**3. Clinical development of intermittent androgen suppression**

Since the introduction of PSA screening in the late 1980s, more prostate cancers have been detected, and at an earlier stage (Gjertson & Albertsen, 2011). Consequently, the majority of prostate cancers are now detected years before the emergence of clinically evident disease, which usually represents locally advanced or metastatic cancer. PSA screening has remained controversial, because many of the prostate cancers detected are low grade and slow growing and will not need aggressive therapy. Prostate cancer is biologically and clinically a heterogeneous malignancy and its imaging evaluation will need to be tailored to the specific phases of the disease in a patient-specific, risk-adapted manner (Jadvar, 2011). With this long natural history and a median survival without treatment that often approaches at least 15-20 years, many patients will die rather with than of prostate cancer. Approximately onethird of patients who undergo radical prostatectomy will develop a detectable PSA level within 10 years (Tzou, *et al*., 2011). Biochemical relapse is defined as a rising PSA level in the absence of clinical or radiographic evidence of tumor. Management of PSA recurrence is controversial, as prostate cancer may take an indolent course, or it may develop aggressively into metastatic disease. The only potentially curative treatment for biochemical failure after prostatectomy is radiotherapy and the other treatment options include hormone therapy or clinical trials of new agents.

Research on hormonal treatment of prostate cancer over the past 20 years has focused on maximizing androgen ablation through combination therapy. This increases treatmentrelated side-effects and expenses and fails to prolong time to progression to androgenindependence (Gleave, *et al*., 1998, Kollmeier & Zelefsky, 2008 ). Preliminary evidence indicates that a low androgen milieu is associated with tumor aggressiveness. Transition to androgen-independence is a complex process and involves both selection and outgrowth of preexisting androgen-resistant clones as well as adaptative upregulation of genes that enable cancer cells to survive and grow after CAS (Corona, et al., 2011). CAS in men with prostate cancer increases the risk of osteoporotic fractures, type 2 diabetes and, possibly, cardiovascular events (Grossmann, *et al*., 2011). The benefits of CAS in treating nonmetastatic prostate cancer need to be carefully weighed against the risks of CAS-induced adverse events. Management of the metabolic sequelae of CAS includes optimal reduction

Intermittent Androgen Suppression Therapy

for Prostate Cancer Patients: A Choice for Improved Quality of Life? 369

In another IAS study, 127 patients from the intermittent arm and 107 patients from the continuous arm progressed, with a hazard ratio (HR) of 0.81 (da Silva, *et al*., 2009). There was no difference in survival, with a HR of 0.99. The greater number of cancer deaths in the IAS arm (106 vs 84) was balanced by a greater number of cardiovascular deaths in the continuous arm (52 vs 41). Side effects were more pronounced in the continuous arm and patients treated with IAS reported better sexual function. Median time off therapy for the IAS-treated patients was 52 weeks. However, significant differences were reported in one study: de Leval and colleagues published that the estimated risk of 3-year progression in CAS patients was significantly higher than in the IAS group. This difference was highlighted in patients with a Gleason score >6, where the 3-year progression rates were significantly higher in CAS rather than in IAS patients (de Leval, *et al.,* 2002). Large phase III clinical trials of intermittent vs continuous androgen deprivation in men with metastatic disease or recurrent disease after localized therapy were requested for more than 2 decades in order to obtain reliable data for

