "in combination with prednisone for the treatment of patients with metastatic hormone-refractory prostate cancer (mhrpc) previously treated with a docetaxel-based regimen." It is the first treatment to be licensed for this. The other new treatment is abiraterone (Zytiga; Janssen-Cilag), which is about to be approved in Israel for the treatment, in combination with prednisone, of metastatic castration-resistant prostate cancer (mcrpc) previously treated with docetaxel. It will be the first oral drug approved for this indication. CASTRATION-RESISTANT METASTATIC PROSTATE CANCER Medical or surgical castration, which stops androgen production by the testicles, is the standard treatment for advanced prostate cancer, but most patients continue to produce some androgens in the adrenal glands and in the tumour itself, and their tumours eventually become resistant to hormone treatment. Docetaxel-based chemotherapy is the only treatment previously shown to offer a survival benefit for men with metastatic prostate cancer that had become resistant to androgen deprivation therapy. In one study in 1006 men, overall survival was significantly longer with docetaxel plus prednisone (18.9 months) than with mitoxantrone plus 1

prednisone (16.5 months); mitoxantrone reduces pain symptoms, but does not improve survival. 1 The standard treatment for those who progress following first-line therapy with docetaxel is evolving; palliative options include mitoxantrone with or without steroids, and a variety of chemotherapy regimens such as 5-fluorouracil, cyclophosphamide and carboplatin /etoposide (these have not been shown to have an impact on survival). Cabazitaxel and abiraterone are the first agents to be specifically approved for use in this setting. MODES OF ACTION Cabazitaxel is a taxane antineoplastic agent that acts by disrupting the microtubular network in cells. It binds to tubulin and promotes the assembly of tubulin into microtubules while simultaneously inhibiting their disassembly. This leads to the stabilisation of microtubules, which results in the inhibition of mitotic and interphase cellular functions. It has activity against tumours sensitive and insensitive to docetaxel. It is designed to be effective in docetaxel-resistant tumours supposedly by avoiding P-glycoprotein-mediated efflux from cancer cells. 2 Abiraterone acetate, a prodrug of abiraterone, is a potent inhibitor of the cytochrome P450 c17 (CYP17) enzyme, a critical enzyme involved in testosterone synthesis, and which blocks androgen synthesis by the adrenal glands and testes and within the prostate tumour itself. 3 Pharmacokinetics: Abiraterone acetate is hydrolyzed in the gastrointestinal tract to abiraterone which reaches peak concentrations (Cmax) in about 2 hours. Taking the drug with food markedly increases Cmax and the area under the time-concentration curve (AUC). The effect of food on abiraterone (5- to 10-fold depending on fat content) is greater than any other marketed drug, yet it is labelled to be taken fasting. 4 Abiraterone is partly metabolised in the liver by CYP3A4 to inactive metabolites and excreted primarily in faeces, with terminal half-life of about 12 hours. CLINICAL STUDIES Cabazitaxel The main study supporting the approval of cabazitaxel is a randomised unblinded trial in 755 men with mcrpc that had progressed during or after treatment with docetaxel. 5 Cabazitaxel 25mg/m 2 was compared to mitoxantrone 12mg/m 2 given IV once every 3 weeks; all patients also received prednisone 10mg daily orally (or similar doses of prednisolone). All had prior castration by orchidectomy and/or GnRH agonist with/without antiandrogen, anti-androgen withdrawal, monotherapy with estramustine, or other hormonal agents. Treatment was continued for a maximum of 10 cycles (to minimise the risk of mitoxantrone-induced cardiac toxicity, allowing for comparable exposure to the study treatment). Those in the cabazitaxel group received a higher median number of treatment cycles than those in the mitoxantrone group (6 vs 4). The median overall survival (OS) was 15.1 (14.1-16.3) months with cabazitaxel and 12.7 (11.6-13.7) months with mitoxantrone (HR 0.70; p<0.0001). Subgroup analyses found that the survival results consistently favoured cabazitaxel; there was however no difference in OS between treatments in the small subgroup of patients who had received 3 cycles or less of docetaxel. Progressionfree survival (PFS) was 2.8 (2.4-3.0) months with cabazitaxel and 1.4 (1.4-1.7) months in the mitoxantrone group (HR 0.74; p<0.0001). Abiraterone A double-blind randomised trial in 1195 patients with mcrpc previously treated with docetaxel compared abiraterone acetate 1000mg orally once daily plus prednisone 5mg twice daily with placebo plus prednisone until disease progression. 