Anders Neijber

Degarelix as an Intermittent Androgen Deprivation Therapy for One or More Treatment Cycles in Patients with Prostate Cancer

BACKGROUND Guidelines for prostate cancer treatment suggest that intermittent androgen deprivation (IAD) can be considered for certain patients. OBJECTIVE To evaluate the efficacy and safety of degarelix as IAD for one or more treatment cycle(s) in prostate cancer patients requiring androgen deprivation. DESIGN, SETTING, AND PARTICIPANTS This open-label uncontrolled multicenter study included patients with prostate-specific antigen (PSA) >4 to 50 ng/ml or PSA doubling time <24 mo. Induction included 7-mo treatment. Off-treatment period started when PSA was ≤4 ng/ml and lasted up to 24 mo based on PSA and testosterone levels. Treatment was reinitiated when PSA was >4 ng/ml. INTERVENTION Each induction period included a starting dose of degarelix 240mg, and thereafter 80mg once a month for 6 mo, followed by off-treatment periods. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point was time to PSA >4 ng/ml. Secondary end points were subgroup analysis of the primary end point, time to testosterone >0.5 and >2.2 ng/ml, quality of life (QoL), and sexual function during the first off-treatment period. RESULTS AND LIMITATIONS Of 213 patients in the first induction period, 191 entered the first off-treatment period, 35 patients entered the second induction, and 30 entered the second off-treatment period. Only two patients entered the third cycle. Median time to PSA >4 ng/ml and duration of first off-treatment period was 392 d each. Significant differences in time to PSA >4 ng/ml were observed between subgroups stratified by prognostic factors (previous curative treatment, cancer stage, PSA levels, and Gleason scores). Time to testosterone >0.5 and >2.2 ng/ml was 112 and 168 d, respectively. Change in QoL remained nonsignificant, and sexual function gradually improved during the off-treatment period. Adverse events were fewer during the off-treatment period and subsequent treatment cycles. CONCLUSIONS IAD with degarelix resulted in an improvement in sexual function commensurate with increased testosterone levels while PSA remained suppressed. The treatment for one treatment cycle or more was well tolerated. PATIENT SUMMARY Guidelines for prostate cancer treatment suggest that intermittent androgen deprivation (IAD) can be considered for certain patients. IAD with degarelix resulted in improved sexual function commensurate with increased testosterone levels while prostate-specific antigen remained suppressed. The treatment for one treatment cycle or more was well tolerated. TRIAL REGISTRATION Clinicaltrials.gov identifier NCT00801242.

EFFICACY AND SAFETY OF A NEW TOPICAL TESTOSTERONE REPLACEMENT GEL THERAPY FOR THE TREATMENT OF MALE HYPOGONADISM

OBJECTIVE Testosterone replacement therapy is indicated for male hypogonadism. This study aimed to evaluate the efficacy and safety of testosterone gel 2% (Tgel) over 90 days. METHODS This phase 3, open-label, noncomparator study was conducted in adult hypogonadal men (2 consecutive fasting serum testosterone values <300 ng/dL and >86% subjects with symptoms consistent with testosterone deficiency). Subjects applied Tgel 23 mg/day (single pump-actuation using a hands-free cap applicator). The dose was uptitrated to 46 mg/day after 2 weeks if the 4-hour serum total testosterone level was <500 ng/dL. The dose could be further up- or downtitrated to 23, 46, and 69 mg on Days 21, 42, and 63. The primary endpoint included the percentage of subjects with average testosterone concentration (Cave (0-24)) between 300 and 1,050 ng/dL on Day 90. Safety endpoints were adverse events (AEs), laboratory parameters, and vital signs. RESULTS Of the 159 who enrolled, 139 men completed the study. Approximately three-quarters (76.1%) of subjects met Cave criteria on Day 90. Most AEs were mild to moderate. There were 5 serious AEs, and 1 (myocardial infarction) was judged as possibly related to Tgel. Confirmed excessive increases in prostate-specific antigen or hematocrit levels were rare. Tgel had a favorable local skin tolerability profile. CONCLUSION Overall, 76% of subjects achieved Cave between 300 and 1,050 ng/dL with Tgel. Symptoms of testosterone deficiency improved with few safety concerns. ABBREVIATIONS AE = adverse event Cave(0-24) = average testosterone concentration CI = confidence interval Cmax = maximum concentration IIEF = International Index of Erectile Function MAF = Multidimensional Assessment of Fatigue PK = pharmacokinetic PSA = prostate-specific antigen SAE = serious adverse event SF-12 = Short Form 12 Health Survey Tgel = testosterone gel 2% Tmax = time to achieve maximum concentration TRT = testosterone replacement therapy.