Finally, the Intergroup randomized phase III trial, which compared IAS vs CAS to test for non-inferiority of IAS with respect to overall survival was presented in February 2011 (Klotz, *et al*., 2011). Eligible men had rising PSA > 3.0 ng/ml >1 year post irradiation that was either initial or salvage for treatment of localized prostate cancer. IAS was delivered for 8 months in each cycle with restart when PSA reached >10 ng/ml in the off-treatment phase. Primary endpoint was overall survival (OS); secondary endpoints included time to hormone refractory state, quality of live, duration of treatment/non-treatment intervals and time to recovery of testosterone and potency. 1,386 patients were randomized to IAS (690) or CAS (696) arms and median follow-up was 6.9 years. IAS patients completed a median of 2 x 8 months cycles (range: 1-9). Median OS was 8.8 vs 9.1 years in IAS and CAS arms, respectively, with more disease-related (122 vs 97) in the IAS and fewer disease-unrelated (134 vs. 146) deaths in the CAS arm. Time to hormone resistance was statistically significantly improved in the IAS arm (HR 0.80, p = 0.024). Time to development of castration resistance was close to 10 years and in favour of IAS, but the trial design was biased towards IAS. In order to achieve castration resistance status, patients had to be being on treatment. Therefore, some patients who had a rising PSA off-treatment may in fact have had castration-resistant disease, but treatment had to be restarted and the PSA seen to continue to rise before this status could be defined. IAS patients had reduced occurrences of hot flashes, but there was no evidence of differences in adverse events, including myocardial problems or osteoporotic fractures. Thus, in men with PSA recurrence after irradiation IAS is non-inferior to CAS with respect to OS. IAS was suggested to be considered as the new standard of care for most patients with PSA recurrence after radical surgery. High-risk patients seem to be poor candidates for any type of androgen suppression. In summary, it can be concluded from the clinical trials that IAS is neither inferior nor superior to CAS, with respect to the end points, namely the time period until hormone-resistance as well as cancer-specific survival, but offers significant advantages in terms of adverse effects, quality of life and costs. Still, a number of important questions are remaining, regarding appropriate patient selection for therapy, optimum duration of therapy and exact scheduling of treatment reinstallation after the off-cycle. The offtreatment periods particularly hold the possibility to apply drugs such as finasteride or chemotherapeutics, in order to delay disease progression (Locke & Bruchovsky, 2010). Moreover, the study has economic implications: patients in the IAS arm were on therapy

the comparative impact of these therapies on quality of life and survival.

only 27% of the time, reducing the cost of therapy significantly.

of cardiovascular risk factors, with particular attention to weight, blood pressure, lipid profile, smoking cessation and glycemic control.

The rationale behind IAS is based on the hypothesis that, if tumor cells, which survive androgen withdrawal, are forced into a normal differentiation pathway by androgen replacement, their apoptotic potential might be restored and progression to androgen independence may be delayed. Furthermore, immediate androgen ablation can be accomplished with less side effects and quality of live can be improved in a palliative setting. Observations from animal model studies suggest that progression to androgenindependence involves adaptive responses to androgen deprivation, which seem to be delayed by intermittent androgen replacement. Supported by these results, several centers tested the feasibility of IAS in non-randomized groups of prostate cancer patients with serum PSA as trigger point (Buchan & Goldenberg, 2010).

For example, in a small pilot trial in four stage C and three stage D patients with prostate cancer androgen withdrawal was initiated with cyproterone acetate and diethylstilbestrol and then maintained with cyproterone acetate in combination with the LHRH agonist goserelin acetate (Akakura, *et al*., 1993). After 6 or more months of suppression, treatment was interrupted for 2-11 months. After recovery of testicular function, androgen-withdrawal was resumed when serum PSA increased to a level of about 20 ng/ml. This cycle was sequentially repeated to a total of 2-4 times over treatment periods of 21-47 months with no loss of androgen-dependence. These early results demonstrate that IAS can be used to induce multiple apoptotic regressions of a tumor.

