Urology Textbook
Clinical Essentials
By Dirk Manski, MD

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Metastatic Prostate Cancer: Androgen deprivation therapy

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

Advanced prostate cancer is classified into different disease states according to the response to androgen deprivation therapy (ADT), imaging findings, and genetic testing. Pivotal trials have further defined disease states to precisely determine the indications for modern systemic therapies:

Castration-sensitive prostate cancer:

Advanced prostate cancer with biochemical progression or proven metastases that responds to androgen deprivation therapy (ADT), known as castration-sensitive prostate cancer (CSPC). Depending on whether metastases are detected on imaging, the disease is classified as M0 CSPC or M1 CSPC. Distinguishing M0 CSPC from local recurrence after curative treatment may be difficult.

M1 CSPC with high tumor volume:

Castration-sensitive prostate cancer with at least 4 bone metastases, including at least 1 beyond the pelvis or spine, or with visceral metastases.

M1 CSPC with high risk:

Castration-sensitive prostate cancer with at least 2 of the following risk factors: Gleason score ≥ 8, at least 3 bone metastases, or visceral metastases.

Oligometastatic prostate cancer:

Castration-sensitive prostate cancer with a low metastatic burden and a maximum of 2–4 visible bone metastases, depending on the study, on conventional imaging.

Castration-resistant prostate cancer:

Advanced prostate cancer with biochemical progression or radiologic progression despite adequate androgen deprivation therapy, known as castration-resistant prostate cancer (CRPC).

M0 CRPC:

Biochemical progression of prostate cancer despite adequate androgen deprivation therapy, without metastases on imaging.

M0 CRPC with high risk:

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

M1 CRPC:

Progression of prostate cancer despite adequate androgen deprivation therapy, with metastases detected on imaging.

Prognosis of Metastatic Prostate Cancer

Favorable prognostic factors include low tumor volume, absence of pain and visceral metastases, metachronous metastases after prior local treatment, a low Gleason score and PSA concentration, a good PSA response to ADT, and a long PSA doubling time; see the following table.

Prognosis of metastatic prostate cancer: according to tumor volume and timing of metastasis (Francini et al., 2018).
Time to CRPC Overall survival
Metachronous metastases after local treatment (low tumor volume)26 months92 months
Metachronous metastases after local treatment (high tumor volume)15 months55 months
De novo diagnosis with synchronous metastases (low tumor volume)18 months52 months
De novo diagnosis with synchronous metastases (high tumor volume)12 months43 months

Treatment Options

The following options are available for advanced and metastatic prostate cancer:

The treatment options are used sequentially or in combination according to disease progression and response [Figure androgen deprivation therapy of advanced prostate cancer]. See also pharmacokinetics and adverse effects of androgen deprivation therapy.

Androgen deprivation therapy of advanced prostate cancer: 1: A maximum of 2–4 visible bone metastases, depending on the study, on conventional imaging. 2: Options are orchiectomy, GnRH agonists, or GnRH antagonists. 3: At least 2 risk factors: Gleason score ≥ 8, at least 3 bone metastases, or visceral metastases. 4: At least 4 bone metastases, including at least 1 beyond the pelvis or spine, or visceral metastases. 6: M0 CRPC with a PSA doubling time of less than 10 months. 7: The treatment sequence is not defined.
Flowchart of androgen deprivation therapy for advanced prostate cancer

Treatment of Castration-Sensitive Prostate Cancer

Indications for Androgen Deprivation Therapy

The German S3 guideline for prostate cancer recommends ADT for a PSA doubling time < 3 months, symptomatic local progression, proven distant metastases, as an adjunct to radiotherapy, or for extensive lymph node metastases after radical prostatectomy.

Standard Androgen Deprivation Therapy

ADT is most commonly administered with GnRH agonists, such as goserelin or leuprorelin. Because treatment initiation causes a transient increase in testosterone concentration, flutamide or bicalutamide is additionally administered orally for 2–4 weeks. GnRH agonists are available as depot injections at intervals of 1–6 months, depending on the product. Alternatives are bilateral subcapsular orchiectomy or GnRH antagonists.

Modern combination therapies:

Combining ADT with modern androgen receptor antagonists (enzalutamide, apalutamide, or darolutamide) improves progression-free and overall survival in patients with M1 CSPC. This combination is standard treatment for metastatic hormone-sensitive prostate cancer. In suitable patients with high tumor volume, docetaxel can be added as triple therapy.

Comparative trials:

GnRH agonists are oncologically equivalent to orchiectomy, whereas monotherapy with conventional androgen receptor antagonists is oncologically inferior. GnRH antagonists reduce testosterone concentrations more rapidly than GnRH agonists.

Adverse Effects

For adverse effects of ADT and their prevention, see androgen deprivation therapy.

Follow-up

Standard imaging for metastatic disease consists of CT of the abdomen and chest and bone scintigraphy. PSMA-PET detects metastases earlier, but its therapeutic consequences must be assessed individually. Repeat imaging if the disease progresses.

Laboratory tests:

Measure PSA every 3–6 months. Depending on symptoms or suspected progression, also measure complete blood count, creatinine, liver enzymes, alkaline phosphatase, and testosterone.