The efficacy, bioavailability and safety of a novel hydroalcoholic testosterone gel 2% in hypogonadal men: results from phase II open-label studies

Pharmacokinetics, pharmacodynamics and safety of a novel hydroalcoholic testosterone gel 2% (TG) were evaluated in phase II sequential dose escalation studies using 3 application sites (thigh, abdomen and shoulder/upper arm) and 2 application methods. Hypogonadal men (n = 40), 18–75 years, with serum testosterone <300 ng dl−1 were included in both studies. Study 1 evaluated hand‐applied multiple doses of TG 1.25, 2.50 and 3.75 ml (23, 46 and 70 mg of testosterone, respectively), once daily for 10 days to shoulder/upper arm. Study 2 evaluated applicator‐applied (TG 1.25, 2.50 and 3.75 ml) versus hand‐applied (TG 2.5 ml) doses, once daily for 7 days to shoulder/upper arm. Primary endpoint for both studies was responder rate (Cave testosterone levels between 298 and 1050 ng dl−1). In Study 1 following multiple applications, >70% participants in each group were responders. Dose‐dependent increase was observed in PK values for total testosterone, free testosterone and DHT. In Study 2, responder rate was dose proportional: 16.7%, 50.0% and 77.8% responders in TG 1.25, 2.50 and 3.75 ml groups respectively. The bioavailability was highest for the shoulder application. There was a significant improvement in almost all the domains of sexual functioning. Applicator‐application was preferred over hand‐application by majority of the participants. TG was found to be safe and well tolerated in hypogonadal men.

Pharmacokinetics and bioavailability of a new testosterone gel formulation in comparison to Testogel® in healthy men

This randomized, open‐label, multiple‐dose three‐way cross‐over study compared the pharmacokinetics of a new testosterone gel formulation in two strengths, testosterone gel 1% and testosterone gel 2% (FE 999303), with Testogel® in 11 testosterone‐suppressed healthy men. Subjects received one of six treatment sequences; 50 mg of testosterone was administered once daily for 7 consecutive days, with different treatments separated by washout‐periods of 6–9 days. Testosterone gel 1% and testosterone gel 2% displayed greater relative bioavailability (2.6‐ and 1.6‐fold, respectively) than Testogel on Day 1, which persisted, to a smaller extent, on Day 7. Initial absorption was highest and most rapid for testosterone gel 1% and 2%, showing apparent first‐order absorption kinetics. Maximum serum concentrations (Cmax) were 6.25 and 2.97 ng/mL, respectively, occurring ∼5–6 hours post‐application on Day 1 versus Cmax of 1.71 ng/mL after ∼24 hours with Testogel, showing apparent zero‐order absorption kinetics. Similar differences were observed on Day 7. All treatments appeared to reach approximately the same steady‐state level within the first 24 hours. No application‐site skin reactions occurred with any preparation. In conclusion, the new testosterone formulation showed higher bioavailability, and the ability to deliver more testosterone in a smaller volume.

Efficacy and safety of testosterone replacement gel for treating hypogonadism in men: Phase III open-label studies

Efficacy and safety of testosterone gel 2% (TG) were evaluated in two phase 3, open‐labelled, single‐arm, multicentre studies (000023 and extension study 000077). Hypogonadal men having serum testosterone levels <300 ng/dl at two consecutive measurements were included. Study duration was 9 months (000023: 3 months; 000077: 6 months). Starting dose of TG (46 mg) was applied on upper arm/shoulder. The primary endpoint (000023) was responder rate (subjects with average 24‐hour serum testosterone concentration 300‐1050 ng/dl on Day 90). Study 000077 evaluated the safety of TG in patients rolling over from study 000023 over a period of 6 months. Of 180 subjects in 000023, 172 completed and 145 rolled over to 000077, with 127 completers. The responder rate was 85.5%. Fewer subjects in 000077 (12.7%) versus 000023 (31.8%) had maximum testosterone concentration (Cmax) >1500 ng/dl, with no significant safety concerns. Significant improvements in sexual function and quality of life were noted in both studies. Subjects experienced few skin reactions without notable increases in prostate‐specific antigen and haematocrit levels. TG was efficacious with an acceptable safety profile. Cmax >1500 ng/dl did not exhibit distinct impact on safety parameters. However, further optimisation of titration schema to reduce Cmax is warranted while maintaining the average steady state total testosterone concentration.