Overall, these trials suggest that IAS is neither inferior nor superior to CAS, with respect to time to castration resistance and cancer-specific survival, but has significant advantages in terms of adverse effects, quality of life and costs (Buchan & Goldenberg, 2010). A number of unresolved questions remain regarding patient selection for therapy, optimum duration of treatment, optimal time point of reinitiation oftherapy after the off-phase and definition of progression to castration-resistant disease. In future, the use of second-line drugs during offtreatment phases holds potential for delaying disease progression in men undergoing IAS. In a review data from 19 phase II studies were discussed with respect to PSA values for treatment suspension/reinitiation, treatment regimen, cycle lengths, testosterone normalization and tolerability. Most trials reported an improvement in quality of life during the off-therapy periods. Interim data from 8 phase III trials comparing IAS and CAS were found to corroborate the phase II results (Abrahamsson, 2009). Phase II/III data suggested that IAS was as effective as CAS but was characterized by better tolerability and quality-oflife advantages; however, more data are required to determine the effect of IAS on the longterm complications of androgen deprivation. Disease progression in 96 patients with biochemically relapsed prostate cancer under IAS was associated with pretreatment PSA doubling time (PSADT) ≥6 vs. <6 months, first off-treatment interval PSADT of ≥3 vs. <3 months and PSA nadir during the first treatment interval of <0.1 vs. ≥0.1 ng/ml. During IAS PSADT became shorter and was associated with testosterone recovery (Keizman, *et al.,* 2011). The duration of the first off-treatment interval (< or > 40 weeks) was correlated with shorter time to hormone-insensitivity and death after adjusting for age, stage, grade and PSA at diagnosis (Yu *et al*., 2010, Sciarra, *et al*., 2011).

Few randomized studies compared IAS with CAS for the treatment of advanced prostate cancer. Early survival results from phase III trials were limited and inconsistent. Mottet and colleagues reported no significant difference between patients receiving IAS and CAS with respect to median overall survival and median progression-free survival (Mottet, *et al*., 2006).

of cardiovascular risk factors, with particular attention to weight, blood pressure, lipid

The rationale behind IAS is based on the hypothesis that, if tumor cells, which survive androgen withdrawal, are forced into a normal differentiation pathway by androgen replacement, their apoptotic potential might be restored and progression to androgen independence may be delayed. Furthermore, immediate androgen ablation can be accomplished with less side effects and quality of live can be improved in a palliative setting. Observations from animal model studies suggest that progression to androgenindependence involves adaptive responses to androgen deprivation, which seem to be delayed by intermittent androgen replacement. Supported by these results, several centers tested the feasibility of IAS in non-randomized groups of prostate cancer patients with

For example, in a small pilot trial in four stage C and three stage D patients with prostate cancer androgen withdrawal was initiated with cyproterone acetate and diethylstilbestrol and then maintained with cyproterone acetate in combination with the LHRH agonist goserelin acetate (Akakura, *et al*., 1993). After 6 or more months of suppression, treatment was interrupted for 2-11 months. After recovery of testicular function, androgen-withdrawal was resumed when serum PSA increased to a level of about 20 ng/ml. This cycle was sequentially repeated to a total of 2-4 times over treatment periods of 21-47 months with no loss of androgen-dependence. These early results demonstrate that IAS can be used to

Overall, these trials suggest that IAS is neither inferior nor superior to CAS, with respect to time to castration resistance and cancer-specific survival, but has significant advantages in terms of adverse effects, quality of life and costs (Buchan & Goldenberg, 2010). A number of unresolved questions remain regarding patient selection for therapy, optimum duration of treatment, optimal time point of reinitiation oftherapy after the off-phase and definition of progression to castration-resistant disease. In future, the use of second-line drugs during offtreatment phases holds potential for delaying disease progression in men undergoing IAS. In a review data from 19 phase II studies were discussed with respect to PSA values for treatment suspension/reinitiation, treatment regimen, cycle lengths, testosterone normalization and tolerability. Most trials reported an improvement in quality of life during the off-therapy periods. Interim data from 8 phase III trials comparing IAS and CAS were found to corroborate the phase II results (Abrahamsson, 2009). Phase II/III data suggested that IAS was as effective as CAS but was characterized by better tolerability and quality-oflife advantages; however, more data are required to determine the effect of IAS on the longterm complications of androgen deprivation. Disease progression in 96 patients with biochemically relapsed prostate cancer under IAS was associated with pretreatment PSA doubling time (PSADT) ≥6 vs. <6 months, first off-treatment interval PSADT of ≥3 vs. <3 months and PSA nadir during the first treatment interval of <0.1 vs. ≥0.1 ng/ml. During IAS PSADT became shorter and was associated with testosterone recovery (Keizman, *et al.,* 2011). The duration of the first off-treatment interval (< or > 40 weeks) was correlated with shorter time to hormone-insensitivity and death after adjusting for age, stage, grade and