Intermittent Androgen Deprivation

The aim of intermittent ADT is to reduce adverse effects by minimizing time on treatment; studies have demonstrated benefits for libido, erectile function, hot flashes, and general well-being. Depending on the baseline PSA concentration, ADT is continued until a defined PSA nadir is reached, followed by a treatment break until a defined PSA increase indicates another cycle of ADT [Figure intermittent androgen deprivation therapy]. Testosterone concentrations may return to normal even after several cycles of ADT (Pether and Goldenberg, 2004).

Intermittent ADT is less effective than continuous ADT (Hussain, 2012). This is even more relevant in light of the results achieved with modern ADT-based doublet therapy. Intermittent ADT remains an option for patients with low tumor volume and slowly progressive disease who place a high value on reducing treatment-related adverse effects.

Intermittent androgen deprivation therapy for prostate cancer: Depending on the baseline PSA concentration, ADT is continued until a defined PSA nadir is reached, followed by a treatment break until a defined PSA increase indicates another cycle of ADT (Pether and Goldenberg, 2004).
Flowchart of intermittent androgen deprivation therapy for prostate cancer

Local Therapy for Metastatic Prostate Cancer

In selected oligometastatic patients, radiotherapy to the primary tumor, in addition to ADT and, if necessary, radiotherapy to individual metastases, can improve survival (Burdett et al., 2019). An oncologic benefit of radical prostatectomy in oligometastatic patients has not been sufficiently established, but it remains an option in selected cases (Leyh et al., 2017), particularly in patients with urinary retention or local symptoms.

Chemotherapy for M1 CSPC with High Tumor Volume

Combining ADT with docetaxel improves overall survival in suitable patients with M1 CSPC, particularly in those with high tumor volume. Start chemotherapy within the first months after beginning ADT.

In the CHAARTED trial, 790 men were randomized to ADT with GnRH antagonists or agonists alone or to ADT plus 6 cycles of docetaxel. In patients with high tumor volume, adding docetaxel improved median overall survival by 17 months (49 versus 32 months). High tumor volume was defined as at least 4 bone metastases, including at least 1 beyond the pelvis or spine, or visceral metastases (Sweeney et al., 2015). In the STAMPEDE trial, 2962 men were randomized to ADT alone, ADT plus docetaxel, ADT plus zoledronic acid, or ADT plus both docetaxel and zoledronic acid. ADT plus docetaxel prolonged survival by 10 months (81 versus 71 months), whereas zoledronic acid did not improve survival (James et al., 2016).

Triple Therapy for M1 CSPC with High Tumor Volume

In randomized trials, triple therapy with ADT, docetaxel, and either abiraterone/prednisolone or darolutamide improved overall survival and delayed disease progression. In PEACE-1, ADT plus abiraterone and docetaxel improved overall survival (HR 0.75) and progression-free survival (HR 0.50) compared with ADT plus docetaxel (Fizazi et al., 2022). In ARASENS, ADT plus darolutamide and docetaxel improved overall survival (HR 0.68) and progression-free survival compared with ADT plus docetaxel (Smith et al., 2022). Triple therapy with ADT, darolutamide, and docetaxel has been approved in the United States since 2022 and in Europe since 2023 and is a standard option for patients with high tumor volume.

Enzalutamide Combined with ADT for M1 CSPC

The randomized ENZAMET trial demonstrated that ADT combined with enzalutamide improves overall survival and delays disease progression (Davis et al., 2019). Benefits were observed across risk groups. The ARCHES trial confirmed these findings (Armstrong et al., 2021). Enzalutamide has been approved for hormone-sensitive prostate cancer across risk groups since 2021.

Apalutamide Combined with ADT for M1 CSPC

The randomized TITAN trial demonstrated that ADT combined with apalutamide improves overall survival and delays disease progression (Chi et al., 2019). Benefits were observed across risk groups. Apalutamide has been approved for hormone-sensitive prostate cancer across risk groups since 2020.

Darolutamide Combined with ADT for M1 CSPC

The randomized ARANOTE trial demonstrated that ADT combined with darolutamide delays disease progression and showed a trend toward improved overall survival (Saad et al., 2024). Benefits were observed across risk groups. Darolutamide has been approved for hormone-sensitive prostate cancer across risk groups since 2025.

Abiraterone Combined with ADT for High-Risk M1 CSPC

Approval of abiraterone was extended on the basis of STAMPEDE (James et al., 2017) and LATITUDE (Fizazi et al., 2017). Adding abiraterone 1000 mg/d plus prednisolone 5 mg/d to ADT improved survival, prolonged progression-free survival, and delayed the start of chemotherapy. Because abiraterone has an important role in castration-resistant disease, including in combination with olaparib, its early use in CSPC should be considered cautiously.

PARP Inhibitors for M1 CSPC with BRCA1/2 Mutations

In patients with M1 CSPC and a pathogenic HRR mutation, niraparib/abiraterone plus prednisone can be prescribed early in addition to ADT. In the randomized phase III AMPLITUDE trial, niraparib combined with abiraterone and prednisone improved radiographic progression-free survival in HRR-altered metastatic CSPC, particularly in patients with BRCA1/2 mutations (Attard et al., 2025). Despite the substantial radiographic progression-free survival benefit in BRCA1/2-altered disease, early use of a PARP inhibitor plus abiraterone in M1 CSPC should be considered critically: a significant overall survival benefit has not yet been conclusively established, highly effective alternatives are available, and treatment causes relevant hematologic and cardiovascular toxicity.






Index: 1–9 A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

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