Dr. med. Dirk Manski

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Prostate Cancer: Hormonal Therapy (Androgen Ablation)

Guidelines and review literature: (EAU Guidelines Prostate Cancer) (S3-Leitlinie Prostatakarzinom) (Walsh-Campbell Urology).

Advanced prostate cancer is classified into different stages depending on the response to standard hormone therapy and imaging results. Further disease stages have been defined by pivotal studies to precisely narrow the indications for modern hormone therapy:

Castration-sensitive prostate carcinoma (CSPC):

Advanced prostate carcinoma (biochemical progression or proven metastases) with response to androgen deprivation (see below). Depending on the detection of metastases on imaging, the stage is referred to as M0 CSPC or M1 CSPC. It is difficult to distinguish stage M0 CSPC from a local recurrence after curative therapy. Histology and PSA are helpful in this context (see table #tab_pca_rezidiv).

M1 CSPC with high tumor volume:

Castration-sensitive prostate cancer with at least 4 bone metastases (including at least one beyond the pelvis or spine) or the presence of visceral metastases.

M1 CSPC with high risk:

Castration-sensitive prostate cancer with at least two of the following risk factors: Gleason score ≥8, at least 3 bone metastases, or presence of visceral metastases.

Castration-resistant prostate carcinoma (CRPC):

Advanced prostate carcinoma with biochemical (rising PSA) or radiological progression despite sufficient androgen deprivation.

M0 CRPC:

Biochemical progression of prostate carcinoma under sufficient androgen deprivation and without evidence of metastases on imaging.

M0 CRPC with high risk:

M0 CRPC with a PSA doubling time of less than 10 months.

M1 CRPC:

visible metastases and radiological progression despite sufficient androgen deprivation.

Prognosis of metastatic prostate carcinoma:

Low tumor volume, no pain, no visceral metastases, metachronous metastases after previously performed local therapy, low Gleason score, a low PSA concentration, good PSA response with hormonal therapy and a long PSA doubling time are favorable prognostic factors, see table Prognosis of metastatic prostate carcinoma.

Prognosis of metastatic prostate carcinoma: OS=overall survival, DN=de-novo diagnosis of prostate cancer with synchronous metastases, LT=metachronous metastases after local therapy, LV=low volume disease, HV=high volume disease (Francini u.a., 2018).
Time to CRPC Median OS
LT/LV 26 months 92 months
LT/HV 15 months 55 months
DN/LV 18 months 52 months
DN/HV 12 months 43 months

Treatment Options

The following options exist for the treatment of advanced and metastatic prostate cancer:

The individual therapy options are applied sequentially or in combination depending on disease progression and response [fig. hormonal therapy of prostate cancer]. See also pharmacokinetics and side effects of androgen deprivation therapy. Review literature: (Albers et al., 2020).

Hormonal therapy of advanced prostate cancer:
(*) Options are orchiectomy, GnRH analoga or GnRH antagonists.
(**) See figure intermittend androgen suppression for details.
(***) No definitive evidence exists on the optimal treatment sequence for CRPC.
Flowchart Hormonal therapy of advanced prostate cancer

Hormone-sensitive Prostate Cancer

Therapeutic Options for Androgen Ablation in Hormone-Sensitive Prostate Cancer

The following options exist for androgen ablation in hormone-sensitive prostate cancer:

The therapeutic options are used as a sequence or in combination, depending on severity and progression of the disease [see figure Hormonal therapy of advanced prostate cancer. Please see section pharmacology/androgen ablation.

Indications For Hormonal Therapy in Prostate Cancer:

Timing of Hormone Therapy:

The survival benefit of immediate hormone therapy in asymptomatic metastases compared to hormone therapy of symptomatic metastases is low to moderate (Loblaw et al., 2004). There is no proven benefit for the common practice of starting androgen ablation in patients with asymptomatic PSA progression after curative therapy without visible metastases. The mean survival time for patients with biochemical progress after prostatectomy is 13 years (Pound et al., 1999), this should be considered for the timing of androgen ablation, since serious side effects such as osteoporosis and anemia are time-dependent.

 

Follow-Up for Patients With Hormonal Therapy

Side effects and clinical success (symptoms, PSA) should be determined three and six months after the initiation of hormone therapy. Further follow-up examinations and imaging are indicated individually depending on the risk of progression and symptoms.

  

Pharmacology and Side Effects of Hormonal Therapy:

For details of the pharmacology of hormonal therapy, the side effects of androgen ablation and its prophylaxis please see section pharmacology/hormonal therapy, flutamide, bicalutamide, GnRH agonists and GnRH antagonists.

Comparative Studies for Hormonal Therapy:

Compared to scrotal orchiectomy, GnRH agonists are oncologically equivalent, the androgen receptor antagonists are only slightly inferior. The side effects of the androgen receptor antagonists are more favorable.

