Clinical phase III studies of IAS

Nowadays a number of phase III trials have been completed comparing IAS with CAS [16]. Of the ten reported trials, two included patients with relapse after radical prostatectomy or radiation therapy, all others studied locally advanced and metastatic disease [22,34]. The number of patients in these trials varied from 68 to 1386, but only four involved >500 patients; the average age of patients was around 70 years. Full details of trial design are not available for all studies, several reports are available only in abstract form [16]. The treatment regimen in all but one of the trials consisted of a LHRH agonist and an antiandrogen. The exception was Verhagen et al., in which antiandrogen monotherapy (cyproterone acetate/CPA) was the sole regimen studied [35]. Although there was generally consistency in the PSA levels designated for AS discontinuation (0.1/4 ng/ml or 20% of the initial PSA value), the criteria for resuming treatment were less uniform, with 4 ng/ml for biochemical relapses and 10 or 20 ng/ml 20 ng/ml for locally advanced or metastatic disease, respectively. The low PSA nadir and reinitiation values used by Tunn et al. and Klotz et al. are due to the fact that the study involved patients who had relapsed after radical prostatectomy [22,34]. End points in these studies also varied to some degree: whereas the majority had time to progression as the primary end point, three assigned survival and one focussed on QoL outcomes [35]. Average follow-up times in these studies have all been >2 yr, with a maximum of 12 years cited by Calais da Silva et al. [13].

2.3.1. South European uroncological trial [13]

Patients with locally advanced or metastatic with histologically confirmed prostate adeno-carcinoma, cT3-cT4 M0, cT3-cT4 M1, PSA >4 ng/ml, were recruited for this study and end point was time to subjective or objective progression. All registered patients had an initial 3-months induction treatment with CPA (200 mg daily for two weeks) followed by monthly depot injections of a LHRH analog plus 200 mg of CPA daily. Patients (n = 626) whose PSA level decreased to <4 ng/ml or by at least 80% of the initial level by the end of the induction were randomized. Time to any progression was slightly longer in the continuous arm, with an HR of progression of 0.81. Both metastatic status and PSA level were independent predictors of progression, with M1 and PSA level > 4 ng/ml associated with a greater hazard of progressing. In the intermittent and continuous arm there was no significant difference in OS (p = 0.84) and the HR was 0.99 for CAS compared with IAS. The greater number of cancer deaths in the IAS treatment group was balanced by a greater number of cardiovascular deaths under CAS. Both PSA level and metastatic status at randomization were independently associated with survival. A significant interaction of metastatic status with treatment was almost reached (p = 0.07). Among M0 patients, the HR for continuous therapy compared with intermittent therapy was 0.86 (95% CI: 0.65-1.14), favouring continuous; among M1 patients, the HR was 1.26 (95% CI: 0.90-1.78), favouring intermittent. It was concluded that IAS should be considered for use in routine practice because it is associated with no re duction in survival, no clinically meaningful impairment in QoL, better sexual activity, and considerable economic benefit to the individual and the community. Since this study used only three months of therapy before stopping treatment in the intermittent arm, without impairing survival, there are significant savings for a patient receiving IAS for one year relative to CAS.

In this trial, a total of 68 evaluable patients with hormone-naive advanced or relapsing prostate cancer were randomized to receive AS (goserelin and flutamide) according to a continuous (n = 33) or intermittent (n = 35) regimen. The outcome variable was time to androgen-independence and mean follow-up was 30.8 months. The estimated 3-year progression rate was significantly lower in the IAS group (7.0%) than in the CAS group (38.9%). It was concluded that IAS treatment may maintain the androgen-dependent state of advanced human prostate cancer, as assessed by PSA measurements, at least as long as CAS treatment. This study may be regarded as underpowered to assess the full impact of IAS and the authors recommended further studies with longer follow-up times and larger patient cohorts to determine the comparative impacts of CAS and IAS with certainty.

