Oncology Prostate Cancer


degarelix has been tested against leuprolide in a one-year, phase III trial.30


In all, 610 patients with PCa (any stage, median age 72 years, median PSA 19ng/ml) were randomised into three arms: one degarelix subcutaneous 240mg starting dose followed by monthly maintenance doses of 80 or 160mg for a total of 12 months, or intramuscular leuprolide 7.5mg monthly. The primary end-point of the trial, defined by the US Food and Drug Administration and European Medicines Agency, was suppression of testosterone to ≤0.5ng/ml at all monthly measurements from day 28 to 364, thus defining the treatment response. The primary end-point was achieved by 97.2, 98.3 and 96.4% of patients in the degarelix 240/80mg, degarelix 240/160mg and leuprolide groups, respectively. Three days after starting treatment, testosterone levels were ≤0.5ng/ml in 96.1 and 95.5% of patients in the degarelix 240/80mg and 240/160mg groups, respectively, and in no patients in the leuprolide group. No transient testosterone surge was seen in the degarelix arm, in contrast to leuprolide. The median PSA levels at 14 and 28 days were significantly lower in the degarelix groups than in the leuprolide group (p<0.001). The hormonal side effect profiles of the three treatment groups were similar to the previously reported effects for ADT. The degarelix injection was associated with a higher rate of injection-site reactions than with the leuprolide injection (40 versus <1%, respectively; p<0.001). There were no systemic allergic reactions seen with degarelix. More interestingly, and less expected, pre-planned subanalyses showed degarelix to be significantly superior to leuprolide in decreasing the rate of PSA and alkaline phosphatase failure, especially in patients with the most advanced cancers.31,32 first subanalysis focused on PSA progression-free survival.32


The Patients


receiving degarelix showed a significantly lower risk of PSA progression or death compared with leuprolide (p=0.05). PSA recurrences occurred mainly in patients with advanced disease and exclusively in those with baseline PSA >20ng/ml. Patients with PSA >20ng/ml had a significantly longer time to disease recurrence with degarelix (p=0.04). The second subanalysis has focused on alkaline phosphatases (S-ALP).31


Baseline


S-ALP levels were higher in metastatic patients. In metastatic disease, after initial peaks in both groups, S-ALP levels were suppressed to below baseline with degarelix but remained around baseline with leuprolide. The late rise in S-ALP level seen with leuprolide was not apparent with degarelix. The pattern of S-ALP response was similar in patients with a baseline PSA level of ≥50ng/ml. Between-treatment differences in patients with metastatic disease and those with a PSA level ≥50ng/ml were significant at day 364 (p=0.014 and p=0.007, respectively). Patients in the degarelix group maintained S-ALP suppression throughout the study, in contrast to those in the leuprolide group. These studies pinpoint at a potential additional benefit of LHRH antagonists beyond initial flare suppression.


Improving on Testosterone Recovery


One of the main advantages of LHRH agonists over orchiectomy is reversibility, allowing adjuvant use for a fixed period of time and intermittent ADT. Testosterone recovery, however, is highly variable between patients and frequently exceeds the intended treatment duration. The time taken for serum testosterone levels to increase to above castrate levels is highly dependent on the duration of ADT.33 Normalisation may be achieved in 73–100% of patients within six months of stopping ADT that lasted for one year or less, whereas the rate of normalisation may be as low as 0–18% at six months in patients who have received ADT for a period of three years.33,34


For example,


the period of attenuated serum testosterone concentrations in most patients who have received ADT for three years is approximately 18 months.34,35


24


Another confounding factor of serum testosterone recoverability is patient age. Bong et al. demonstrated that when patients who had received goserelin following radical prostatectomy, external beam radiotherapy or as primary therapy were stratified by age at the initiation of therapy, 78% of patients who were >70 years of age remained castrated versus 17% of those who were ≤70 years of age.36


Reversibility may be improved by using removable implants, such as the Vantas histrelin acetate implant. Indeed, physically removing the agonist may lead to a more rapid normalisation of the hypothalamic– pituitary–testicular axis. In a study by Fridmans et al., it was demonstrated that in patients with PCa who had received treatment with the histrelin implant, LH levels increased in >50% of patients and in all patients within two and six weeks of implant removal, respectively. Serum testosterone increased in all these patients within 10 weeks of treatment cessation.37


In contrast, serum LH and


testosterone levels remained fully suppressed for nine months in seven out of eight patients receiving a standard LHRH.37


Improving Intracellular Control Inhibiting Intracellular Synthesis of Androgens Despite optimal suppression of serum testosterone, PCa cells will invariably become ‘resistant’ if the patient survives for a sufficient period of time.38


This does not mean that the tumour has become insensitive to any other hormonal manipulation. Indeed, recent studies have indicated that PCa cells, even in a low testosterone environment, remain dependent on androgens of non-gonadal origin, e.g. from the adrenal glands and intratumoural biosynthesis.39,40


This is why the term


‘hormone-refractory prostate cancer’ has been replaced by ‘castration-resistant prostate cancer’ (CRPC).


One of the most important observations of the last decade is the ability of CRPC cells to overexpress major enzymes of androgen biosynthesis and therefore synthesise androgens intracellularly.41


This


intratumoural ‘reservoir’ of androgens may be sufficient to maintain the androgen dependence of PCa during ADT.42


CRPC cells upregulate


17α-hydroxylase (CYP17A), one of the main enzymes in the biosynthesis of androgens.43


Abiraterone acetate is an inhibitor of CYP17 that is currently in clinical development. Administration of abiraterone increases adrenocorticotropic hormone levels upstream of CYP17 and decreases biosynthesis of androgens, including testosterone, downstream.43


Abiraterone has been tested in a phase I/II programme in patients with CRPC. The drug has been proved to be safe in doses ranging from 200 to 2,000mg. Toxicities relating to elevated mineralocorticoid levels were moderate and easily prevented by the mineralocorticoid receptor antagonist eplerenone at 50–200mg/day. PSA reductions to ≥50 and ≥90% were observed in 57 and 29% of patients, respectively, and lasted between 69 and 578 days. Radiological regression and improved symptoms, with a reduction in analgesic use, were also documented.43,44


Based on these


initial results, abiraterone has been tested in a placebo-controlled, randomised, phase III trial conducted in 1,195 patients with metastastic CRPC previously treated with docetaxel.45


Patients were


randomised 2:1 to abiraterone 1,000mg plus prednisone 5mg twice daily (n=797) or placebo plus 5mg prednisone twice daily (n=398). Abiraterone increased overall survival by 3.9 months, from 10.9 months in the placebo arm to 14.8 months in the abiraterone arm (HR 0.65, 95% CI 0.54–0.77).45


Abiraterone also significantly improved time to progression and PSA response rate. Mineralocorticoid-related EUROPEAN UROLOGICAL REVIEW


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