Few randomized studies compared IAS with CAS for the treatment of advanced prostate cancer. Early survival results from phase III trials were limited and inconsistent. Mottet and colleagues reported no significant difference between patients receiving IAS and CAS with respect to median overall survival and median progression-free survival (Mottet, *et al*., 2006).

profile, smoking cessation and glycemic control.

serum PSA as trigger point (Buchan & Goldenberg, 2010).

induce multiple apoptotic regressions of a tumor.

PSA at diagnosis (Yu *et al*., 2010, Sciarra, *et al*., 2011).

In another IAS study, 127 patients from the intermittent arm and 107 patients from the continuous arm progressed, with a hazard ratio (HR) of 0.81 (da Silva, *et al*., 2009). There was no difference in survival, with a HR of 0.99. The greater number of cancer deaths in the IAS arm (106 vs 84) was balanced by a greater number of cardiovascular deaths in the continuous arm (52 vs 41). Side effects were more pronounced in the continuous arm and patients treated with IAS reported better sexual function. Median time off therapy for the IAS-treated patients was 52 weeks. However, significant differences were reported in one study: de Leval and colleagues published that the estimated risk of 3-year progression in CAS patients was significantly higher than in the IAS group. This difference was highlighted in patients with a Gleason score >6, where the 3-year progression rates were significantly higher in CAS rather than in IAS patients (de Leval, *et al.,* 2002). Large phase III clinical trials of intermittent vs continuous androgen deprivation in men with metastatic disease or recurrent disease after localized therapy were requested for more than 2 decades in order to obtain reliable data for the comparative impact of these therapies on quality of life and survival.

Finally, the Intergroup randomized phase III trial, which compared IAS vs CAS to test for non-inferiority of IAS with respect to overall survival was presented in February 2011 (Klotz, *et al*., 2011). Eligible men had rising PSA > 3.0 ng/ml >1 year post irradiation that was either initial or salvage for treatment of localized prostate cancer. IAS was delivered for 8 months in each cycle with restart when PSA reached >10 ng/ml in the off-treatment phase. Primary endpoint was overall survival (OS); secondary endpoints included time to hormone refractory state, quality of live, duration of treatment/non-treatment intervals and time to recovery of testosterone and potency. 1,386 patients were randomized to IAS (690) or CAS (696) arms and median follow-up was 6.9 years. IAS patients completed a median of 2 x 8 months cycles (range: 1-9). Median OS was 8.8 vs 9.1 years in IAS and CAS arms, respectively, with more disease-related (122 vs 97) in the IAS and fewer disease-unrelated (134 vs. 146) deaths in the CAS arm. Time to hormone resistance was statistically significantly improved in the IAS arm (HR 0.80, p = 0.024). Time to development of castration resistance was close to 10 years and in favour of IAS, but the trial design was biased towards IAS. In order to achieve castration resistance status, patients had to be being on treatment. Therefore, some patients who had a rising PSA off-treatment may in fact have had castration-resistant disease, but treatment had to be restarted and the PSA seen to continue to rise before this status could be defined. IAS patients had reduced occurrences of hot flashes, but there was no evidence of differences in adverse events, including myocardial problems or osteoporotic fractures. Thus, in men with PSA recurrence after irradiation IAS is non-inferior to CAS with respect to OS. IAS was suggested to be considered as the new standard of care for most patients with PSA recurrence after radical surgery. High-risk patients seem to be poor candidates for any type of androgen suppression. In summary, it can be concluded from the clinical trials that IAS is neither inferior nor superior to CAS, with respect to the end points, namely the time period until hormone-resistance as well as cancer-specific survival, but offers significant advantages in terms of adverse effects, quality of life and costs. Still, a number of important questions are remaining, regarding appropriate patient selection for therapy, optimum duration of therapy and exact scheduling of treatment reinstallation after the off-cycle. The offtreatment periods particularly hold the possibility to apply drugs such as finasteride or chemotherapeutics, in order to delay disease progression (Locke & Bruchovsky, 2010). Moreover, the study has economic implications: patients in the IAS arm were on therapy only 27% of the time, reducing the cost of therapy significantly.