3 70% of the study population had only received one prior chemotherapy regimen. At the time of the first interim analysis, overall survival, the primary endpoint, was 14.8 months with abiraterone and 10.9 months with placebo, a significant difference (HR 0.65; p<0.001). The study was terminated early based on these results (at which time it was underpowered, as only 552 of the 797 survival events that the power calculation was based on had occurred). The second and final analysis (at which time 775 events had taken place), showed that the median OS advantage had increased to 4.6 months (HR 0.74; p<0.0001). 6 Patients randomised to placebo are able to cross over to abiraterone and will be evaluated in the extension study. The effect of abiraterone on OS was seen to be consistent across virtually all subgroups tested and the statistical significance of the result was robust after adjustment for stratification factors in a multivariate analysis (HR 0.66; p<0.001). 90% of enrolled patients had good ECOG performance status (0 or 1), which is higher than would be expected in patients likely to be treated and may affect the response achieved in clinical practice. There was no significant improvement in OS in the 10% of patients with performance status 2, possibly due to patient numbers. PFS was 5.6 months with abiraterone and 3.6 months with placebo (HR 0.67; p<0,001). The study authors comment that their results show that continued androgen-receptor signalling contributes to disease progression in this setting, and that other endocrine therapies should be evaluated in this stage of disease. They note that the study validates the hypothesis that biosynthesis of steroids downstream of CYP17 contributes to disease progression in a subgroup of men who have disease that remains driven by steroid ligands. As this subgroup cannot be identified a priori, they note that continuing to call this disease 'hormone refractory' is imprecise. Another Phase III study is evaluating abiraterone in patients with mcrpc who have not 2

received previous treatment with a docetaxel-based chemotherapy. ADVERSE EFFECTS Cabazitaxel In the clinical trial, the most common serious adverse effect was grade 3/4 (severe to life-threatening) neutropenia, which occurred in 82% of patients treated with cabazitaxel and 58% of those treated with mitoxantrone. Febrile neutropenia was also more common with cabazitaxel (8% vs 2%). Six of the patients who developed grade 4 neutropenia died. Granulocyte colony stimulating factor (G-CSF) can be given to treat or prevent neutropenia. Deaths related to severe diarrhoea, electrolyte imbalance and renal failure have also occurred. Other adverse effects have included anemia, fatigue, asthenia and peripheral neuropathy. Nausea is common, but not severe. Severe hypersensitivity reactions may occur. Serious toxic effects of cabazitaxel are of concern, especially in older men with mcrpc and those with comorbidity. 7 Drug interactions: Strong inhibitors of CYP3A, such as the protease inhibitors, may increase cabazitaxel serum concentrations. Strong inducers of CYP3A such as rifampin may decrease them. Abiraterone CYP17 inhibition by abiraterone causes adrenocortical insufficiency, hypertension, hypokalaemia and fluid retention; co-administration of prednisone reduces the severity of these effects. 8 Although cardiac events occurred in a higher number of patients randomised to abiraterone, these were primarily grade 1 or 2 and there was no statistically significant difference in the rate seen with abiraterone versus placebo (13% vs 11%). There were no increases in levels of fatal cardiac events between the two groups (1.1% vs 1.3%, respectively). However, the pivotal study excluded patients with uncontrolled hypertension and clinically significant heart disease; abiraterone should be used with caution in patients with a history of cardiovascular disease. Although abiraterone was associated with elevated aminotransferase levels, liver function test abnormalities occurred in a similar proportion of patients (10% abiraterone versus 8% placebo; grade 3/4 changes 3.5% and 3.0%, respectively). Other common adverse events seen in the study (rate in abiraterone versus placebo) included fatigue (44% vs 43%), back pain (30% vs 33%), nausea (30% vs 32%), constipation (26% vs 31%), bone pain (25% vs 28%), arthralgia (27% vs 23%), and urinary tract infections (12% vs 7%). Overall, adverse events led to discontinuation in 19% of the abiraterone group and 23% of the placebo group (p=0.09). Abiraterone did not appear to increase the risk of metabolic changes or symptoms associated with chronic androgen deprivation, but that longer follow-up is required to evaluate any late toxic effects. Drug interactions: Abiraterone is an inhibitor of CYP2D6; it can increase serum concentrations and possibly the toxicity of drugs metabolised by that enzyme. Abiraterone is a substrate of CYP3A4 in vitro; strong inhibitors of CYP3A4 could increase its serum concentrations and inducers of CYP3A4 could decrease them. DOSAGE AND COST Drug IV infusion every 3 weeks* Cost per 3 week cycle** (NIS) Cabazitaxel (Jevtana) 25mg/m 2 20,766 Docetaxel (Taxotere) 75mg/m 2 3,580 Mitoxantrone 12mg/m 2 585 Drug Oral Dose* Cost (NIS) Abiraterone (Zytiga) 1000mg once daily 13,839 (3 weeks); 18,452 (4 weeks) *With prednisone 10mg daily. **Costs are based on an adult with a body surface area of 1.8m 2 rounded to the nearest vial size and does not include the cost of infusion fluids, pre-medication or prednisone. They are based on the maximum price to pharmacies as approved by the MoH. Abiraterone (Zytiga) is available as 250mg tablets that should be taken with water and swallowed whole. Patients should not eat for 2 hours before taking the drug, or for 1 hour afterwards. The recommended dosage of abiraterone is 1000mg once daily with prednisone 5mg twice daily. The dosage should be decreased to 250mg once daily in patients with moderate hepatic impairment; it is contraindicated in patients with severe hepatic impairment. If ALT and/or AST increase to 5x the upper limit of normal 9ULN or bilirubin increases to 3x ULN, the drug should be stopped and restarted at a lower dose. CONCLUSIONS Cabazitaxel may prolong survival in patients with mcrpc that has progressed during or after treatment with docetaxel, but adverse effects can be severe. It resulted in increased treatment-related mortality, probably because of substantial neutropenia and diarrhoea. Although these two toxicities are manageable if carefully monitored during treatment they may have an impact on patients with advanced disease who may have been heavily pre-treated with docetaxel. In practice, dose reductions are likely to be used in response to neutropenic episodes. It is uncertain whether the relative dose intensity of cabazitaxel treatment managed in the clinical study (96%) will be reproducible in practice. There is uncertainty about the effects of cabazitaxel on renal and cardiac adverse events and about the effect of cabazitaxel on OS and PFS in the long-term. Abiraterone is an oral drug that can extend survival in patients with mcrpc previously treated with docetaxel. 3

Patients who may receive the most benefit from are those who have previously been treated with one docetaxelcontaining chemotherapy regimen. How it compares with other drugs for this indication remains to be determined. It is not possible to identify patients who have disease that remains driven by steroids before treatment is started. At the present time therefore it would not be possible to identify particular patients who are more likely to respond to abiraterone. If this could be done it would allow more effective targeting of treatment so that those with true hormone-resistant disease could receive other therapies. Cabazitaxel and abiraterone are the first two agents to improve outcome of men with mcrpc for whom treatment with docetaxel-based chemotherapy failed. Patients enrolled into the drugs' pivotal trials had similar baseline characteristics, and cabazitaxel and abiraterone showed benefits of similar magnitude, although abiraterone was less toxic. Abiraterone was associated with manageable toxicity distinct from that associated with cytotoxics and should give it an advantage over cabazitaxel and palliative chemotherapy regimens in this setting. References 1. Tannock I et al, N Engl J Med 351:1502, 2004. 2. Mita A et al, Clin Cancer Res 15:723, 2009. 3. De Bono J et al, N Engl J Med 364:1995, 2011. 4. Ratain M, J Clin Oncol, doi.10/1200/jco.2011.37.1167. 5. De Bono J et al, Lancet 376:1147, 2010. 6. Fizazi K et al, abstract 7000, European Multidisciplinary Cancer Congress 2011. 7. Seruga B & Tannock I, J Clin Oncl, doi:10.1200/ JCO.2010.34.3996. 