Prostate cancer

Overview 
Theory 
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Your Organisational Guidance

ebpracticenet urges you to prioritise the following organisational guidance:

Recommendations nationales de bonne pratique pour la prise en charge du cancer localisé de la prostate: première partiePublished by: KCELast published: 2014Nationale praktijkrichtlijn voor de aanpak van gelokaliseerde prostaatkanker: deel 1Published by: KCELast published: 2014

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

very low-risk disease

life expectancy <10 years

1st line – observation

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1st line –

observation

For very low-risk disease, the following criteria must be met: cT1c tumour, Grade Group 1, prostate-specific antigen (PSA) <10 micrograms/L (<10 nanograms/mL), <3 prostate biopsy fragments/cores positive, ≤50% cancer in each fragment/core, and PSA density <0.15 micrograms/L/g (<0.15 nanograms/mL/g).[3]

Observation is recommended for patients with very low-risk disease with life expectancy <10 years. This involves monitoring the course of the disease with a view to delivering treatment or palliative therapy when symptoms arise or when there is a change in clinical findings that suggest symptoms are imminent.[3]

Observation should include a history and physical examination no more often than every 12 months (without prostate biopsies).[143] If patients become symptomatic, assessment should be performed (including prostate-specific antigen [PSA] and PSA doubling time, life expectancy estimate, and quality-of-life measures) to determine need for, and consideration of, treatment or palliation.[3]

2nd line – androgen deprivation therapy alone (if symptomatic and life expectancy ≤5 years)

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2nd line –

androgen deprivation therapy alone (if symptomatic and life expectancy ≤5 years)

Patients with life expectancy ≤5 years who become symptomatic during observation can receive androgen deprivation therapy alone (a luteinising hormone-releasing hormone [LHRH] agonist or antagonist, or orchiectomy) for palliation.[3]

Advise patients about the risk of adverse effects with ADT, including rapid loss of bone mineral density, which increases the risk of osteoporosis and fractures.[147] Risk assessment for treatment-related bone loss is recommended for all patients starting ADT.[3][148] University of Sheffield: FRAX tool Opens in new window See Complications.

See local specialist protocol for dosing guidelines.

Primary options

leuprorelin

goserelin

triptorelin

degarelix

relugolix

life expectancy ≥10 years

1st line – active surveillance

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1st line –

active surveillance

If life expectancy is ≥10 years, active surveillance is recommended.[3]

Active surveillance involves monitoring the course of the disease (with additional use of prostate biopsies) until symptoms or signs of disease become clinically evident with the expectation to treat with definitive treatment if there is disease progression.

Patients can move to observation if their life expectancy decreases to <10 years.

PSA level and digital rectal examination are checked no more than every 6 and 12 months, respectively, unless clinically indicated.[3][143]

Repeat prostate biopsy and repeat multiparametric magnetic resonance imaging (MRI) are carried out no more often than every 12 months unless clinically indicated.[3] Intensity of active surveillance may be individualised based on patient and tumour factors, risk of progression, and life expectancy. However, most patients should have repeat biopsies every 2-5 years.

Confirmatory testing is recommended before starting active surveillance (within 6-12 months of diagnosis) if prebiopsy multiparametric MRI was not performed prior to diagnostic biopsy.[144] The role of confirmatory testing is to identify those at high risk for future disease upgrading or progression, and to ensure appropriate patients are selected for active surveillance.[144]

Confirmatory testing for active surveillance involves performing a multiparametric MRI (with PSA density calculation), if available, and/or biopsy (systematic and targeted), and/or molecular tumour analysis.[3][90][145] All patients should have a confirmatory prostate biopsy within 1-2 years of initial diagnostic biopsy.[3]

low-risk disease

life expectancy <10 years

1st line – observation

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1st line –

observation

For low-risk disease, patients have all of the following and do not qualify for very low-risk disease: cT1-cT2a tumour, Grade Group 1, and prostate-specific antigen (PSA) <10 micrograms/L (<10 nanograms/mL).[3]

Observation is recommended for patients with low-risk disease with life expectancy <10 years. This involves monitoring the course of the disease with a view to delivering treatment or palliative therapy when symptoms arise, or when there is a change in clinical findings that suggest symptoms are imminent.[3]

2nd line – androgen deprivation therapy alone (if symptomatic and life expectancy ≤5 years)

Back

2nd line –

androgen deprivation therapy alone (if symptomatic and life expectancy ≤5 years)

See local specialist protocol for dosing guidelines.

