Testosterone based dosing regimen of goserelin in patients with prostate cancer

Rationale: Chemical or surgical castration is a key strategy in patients with
locally advanced or metastatic prostate cancer. Chemical castration is achieved
by administering Luteinizing Hormone Releasing Hormone (LHRH) agonists on a
regular basis. Successful castration is internationally characterized by
prolonged serum testosterone levels <= 1.7nmol/L. Currently, the dosing regimen
for LHRH agonist goserelin is a manufacturer recommended fixed dose (10.8 mg)
in a fixed interval of 12 weeks. Also, during this fixed dose goserelin
LHRH-therapy, testosterone levels are not routinely monitored.
Several studies have also shown that serum testosterone levels remain
suppressed below the 1.7 nmol/L level for more than three months after
administration of a single dose or after cessation of LHRH therapy. These
results suggest that a more personalized way of dosing LHRH agonists, namely
dosing based on a patient*s testosterone level, could be equally effective in
achieving chemical castration compared to 12-weekly based dosing of LHRH
agonists.
In a recent study, researchers investigated the possibility of extending the
dosing interval of goserelin, straight from the onset of treatment, with a
testosterone level-based dosing regimen. The median time to the next goserelin
injection in the study group was 22.8 weeks, versus the current fixed dosing
interval of 12 weeks in the control group. In two patients, an unpredicted
rapid rise of the testosterone level above the castrate level (>1.7 nmol/L)
occurred [6]. Possible explanations for the rapid rise of testosterone levels
are reactivation of the available LHRH-receptors, a fast upregulation of
LHRH-receptors or a combinations of both mechanisms. These effects might be
stronger in patients that only have a limited number of injections of LHRH.
Prolonging the dosing interval in patients who have been treated with androgen
deprivation therapy ADT for a longer period of time seems promising. The
hypothesis in this study, is that in patients who have been treated with ADT
for a longer period of time, the testis are less active and are less likely to
produce testosterone to the extent of rising above 1.7 nmol/L. So prolonging
the dosing interval in patients who have been treated with ADT for a longer
period of time seems promising.

The primary objective is to determine in which percentage of patients with
prostate cancer with an indication for ADT, it is safe to extend the
dosing interval of goserelin 10,8 mg by four weeks, before the 4th injection,
using a testosterone based dosing
regimen.

Secundairy objectives:
• to determine the percentage of the included patients, that can safely extend
the dosing interval of the 4th goserelin 10,8 mg injection with 8 or 12 or
weeks, before the 4th injection, using a testosterone based dosing regimen.
• to determine the percentage of the included patients, for whom the dosing
interval of the fourth injection was extended with maximum 12 weeks, that can
safely extend the dosing interval of the 5th goserelin 10,8 mg injection with
4, 8 or 12 weeks, using a testosterone based dosing regimen.
• Time to castrate refractory disease
• to establish the patient preference for either testosterone-based dosing
regimen of goserelin 10.8 mg injection or regular treatment with
a 12-weekly based goserelin 10.8 mg injection.
• to perform a pharmaco-economic analysis. To determine whether a
testosterone-based dosing regimen of goserelin 10.8 mg is cost-saving
compared to regular treatment with a 12-weekly based goserelin 10.8 mg
injection.
• To explore the metabolites of testosterone.

Study design: This study is a non-randomized prospective interventional study.
Patients will be included after they have been treated with 3 goserelin 10.8 mg
injections according to standard of care, being 12-weekly depot injections of
goserelin 10.8 mg (see Figure 1). During the study patients will be treated
with 1 or 2 goserelin 10.8 mg injections (dependent on the dosing regimen of
the 4th goserelin injection) following a testosterone-based dosing regimen,
according to the defined algorithm.

A conservative algorithm will be applied to ensure that testosterone will
remain at castrate level (below 1.7 nmol/L). Approximately 11 weeks
after the third depot injection of goserelin 10.8 mg, blood levels of
testosterone will be measured. When one of the following rule does not
apply, a depot injection of goserelin 10.8 mg is injected subcutaneously
administer at 12 weeks:

A. The testosterone level <= 1.2 nmol/L.
B. An increase of < 0.5 nmol/L from the nadir

When the testosterone level does meet both of the above mentioned requirements,
goserelin treatment will be postponed, blood levels of
testosterone will be measured again after 3 weeks and according to the
described algorithm the next injection of goserelin is given or again
postponed for 3 weeks, with a maximum of 12 weeks.

If a patient participates in the study, there is no therapeutic benefit in the
treatment of prostate cancer. But it helps the researchers gain more insight
into the treatment of prostate cancer with goserelin. Participation in this
studies might lead to patients receiving fewer injections of goserelin in the
future. This ultimately leads to patient convenience and savings costs for
society.

Participating in the study may have these drawbacks:
- blood sampling may hurt, bruising may occur.
- Participating in the study takes extra time, blood is taken every month, this
takes about 15 minutes at a time.

The risk of getting side effects in this study is the same as with regular
treatment.