Intermittent Androgen Suppression Therapy

metabolic bone diseases (Okabe, *et al*., 2004).

is depicted in figure 3A.

androgen suppression in IAS cycles.

for Prostate Cancer Patients: A Choice for Improved Quality of Life? 371

by treatment cessation and resuming of the therapy upon increases of PSA >4 and >20 ng/ml, respectively. Serum testosterone was measured using an ELISA assay (Biomar Diagnostics, Marburg, Germany) according to the manufacturer´s instructions. PSA was determined by the microparticulate enzyme immunoassay (MEIA, AxSYM PSA assay, Abbott, USA). CrossLaps ELISA was obtained from Nordic Bioscience Diagnostics, Herlev, Denmark, and used according to the manufacturer´s instructions (Rosenquist, *et al*., 1998). This assay is used for follow-up of anti-resorptive treatment of patients with

Amino-terminal propeptide of type I procollagen (PINP) and PSA were determined using the Elecsys 2010 Chemistry Analyzer (Roche Diagnostics, Vienna, Austria). All patients (n=75; mean age ±SD: 68±7 years, range: 53-84 years) exhibited progression of disease without metastases following radical prostatectomy and/or irradiation therapy. The lengths of the treatment cessation periods (mean ±SEM) for the respective off-treatment cycles (I–VI) in months were: 16±2 (n=75), 10±1 (n=31), 8±2 (n=18), 8±1 (n=12), 10±2 (n=8), 7±6 (n=2), respectively. The first treatment cessation period (PI) was significantly longer compared to the following breaks, which were not significantly different among each other. Individual time courses of testosterone and CrossLaps for a representative patient and four IAS cycles

CrossLaps are elevated during androgen suppression phases indicating bone matrix degradation and normalize during treatment cessation periods on a regular basis (Theyer, *et al*., 2010). After a prolonged time without androgen suppression, CrossLaps values exhibited a gradual increase, most likely due to regrowth of the tumor (data not shown; Nguyen-Pamart, *et al*., 1997). Time courses of PINP and PTH were compared with PSA during the same IAS cycles in further measurements (figure 3B). The results show that PINP is a suitable alternative parameter for the assessment of bone matrix turnover during androgen suppression phases that are accompanied by low PSA levels. The parallel course of blood PTH indicates a participation of this hormone in androgen suppression-induced bone loss. This finding corroborates reports of decreased loss of BMD in bone scans in prostate cancer patients under IAS therapy. Since pretreatment concentrations of CrossLaps were restored within several months of therapy cessation and mean duration of the off-treatment periods ranged from 8–16 months in our patients, this protective effect of IAS is expected to be effective for several treatment cycles (Theyer, *et al*., 2010). The bone matrix synthesis product PINP was used to assess bone turnover in metastatic prostate and breast cancer among other malignancies (Jung, *et al*., 2011; Koopmans, *et al.,* 2007; Pollmann, *et al*., 2007). Studies in metastatic prostate cancer patients showed that both PINP and ICTP (carboxy-terminal telopeptide of type I collagen) were most indicative of predicting metastatic progression and skeletal complications, respectively. Although androgen deprivation has been associated with bone loss in patients with prostate cancer, its mechanism remains unclear. The growth hormone (GH)/insulin-like growth factor-1 (IGF-1)/parathyroid hormone (PTH) axis that plays a critical role in bone synthesis was investigated during CAS (Isahaya, *et al*., 2010). PTH is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids and effects to increase the concentration of calcium in blood (Poole & Reeve, 2005). The serum PTH level was reduced after CAS by approximately 25% compared with baseline levels, concomitant with increases of bone resorption markers like blood and urinary N-telopeptides (NTx), in good agreement with our measurements during