This randomized study compared AS with goserelin + bicalutamide in CAS with IAS. The primary endpoint was time to clinical and/or biochemical progression of the disease and secondary endpoints were survival time, QoL and side effects. Patients had histologically confirmed adenocarcinoma of the prostate in clinical stage T1-4N1-3M0 or T1-4N0-3M1 (D1 or D2). After an induction phase of six months with AS, 335 patients whose PSA decreased under 4 ng/ml or 90% from baseline were randomized. About two-thirds of the patients of both the intermittent and the continuous therapy arm (65% versus 66%, ITT population) experienced a clinical and/or biochemical disease progression. The median time to progression was longer for patients randomised to IAS (16.6 months) compared with patients randomized to CAS (11.5 months; difference not significant). The median time to death from any cause was 51.4 months in the intermittent arm compared and 53.8 months in the continuous therapy arm (p = 0.658). There were no differences in the incidence of patients with any safety parameter. Patients' self-assessment of their overall health and of their sexual activity appeared to be favourable in the IAS therapy arm. It was concluded that IAS in D1 and D2 prostate cancer patients seems to be safe and superior in respect to QoL.

2.3.4. TAP22 investigators group trial [38]

This study aimed at comparing CAS to IAS with AS consisting of leuproreline and fluta-mide in patients with newly diagnosed metastatic prostate cancer with bone metastases (stage D2). All patients had a positive bone or CT scan and a PSA > 20 ng/ml. After a 6 months induction period with AS, they were randomized into two groups if the PSA was < 4 ng/ml. CAS was continued after randomization and in the IAS group treatment was discontinued until PSA > 10 ng/ml or clinical progression. AS was then resumed for

3 months periods until the PSA became < 4 ng/ml and then treatment was then stopped again until the next progression for a new cycle. 341 patients were selected and received a 6 months induction AS period, and 173 were randomized: 83 to CAS and 86 to IAS. Patients were off-treatment approximately 50% of the first cycle, without decline in succeeding cycles and most had testosterone recovery. A progression occurred in 127 patients (73.4%). The overall QoL did not differ significantly between both arms. Median OS was 52 months for CAS and 42.2 months for IAS (p=0.74) and the median progression-free survial was 15 months for CAS and 20.7 months for IAS (p=0.73). This randomized trial comparing CAS to IAS in metastatic prostate cancer patients suggests that IAS may be as safe as CAS in D2 prostate cancer patients.

2.3.5. Therapy Upgrading Life in Prostate cancer (TULP) study [39,40]

Eligible patients (n = 290) had histologically proven advanced prostate cancer with positive lymph nodes or distant metastases (T2-4N1-3M0 or T2-4NxM1). They received AS with bu-serelin and nilutamide for 6 months. Patients who had a normalisation of PSA (< 4 ng/ml) after the course, were randomized between IAS (n=97) or CAS (n=96). Median time to clinical progression or PSA escape was 18.0 months in the IAS arm and 24.1 months in the CAS arm. In particular, the 2-year risk of progression for baseline PSA < 50 ng/ml, 50 to <500 ng/ml, and >500 ng/ml was 25%, 55%, and 76% (P = 0.03) in CAS, and 38%, 64%, and 85% (p = 0.006) in IAS, respectively. There was no clinically significant difference in QoL scores between patients. Metastatic prostate cancer patients with high baseline PSA, pain, and high PSA nadir, after a 6-months induction course, have a poor prognosis with hormonal therapy. Overall, in this study patients on IAS seem to do worse than CAS patients. Also, patients receiving IAS with low PSA nadir had significantly higher progression rates than CAS patients. In IAS testosterone recovery during the off-treatment phase was incomplete, explaining the missing benefit for QoL, even though more side effects occurred during CAS. Therefore, it was concluded from this study that IAS constitutes not a good treatment option for most metastatic prostate cancer patients.

2.3.6. European trial EC507 [22]

In this multicentre European prospective randomized phase III trial EC507, testosterone serum concentrations under AS were analyzed in prostate cancer patients with PSA progression after radical prostatectomy. Patients were randomized to either CAS or IAS therapy using a 3-months depot with leuprorelin acetate as microcapsule formulation. In 109 patients testosterone recovery to baseline values was achieved in 79% during the first and in 65% during the second IAS cycle, respectively. Median time to testosterone normalization was 100 days in the first and 115 days in the second cycle, respectively. There also appeared to be a QoL benefit during off-treatment intervals owing to the recovery of serum testosterone levels. No significant difference was observed up to 1000 days between IAS and CAS with regard to time to androgen-independent progression. This was the first prospective study of leuprolide, demonstrating normalization of testosterone levels in the off-treatment period in patients undergoing IAS.

This randomized trial compared efficacy and QoL of IAS and CAS treatment by CPA of asymptomatic patients with prostate cancer metastatic to the bone. A total of 366 patients with metastatic prostate cancer received 3 to 6 months CPA (100 mg daily) depending on their PSA response. Patients with a good or moderate response were randomized to continuous or intermittent treatment. Intermittent hormonal therapy of metastatic prostate cancer by CPA has advantages in important QoL domains. However, cognitive function scores appeared reduced in the intermittent group.