A new 2% testosterone gel formulation: a comparison with currently available topical preparations

Testosterone gel formulations have become a popular testosterone replacement therapy in patients with hypogonadism since their advent in the year 2000. The gel formulations restore testosterone levels to mid‐normal physiological levels (14–17.5 nmol/L) as early as within 24 h, and help alleviate the signs and symptoms of testosterone deficiency, thereby leading to an improved quality of life. Although testosterone gels have a favourable efficacy and safety profile as compared to injectable and patch formulations, risk of secondary exposure poses a challenge. Approved testosterone topical formulations include Tostrex® (Tostran®, Fortesta®), Androgel® (Testogel®), Testim® and Axiron® (solution), which have a favourable efficacy profile and positively impacted patient‐reported outcome(s). Besides, Testavan, which is a 2% testosterone gel, is under registration in Europe and already approved in Australia in May 2017. Testavan uses a novel hydroalcoholic and highly viscous topical formulation. This product comes with a metered dose dispenser and a cap applicator that allows a hands‐free application for precise dispensing and application. The present article provides a comprehensive review of pharmacokinetic, tolerability and safety profile of the testosterone gels available in the market along with the new 2% testosterone gel, Testavan.

Factors Predicting the Off-treatment Duration in Patients with Prostate Cancer Receiving Degarelix as Intermittent Androgen Deprivation Therapy

BACKGROUND Intermittent androgen deprivation therapy (IAD) is commonly used in prostate cancer because of the benefits of the off-treatment period (OTP). The off-treatment time for patients depends on cancer progression, often measured as a rise in prostate-specific antigen (PSA). OBJECTIVE To evaluate if certain factors can predict OTP duration following 7-mo degarelix therapy. DESIGN, SETTING, AND PARTICIPANTS This multivariable analysis included 191 prostate cancer patients with baseline PSA 4-50 ng/ml or PSA doubling time <24 mo entering the first OTP with PSA ≤4 ng/ml and testosterone <0.5 ng/ml. OTP continued until disease progression, measured as PSA >4 ng/ml. Despite a study-defined OTP maximum of 24 mo, a 50% failure rate was not observed within certain strata. A Weibull distribution was used to estimate median time to PSA >4 ng/ml adjusted for the following variables: age; baseline (or end of induction period [EOI]) PSA; baseline testosterone; cancer stage/previous curative treatment; and Gleason score. According to the results and the utility of these factors in clinical practice, the model was reduced in a stepwise manner. Time to testosterone recovery (testosterone >0.5 and >2.2 ng/ml) was estimated in a similar manner. RESULTS The full five-factor model showed that baseline PSA (p<0.0001), age (p=0.004), prostate cancer stage/previous therapy (p=0.023), and baseline testosterone (p=0.039) influenced OTP. A reduced two-factor model (baseline PSA, age) showed that only baseline PSA influenced OTP (p<0.0001), and patients with baseline PSA ≤4 ng/ml had the longest OTP. In addition, EOI PSA (p<0.0001) and age (p=0.050) significantly influenced OTP. The times to testosterone >0.5 and >2.2 ng/ml were longer for older patients and those with lower baseline testosterone levels. CONCLUSION Patients with lower baseline and EOI PSA, and older patients can stay off therapy longer and therefore may benefit more from degarelix IAD. These factors may help in proposing an algorithm to predict the OTP and optimise visit frequency. PATIENT SUMMARY We describe extended analysis results for a trial in which patients with prostate cancer received intermittent androgen deprivation treatment. Prostate-specific antigen levels at baseline and at the end of the induction period, as well as older age, predicted the duration of the off-treatment period. Testosterone recovery was slower in older patients and in patients who had lower pretreatment testosterone levels. These factors may help in deciding whether to choose continuous or intermittent treatment as a strategy. TRIAL REGISTRATION Clinicaltrials.gov NCT00801242.