Intermittent Androgen Deprivation Therapy for Prostate Cancer

The aim of intermittent androgen deprivation therapy (IAD) is to reduce the rate of side-effects by minimizing time under hormone therapy. Several studies demonstrated better libido, erection function, general physical well-being and less hot flashes. Intermittent androgen deprivation therapy is begun until a certain PSA-Nadir is reached, which depends on the initial PSA concentration. A therapy pause follows until a certain PSA progress is reached, which again leads to another cycle of hormone therapy [fig. flow chart of intermittent androgen deprivation therapy (IAD)]. The testosterone concentration reaches normal values again even after several cycles of hormone therapy (Pether and Goldenberg, 2004).

The onocological equivalence of intermittent hormonal therapy compared to continuous hormone therapy is debated. Several randomized studies have demonstrated oncological equivalence (Crook et al., 2012) (Mottet et al., 2012) (Salonen et al., 2012). In the largest randomized study (SWOG 9346, n = 1535), however, a lower life expectancy was observed in the group of intermittent hormonal therapy (5.1 vs. 5.8 years, 7 years survival rate 38% vs. 42%). This was even more pronounced in the patient group with low disease volume (Hussain, 2012).

Intermittent androgen deprivation therapy (IAD) for prostate cancer: therapy is begun until a certain PSA-Nadir is reached, which depends on the initial PSA concentration. A therapy pause follows until a certain PSA progress is reached, which again leads to another cycle of hormone therapy (Pether and Goldenberg, 2004).
flow chart: intermittent androgen deprivation therapy (IAD) for prostate cancer

Chemotherapy Combined With Androgen Deprivation Therapy for M1 CSPC with High Tumor Volume

Until recently, there have been no established concepts to use chemotherapy alone or in combination with hormonal therapy to treat hormone-sensitive prostate carcinoma. This has changed with the results of the STAMPEDE and CHAARTED trials (Gillessen et al., 2015). Chemotherapy should be started within the first few months after initiation of hormonal therapy.

The CHAARTED trial randomized 790 patients: one group received standard hormone therapy with GnRH antagonists or analogues; the second group received 6 cycles of docetaxel chemotherapy in addition to hormone therapy. In the group with high disease volume, there was a clear survival advantage of 17 months for docetaxel in addition to hormone therapy (mean survival time 49 vs. 32 months). A high disease volume was defined with at least four bone metastases (including at least one outside spine or pelvis) or the presence of visceral metastases (Sweeney et al., 2015). In the STAMPEDE study, 2962 patients were randomized: hormone therapy versus additional docetaxel (6 cycles) versus additional zolendronic acid versus additional doxetaxel and zolendronic acid. The combination of hormone therapy with docetaxel extended survival by 10 months (71 versus 81 months). No survival advantage could be demonstrated for zoledronic acid (James et al., 2016). In contrast to the STAMPEDE and CHAARTED trial, no advantage in overall survival could be demonstrated in the GETUG 15 trial (Gravis et al., 2013).

Triple combinations in M1 CSPC with high tumor burden:

In randomized trials, the triple combination of standard hormone therapy intensified with abiraterone or darolutamide and docetaxel chemotherapy showed benefits in terms of survival and disease progression. Triple therapy in the PEACE-1 trial (hormone therapy + abiraterone + docetaxel) resulted in better survival (HR 0.75) and prolonged progression-free survival (HR 0.5) compared with hormone therapy and docetaxel (Fizazi et al., 2022). Triple therapy in the ARASENS trial (hormone therapy + darolutamide + docetaxel) resulted in better survival (HR 0.68) and prolonged progression-free survival compared with hormone therapy and docetaxel (Smith et al., 2022a). The additional side effects from intensified hormone therapy are acceptable and probably less with darolutamide than with abiraterone. Triple therapy with darolutamide has been approved in the United States since 2022 and in Europe since 2023.

Abiraterone combined with androgen deprivation therapy for M1 CSPC with high risk:

The approval of abiraterone was extended based on the study results of STAMPEDE (James et al., 2017) and of LATITUDE (Fizazi et al., 2017). The combination of androgen deprivation with abiraterone 1000 mg/d and prednisolone 5 mg/d resulted in improved survival (83% vs 76% and 66% vs 59%, respectively) and prolonged progression-free survival and time to initiation of chemotherapy. Prerequisite is castration-sensitive prostate cancer with at least two of the following risk factors: Gleason score ≥8, at least 3 bone metastases, or evidence of visceral metastases.

Enzalutamid combined with androgen deprivation therapy for M1 CSPC:

The ENZAMET trial (n=1125) demonstrated that androgen deprivation combined with enzalutamide improved overall survival (102 versus 143 deaths at three years) and slowed disease progression (Davis et al., 2019). The benefits were demonstrated in all risk groups. The ARCHES trial confirmed the benefit of enzalutamide (Armstrong et al., 2021), it is approved for the therapy of hormone-sensitive prostate cancer in all risk groups.

Apalutamide combined with androgen deprivation therapy for M1 CSPC:

The TITAN trial (n=1052) demonstrated that androgen deprivation combined with apalutamide improved overall survival (HR 0.67) and slowed disease progression (HR 0.48) \parencite{Chi2019}. Apalutamide has been approved for the treatment of hormone-sensitive prostate cancer in all risk groups since 1/2020.





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