2.3.8. NCIC CTG PR.7/SWOG PR.7/CTSU JPR.7/UK trial [34]

This Intergroup randomized phase III trial compared IAS vs. CAS to test for non-inferiority of IAS with respect to OS. Patients had rising PSA > 3.0 ng/ml >1 year post radical radiotherapy (RRT), either initial or salvage, for localized prostate cancer. Stratification factors were time since RRT (>1-3 vs >3 years), initial PSA (<15 vs >15), prior radical prostatectomy and prior AS. IAS was delivered for 8 months in each cycle with restart when PSA reached >10 ng/ml off-treatment. Primary endpoint was OS, secondary endpoints included time to hormone refractory state, QoL, duration of treatment/non-treatment intervals, time to testosterone and potency recovery. The trial was halted after a planned interim analysis demonstrated that a prespecified stopping boundary for non-inferiority was crossed. 1,386 patients were randomized to IAS (690) or CAS (696) arms. IAS patients completed a median of 2 x 8 months cycles (range: 1-9) and median follow-up was 6.9 years. 524 deaths were observed (268 on IAS vs. 256 on CAS). Median OS was 8.8 vs. 9.1 years on IAS and CAS arms, respectively (HR 1.02, 95%CI 0.86-1.21; p for non-inferiority [HR IAS vs CAS > 1.25] = 0.009). The IAS arm had more disease related (122 vs. 97) and fewer unrelated (134 vs. 146) deaths. Time to androgen insensitivity was statistically significantly improved on the IAS arm (HR 0.80, 95%CI 0.67-0.98; p = 0.024). IAS patients had reduced hot flashes, but otherwise there was no evidence of differences in adverse events, including myocardial events or osteopor-otic fractures. Thus, in men with PSA recurrence after RRT IAS was non-inferior to CAS with respect to OS.

2.3.9. SWOG 9346 intergroup trial [17]

The largest trial comparing IAS and CAS in metastatic patients was reported by Hussain et al. [17]. Between 1995 and 2008, the study enrolled 3040 men with newly diagnosed metastatic disease and PSA levels > 5 ng/mL. The study population was preselected for hormone sensitivity and when PSA level fell to < 4 ng/mL, patients were randomized to either IAS (n = 770) stopping treatment at that point until a rise in PSA level was observed (an increase to 20 ng/mL, or for those with baseline value < 20 ng/mL, when PSA returned to baseline) or CAS (n = 765). Hormone therapy consisted of goserelin and bica-lutamide for 7 months, which was in use in 1995 when the study was launched. At randomization, patients were stratified according to performance status, extent of disease, and prior exposure to hormone therapy.

At a median follow-up of 9.2 years, median overall survival was 5.1 years with IAS and 5.8 years with CAS, an absolute difference of slightly more than 6 months favoring CAS in the entire study population. The study design specified that survival with IAS would be noninferior to CAS if the upper 95% confidence bound for the HR did not reach or include 1.2. This specification would rule out with high confidence the possibility of a 20% or greater increase in the relative risk of death with IAS. The difference between the two treatments resulted in a HR of 1.09 in favor of CAS, but the upper boundary of the 95% confidence interval was 1.24, so the conclusion was that the two treatments could not be called equivalent and survival with IAS therapy was regarded inferior to IAS by these authors. For this study, survival in both arms was much better than the expected 3-year median OS. In all examined subgroups, CAS was slightly better than IAS, with exception of extensive disease, where IAS achieved comparable survival (5 years on IAS vs 4.4 years on CAS). In this subgroup analysis, patients with minimal disease had a median overall survival of 5.2 years in the IAS group vs. 7.1 years with CAS, suggesting that the loss of almost two years of life in the intermittent group could not be ruled out. In this study "minimal disease" was defined as disease that had not spread beyond the lymph nodes or the bones of the spine or pelvis and "extensive disease" as disease that had spread beyond the spine pelvis, and lymph nodes or to the lungs or liver.

Trial participants also compared QoL measures across the two study arms during the first 15 months following patient randomization, including measures of sexual function (impotence and libido), physical and emotional function, and energy level. They found improved sexual function in men who received IAS as compared to those on continuous therapy.

