59 Intermittent Androgen Ablation in Metastatic Prostate Cancer
The role of androgens in the growth of prostate cancer was demonstrated by Huggins in 1941. This led the way for use of androgen deprivation therapy (ADT), which is now the backbone of systemic therapy for metastatic prostate cancer. Since prostate cancer is driven by androgen receptor signaling, ADT lowers testosterone levels into a castrate range, resulting in a decrease in prostate-specific antigen (PSA), which is driven by androgen receptor signaling.
Androgen production takes place mainly in the testes, with a small contribution from the adrenal glands. The hypothalamus secretes gonadotropin releasing hormone (GnRH), which stimulates the anterior pituitary gland to release luteinizing hormone (LH) and follicle stimulating hormone (FSH). LH then circulates to Leydig cells in the testes, leading to the production of testosterone. Testosterone then goes to prostate epithelial cells, where it is converted into dihydrotestosterone (DHT) by the enzyme 5-alpha reductase. DHT binds with the androgen receptor and induces transcription of proteins necessary for function and development of the prostate. Androgens produced by the adrenal glands are androstenedione and dehydroepiandrosterone. These are released under the stimulation of adrenocorticotropic hormone (ACTH), which is secreted by the pituitary gland. The adrenal androgens play a role in the development of castrate resistant prostate cancer.
60ANDROGEN DEPRIVATION THERAPY
ADT can be applied by surgical bilateral orchiectomy or medical castration. Target testosterone levels less than 50 ng/dL are used in most clinical studies and treatment protocols. Surgical bilateral orchiectomy can rapidly achieve testosterone levels less than 20 ng/dL. This method is cost saving, offers potentially fewer injections and clinic visits, and is equally as effective as medical castration in controlling prostate cancer. Interestingly, a study comparing GnRH agonists to orchiectomy in 3,295 men with prostate cancer selected from the Surveillance, Epidemiology, and End Results (SEER) database suggested that patients treated with GnRH analogs were at higher risk for fractures, peripheral arterial disease, venous thromboembolism, cardiac related complications, and diabetes mellitus (P<.01 for all) compared with orchiectomy (1). Despite this, medical castration is much more frequently used than surgical orchiectomy in North America. With medical castration, psychological issues of surgical castration can be avoided. This method is reversible and can be used to ameliorate hypogonadal symptoms. Agents that can be used for medical castration are GnRH agonists (leuprolide, goserelin, buserelin), GnRH antagonists (degarelix), androgen receptor blockers (bicalutamide, enzalutamide), and adrenal androgen synthesis inhibitors (abiraterone, ketoconazole).
INTERMITTENT VERSUS CONTINUOUS ANDROGEN DEPRIVATION THERAPY
ADT may increase the risk of osteoporosis, bone fractures, type 2 diabetes mellitus, myocardial infarction, stroke, erectile dysfunction, loss of libido, metabolic syndrome, weight gain, hot flashes, gynecomastia, fatigue, normocytic anemia, and alopecia (2,3). Multiple side effects from ADT can affect quality of life (QOL). Intermittent androgen deprivation therapy (IADT) involves alternating periods of medical castration and treatment free intervals to allow testosterone recovery. IADT is usually applied when there is a response to treatment with reintroduction of medical castration on progression of disease. The reason to consider IADT is to minimize adverse effects of treatment and improve QOL.
61A study by Labarta et al randomized 49 patients to continuous androgen deprivation therapy (CADT) and 51 patients to IADT. Using a questionnaire, QOL between the two groups were compared. Results showed that the IADT group had significantly improved overall QOL as well as better scores for “sexual life” and “social partner support” (4). A randomized study by Mottet et al compared IADT and CADT in patients with metastatic prostate cancer. Patients with metastatic prostate cancer and prostate-specific antigen (PSA) of greater than 20 ng/mL received 6 months of induction ADT. If PSA level decreased below 4 ng/mL, they were then randomized to IADT or CADT. Results revealed a median overall survival of 52 months with CADT compared to 42 months with IADT, but this was not statistically significant (P = .75). Although scores regarding sexual function were significantly better in the IADT arm, most of the functional and symptom scales for QOL showed no significant differences between the two groups. However, there were significantly fewer treatment-emergent adverse events in the IADT group, with a lower incidence of hot flushes and headaches. This study concluded that IADT might be as safe as CADT in patients with metastatic prostate cancer and could be an option in highly responding and well-informed patients who have significant treatment induced side effects (5). In another study that compared IADT with CADT with regard to QOL, 852 men with metastatic prostate cancer received medical castration with goserelin. Patients whose PSA decreased to less than 10 ng/mL or by greater than 50% were randomized to IADT or CADT. QOL was monitored with a questionnaire. QOL was significantly better in the IADT arm with regard to physical capacity, activity limitation, and sexual functioning. Surprisingly, erectile dysfunction and depressed mood were significantly increased with IADT. There were no statistical differences in cardiovascular events, fractures, hot flushes, or night sweats (Table 9.1) (5–7).
A phase 3 noninferiority study by Hussain et al comparing IADT and CADT included 1,535 patients with metastatic prostate cancer. The coprimary objectives were to assess if IADT was noninferior to CADT in terms of survival, with 1.20 as the upper boundary of hazard ratio (HR), and whether there was any difference in QOL. Results revealed a median survival of 5.8 years with CADT and 5.1 years with IADT (HR 1.10 and confidence interval 0.99–1.23). There were no significant differences in terms of treatment related high grade adverse events. However, IADT had significantly better erectile function and mental health at month 3, but not later. Since the confidence interval for survival exceeded the upper boundary of 1.2 for noninferiority, a 20% greater risk of death with IADT cannot be ruled out (7). Although there are a few studies concluding that IADT is as effective as CADT, these studies had suboptimal designs with mixed patient populations, poor noninferiority margin selection, and short follow-up times.