8. Danila D et al, J Clin Oncol 26:1496, 2010. - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - - - - - - - - - - - - - - DEGARELIX FOR ADVANCED HORMONE-DEPENDENT PROSTATE CANCER Degarelix is a GnRH receptor antagonist that rapidly suppresses testosterone levels in patients with prostate cancer, without causing the disease flare due to testosterone surge. Such a surge occurs with a GnRH agonist used alone but which can be overcome by adding an anti-androgen. A randomised unblinded trial showed that while at first the reduction in testosterone levels is more rapid with degarelix than with GnRH agonist leuprorelin, after about a month there is no significant difference between treatments. Injection-site reactions with subcutaneous degarelix were far more frequent than with intramuscular leuprorelin. The effect of degarelix on prostate cancer clinical endpoints is unknown. Prostate cancer is a hormone-dependent malignancy. Androgen deprivation (medical castration) is one approach to the treatment of prostate cancer. The attainment of castrate levels of testosterone is used as a surrogate to assess efficacy in achieving control of hormonedependent disease. It can be attained by using agonists of gonadotrophin-releasing hormone (GnRH) such as goserelin, leuprorelin and triptorelin. Although these drugs cause an initial surge in testosterone, long-term use leads to decreased production. The testosterone surge may lead to a flare in the clinical symptoms of patients with advanced prostate cancer, including increased bone pain due to metastatic disease, urinary obstruction, and progression of spinal cord compression leading to neurological compromise. A peripheral non-steroidal anti-androgen can be added for several weeks at the beginning of GnRH agonist therapy to counteract the testosterone surge and its effect on tumour growth. DEGARELIX Degarelix (Firmagon; Ferring) reduces testosterone production in the testes by binding reversibly to the GnRH receptor in the anterior pituitary gland. Degarelix cuts testosterone concentrations within a few days, without the surge seen with GnRH agonists. Degarelix was approved in Israel in early 2011 for "treatment of adult male patients with advanced hormonedependent prostate cancer." (In USA it was approved in 2009 for "rapid medical castration of men with advanced prostate cancer.") It was added to the Israel NHI basket this year within its licensed indication for men "with urgent need to reduce testosterone levels such as cord compression, disseminated intravascular coagulation (DIC), urine blockage." CLINICAL STUDIES Two dose-finding studies found that degarelix can suppress testosterone without causing a testosterone surge. 1-2 4

A randomised unblinded non-inferiority study in 610 patients with various stages of prostatic cancer compared two dosing schedules of subcutaneous injection of degarelix (240mg followed by monthly 160mg doses, or 240mg followed by monthly 80mg doses) with monthly intramuscular leuprorelin 7.5mg. 3-5 The degarelix 240mg/160mg and leuprorelin 7.5mg dose regimens are not licensed in Israel. Among the 201 patients randomised to leuprorelin, only 23 (11%) also received the antiandrogen bicalutamide. 3 This is in contrast to routine clinical practice when initiating GnRH agonists in patients with metastatic disease. The study population included patients with localised (31%) and those with nonclassifiable disease (19%). The marketing authorisation restricts use to patients with advanced disease i.e. 50% of the study population. The primary endpoint of the study 3 was the rate of achieving and maintaining castrate-testosterone levels (<0.5ng/mL) for one year. Degarelix-treated patients achieved castrate levels of testosterone more rapidly than patients treated with leuprorelin. In the degarelix groups, the testosterone level rapidly fell to below 0.5ng/ml in 96% of patients 3 days after the first injection, and in 99% of patients after 7 days. In the leuprorelin group, the testosterone level rose initially, as expected, and only 18% of the patients had reached the target concentration 14 days after treatment initiation. 4 PSA levels also declined more rapidly with degarelix than with leuprorelin overall, but patients in the leuprorelin group treated with bicalutamide achieved PSA reductions as rapidly as those receiving degarelix. Medical castration rates after one year of treatment were 98% with degarelix 240mg/160mg, 97% with degarelix 240mg/80mg and 96% with leuprorelin. These differences are not statistically significant. 