2.3.10. FinnProstate study VII [41,42]

The FinnProstate study VII enrolled 852 men with locally advanced or metastatic prostate cancer to receive AS for 24 weeks [41]. Study inclusion criteria were M1 disease at any PSA, M0 disease at PSA 60 ng/ml or greater, or T3-4 M0 prostate cancer at PSA 20 ng/ml or greater, or previously surgically or radiotherapy treated localized prostate cancer and PSA recurrence of 20 ng/ml or greater. Patients in whom PSA decreased to less than 10 ng/ml, or by 50% or more if less than 20 ng/ml at baseline, were randomized to IAS or CAS. In the intermittent therapy arm AS was withdrawn and resumed again for at least 24 weeks based mainly on PSA decrease and increase. Of the 852 men, 554 patients were randomized and observed for a median follow-up of 65.0 months. Of these patients 71% died, including 68% in the intermittent and 74% in the continuous arm (p = 0.12). There were 248 prostate cancer deaths, comprised of 43% under IAS and 47% under CAS (p = 0.29). Median times to progression were 34.5 and 30.2 months in the intermittent and continuous arms, respectively. Median times to death (all cause) were 45.2 and 45.7 months, to prostate cancer death 45.2 and 44.3 months, and to treatment failure 29.9 and 30.5 months, respectively. Therefore, according to this trial, IAS is a feasible, efficient and safe method to treat advanced prostate cancer compared with CAS. However, the prevalence of adverse events was not significantly lower with IAS [42].

2.3.11. Phase III studies - Summary

In general, the phase III trials comparing IAS with CAS involved a varying number of patients, prostate cancer tumor stages ranging from biochemical relapse to metastatic and recurring disease and widely differing durations of initial AS as well as differing PSA values for the start of treatment cessations and reinitiations. Therefore, conclusions to be drawn are restricted to specific tumor stages and treatment schemes.

The Miller randomized trial of IAS versus continuous CAS in 335 patients with advanced (lymph node-positive or metastatic) prostate cancer demonstrated equivalent survival [37]. Patients in the intermittent arm were off-treatment >40% of the time. It is important to note that testosterone recovery after discontinuation of the LHRH agonist is often delayed and may depend on treatment duration, age, baseline testosterone, and ethnicity [22,43]. In the TULP trial of IAS versus CAS for advanced prostate cancer, 193 patients were randomized and, after a mean follow-up of 34 months, no difference in survival was observed [40]. The larger de Silva trial randomized 312 men to CAS and 314 men to IAS [13]. With a median follow-up of 51 months from randomization, there were fewer cancer deaths (84 vs. 106), more cardiovascular deaths (52 vs 41), and an equivalent number of total deaths (169 vs. 170) in the continuous versus intermittent arms respectively. Median time off AS was 52 weeks for patients in the intermittent arm [13]. It should be noted that the randomization criteria for all of these trials are a PSA decline of 80-90%, or to <4ng/ml, on initial AS.

In the study by Miller et al. about two thirds of patients receiving either IAS or CAS experienced clinical and/or biochemical progression, with no significant differences between groups with respect to median time to tumour progression or median time to death [37]. Similarly, Mottet et al. reported no significant difference between patients receiving IAS and CAS with respect to median overall survival (OS; 1265 vs 1560 days) and median progression-free survival (PFS) (620 vs 452 days) [38]. Tunn et al. also reported equivalency between IAS and CAS with respect to PFS (91.7 vs 93.6%) and median time to progression (1.86 vs 2.36 yr), although estimated mean PFS was longer in the IAS group compared with the CAS group (1234 vs 1010 days) [22]. In the TULP study, median time to progression was longer in the CAS arm (24.1 vs 18 months; significance not stated); more recent data from this study show no difference in OS between groups (mean follow-up of 66 months) [39,40]. The Inter-group randomized phase III trial demonstrated non-inferiority of IAS with respect to OS and time to hormone refractory state for patients with biochemical relapses after radical radiotherapy [34]. Similarly, the FinnProstate Study VII, found no significant differences in time to progression and OS, concluding that IAS is an efficient method to treat advanced prostate cancer compared with CAS [41].