4 ADVERSE EFFECTS Adverse effects are common with degarelix. In the comparative unblinded study, 40% of patients had injection-site reactions with the drug; less than 1% of the leuprorelin group suffered from this side effect. Other adverse effects reported in the trial included hot flushes, weight gain, fatigue and altered liver function. Adverse events resulted in approximately 7-9% of the degarelix group and 6% of the leuprorelin group discontinuing treatment. 1 There were no reported instances of the serious consequences of testosterone flare that are the subject of this assessment in any of the treatment groups. There was no difference in terms of adverse effects during the first month of treatment. During treatment with degarelix the QTc interval on the ECG can be prolonged and some patients will develop anemia. Some patients develop antibodies to degarelix although it is yet unclear whether this affects long-term efficacy. Although androgen deprivation has metabolic effects, lipids other than cholesterol, and glucose were not studied. Hypercholesterolaemia occurred in 5% of patients given degarelix. 3 DOSAGE AND COST Drug Dose Regimen Cost per month (NIS)* Degarelix injection 240mg initial dose followed by 80mg 1,547 initially, (Firmagon) SC injection monthly 856 thereafter** GnRH Agonists Buserelin nasal spray 0.1mg spray into each nostril six times 920 (Suprefact) daily Goserelin implant (Zoladex) 3.6mg SC injection monthly 740 (Zoladex LA) Leuprorelin inj. (Lucrin Depot) 10.8mg SC injection every 12 weeks 3.75mg IM or SC injection every month 11.25mg IM or SC injection every 3 months 740 781 705 Triptorelin inj. (Decapeptyl Depot) 3.75mg IM every 4 weeks 11.25mg IM every 12 weeks 774 693 Anti-Androgens Cyproterone tabs (Androcur) 50-300mg daily in divided doses 125-753 Flutamide tabs 250mg 3 times daily 288 Bicalutamide tabs 50mg once daily 384 *Based on maximum retail price approved by the MoH. **Degarelix was included in the NHI basket in 2012 without extra funding, suggesting that the reimbursable cost to sick funds is no higher than the cost of GnRH agonist plus anti-androgen. CONCLUSIONS The risk of symptom aggravation linked to prostate cancer associated with the initial testosterone surge during GnRH agonist therapy can be offset by adding an anti-androgen during the first month of treatment. 5

In patients with prostate cancer, the only available comparative trial shows that degarelix, a GnRH antagonist, provides more rapid castration than leuprorelin, a GnRH agonist, without an initial testosterone flare. However, only a minority of patients actually received add-on anti-androgen therapy in the comparative trial. Castration is almost always achieved with either drug after one month and is maintained for at least the first year of treatment. There is a lack of long-term data to show whether breakthrough occurs less frequently and/or later with degarelix than with leuprorelin. Data are available assessing surrogate outcomes only. The clinical benefit of avoidance of tumour flare with degarelix has not been assessed in clinical trials as an outcome measure. The effect of degarelix on prostate cancer clinical endpoints is unknown. Further study will be needed to see the effect of degarelix on survival and whether it has any role in patients who have not responded to a GnRH agonist. The only advantage of degarelix treatment is that it dispenses with the need for concomitant anti-androgen therapy. In long-term therapy GnRH agonists offer the convenience of depot formulations that can be given at intervals of up to 6 months. The use of degarelix requires subcutaneous administration of a large volume of solution, leading to frequent reactions at the injection site. References 1. Gittelman M et al, J Urol 180:1986, 2008. 2. Van Poppel H et al, Eur Urol 54:805, 2008. 3. Klotz L et al, BJU Int 102:1531, 2008. 4. FDA (CDER), Medical review, 19 December 2008. 5. European Medicines Agency, Assessment report EMEA/ CHMP?635761/2008. - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Although great care has been taken in compiling the contents of this publication, the publisher and the editor are not responsible or in any way liable for the accuracy of the information, for any errors, omissions or inaccuracies, or from any consequences therefrom. Inclusion or exclusion of any product does not imply its use is either advocated or rejected. Opinions expressed do not necessarily reflect the views of the publisher or editor. In addition to the information supplied herein, reference should always be made to the manufacturer s literature in respect of each drug before it is prescribed. Administration and Production: Dvora Sax PHARMA Drug Bulletin is a Member of the International Society of Drug Bulletins 6