However, differences in OS between CAS and IAS have been reported in two studies. De Leval et al. reported that the estimated risk of 3-year progression in CAS patients was significantly higher than in the IAS group (38.9% vs. 7%; p = 0.0052) [36]. In patients with a Glea-son score >6, 3-year progression rates were significantly higher in CAS than in IAS patients (p = 0.018) but not in patients with lower Gleason scores. Compared with CAS, the IAS

group had better results with respect to the number of deaths from hormone-refractory disease (4 vs. 2), number of patients with disease progression (10 vs. 3), and mean time to progression (21 vs. 28 months) (level of significance not stated for any outcome). In patients without bone metastases at initiation, risk of progression was significantly higher in CAS than IAS patients (p < 0.001). The largest trial comparing IAS to CAS is the SWOG 9346 in-tergroup trial, which included metastatic prostate cancer patients [17]. At a median follow-up of 9.2 years, the median overall survival was six months longer with CAS in the entire study population. This was caused by a comparable survival in extensive disease and an inferior survival in response to IAS in patients with minimal metastatic disease. The results of these two studies point to an inferior clinical results of IAS in metastatic prostate cancer.

Early results from the study by Calais da Silva et al. showed no clinically meaningful differences between groups in virtually all QoL parameters and no evidence that IAS carries a significantly higher risk of death [13]. Mottet et al. also reported no significant difference in QoL outcomes in patients receiving either IAS or CAS [38]. However, updated results from a larger cohort of the Calais da Silva study (maximum follow-up of 7 years; median: 2 years) suggest a better tolerability profile for IAS versus CAS, with up to three times as many patients in the CAS arm reporting side effects compared with IAS patients (hot flushes: 23% vs. 7%; gynaecomastia: 33% vs. 10%; headaches: 12% vs. 5%; all p < 0.0001) [44]. Levels of sexual activity also increased in the IAS group compared with the CAS group, reported in 28 vs. 10% of patients after 15 months. Similarly, Miller et al. reported that patients' self-assessment of their overall health and sexual activity appeared to favour IAS; however, no differences in incidence of adverse events or other safety parameters were noted in this study [37]. Further evidence of QoL advantages comes from Verhagen et al. who note that EORTC scores on physical and emotional function were significantly better in the IAS group than in the CAS group. Role and social function were equivalent between groups, although cognitive function was surprisingly reduced in the IAS group, but not in the CAS group [35]. AS-related side effects were reported in most patients by de Leval et al., most of which resolved in the IA group on discontinuation of therapy [36]. In the TULP study, 26 preliminary withdrawals were reported due to adverse events, 20 in the CAS group and 6 in the IAS group [39,40]. The FinnProstate Study VII reported no significant difference in the prevalence of adverse with IAS [42]. Improved sexual function in men who received IAS as compared to CAS was confirmed in the SWOG 9346 intergroup trial [17].

2.3.11.3. IAS - phase III trials - Conclusion

Following pilot and phase II clinical trials comparing IAS to CAS, results of phase III studies were awaited eagerly to get a definite judgement of these different regimens of AS. The clinical results, time to progression and OS, seem to be comparable between IAS and CAS for prostate cancer patients with biochemical relapses and localized disease. With the exception of two studies, namely trials performed by the South European Uroncological Group and the SWOG 9346 intergroup, IAS was not inferior to CAS in respect to progression of disease and OS in metastatic prostate cancer. In the two dissenting studies, patients with limited metastatic disease seem to have an impaired OS under IAS. However, the statement that IAS is possibly inferior to CAS and not standard therapy of all prostate cancer patients is an oversimplification [17]. Improvements in QoL parameters were confirmed by most studies, depending on testosterone recovery and extent of disease.

NCI Trial #

Treatment

End point/Study subject

Start

Status

NCT002S3S03

Exlsullnd

Duration of off-treatment period

2006

Unknown

NCT00686036

Zactima (18 mo)

Duration of off-treatment period

2008

Terminated

NCT00553S7S

Dutasteride

Duration of off-treatment period

2007

Ongoing

NCT006S8642

Dutasteride

Androgen-Response Gene Expression

2008

Recruiting

NCT00801242

Degarelix (1 mo)

Duration of off-treatment period

2008

Ongoing

NCT00928434

Degarelix IAS

Duration of off-treatment period /QoL

2009

Ongoing

NCT01512472

Degarelix (4 vs 10 mo)

Duration of off-treatment period

2011

Recruiting

NCT00002651

IAS vs. CAS

Survival/QoL Prostate cancer D2

1999

Recruiting

NCT00223665

IAS

Progression/QoL Localized Prostate Cancer

2005

Recruiting

NCT00378690

ELIGARD

Survival/QoL Metastatic Prostate Cancer

2006

Ongoing

Table 2. Overview of the IAS trials currently under investigation

Table 2. Overview of the IAS trials currently under investigation

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