Primary options

leuprorelin

goserelin

triptorelin

degarelix

relugolix

life expectancy ≥10 years

1st line – active surveillance

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1st line –

active surveillance

Patients with low-risk disease and life expectancy ≥10 years can delay definitive treatments (e.g., external beam radiotherapy, brachytherapy, or radical prostatectomy) and undergo active surveillance instead, depending on the patient's wish to avoid treatment-related adverse effects.[164][165][166]

Active surveillance is the preferred approach for most patients with low-risk disease if life expectancy is ≥10 years, but is often underutilised due to patient preference and lack of adherence.[176][177] Use of standardised patient information, clinician education, and guidelines may improve uptake of and adherence to active surveillance.[176] Factors that may increase the likelihood of regrading, and initiation of treatment, include high PSA density, ≥3 positive cores, high genomic risk, and/or a known BRCA2 germline mutation.[3]

PSA level and digital rectal examination are checked no more than every 6 and 12 months, respectively, unless clinically indicated.[3][143]

1st line – brachytherapy

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1st line –

brachytherapy

Brachytherapy (low-dose rate or high-dose rate) is a treatment option for patients with low-risk disease and life expectancy ≥10 years.

Brachytherapy is a definitive treatment. The treatment goal is cure.

Low-dose rate brachytherapy involves the permanent transperineal implantation of radioactive sources into the prostate without any incision. The highest radiation dose is confined to the prostate and a small volume of surrounding tissue. The strength of radiation decreases over time, but low levels of radioactivity in the prostate will persist for 4-6 months depending on the half-life of the isotope used. Precautions should be taken in the short term to minimise close contact with pregnant women and small children.

High-dose rate brachytherapy involves the transperineal placement of treatment catheters through which an individual radioactive source is robotically placed temporarily at various dwell positions to achieve a conformal dose of radiation to the prostate. At the end of treatment the catheters are removed. Treatment is repeated up to five times to achieve a curative dose to the prostate.

1st line – external beam radiotherapy

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1st line –

external beam radiotherapy

External beam radiotherapy (EBRT) is a treatment option for patients with low-risk disease and life expectancy ≥10 years.

EBRT is a definitive treatment. The treatment goal is cure.

Several EBRT regimens have acceptable efficacy and toxicity, including moderate hypofractionation, conventional fractionation, and ultra-hypofractionation.[3][155][156][157] [ ]

Moderate hypofractionation is the preferred approach.[158] Although it shortens treatment duration, it may slightly increase the risk of acute gastrointestinal adverse effects compared with conventional fractionation.[155] Comparable biochemical control and toxicity have been reported with ultra-hypofractionation versus more protracted fractionation schedules, but higher total doses are associated with a greater risk of severe late genitourinary complications.[157]

Moderate hypofractionation or ultra-hypofractionation may be options across all risk groups; conventional fractionation is not recommended for low-risk or favourable intermediate-risk disease.[3]

Intensity-modulated radiotherapy and image-guided radiotherapy are the standard EBRT techniques because they allow for a highly conformal delivery of radiation that minimises dose to normal tissues (bladder, rectum, and small bowel), thereby potentially decreasing toxicity to these structures. Stereotactic body radiotherapy is the technique used to deliver ultra-hypofractionated radiotherapy.

Biocompatible and biodegradable perirectal spacer materials can be implanted between the prostate and rectum in patients with organ-confined disease to reduce toxicity to the rectum.[3][153][154]

Patients with significant baseline urinary symptoms may not be suitable for EBRT due to increased risk of urinary obstruction.

1st line – radical prostatectomy

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1st line –

radical prostatectomy

Radical prostatectomy is a treatment option for patients with low-risk disease and life expectancy ≥10 years (depending on patient preference and suitability for surgery).

Radical prostatectomy is a definitive treatment. The treatment goal is cure.

Classically, the prostate and prostatic capsule are removed by excision of the urethra at the prostatomembranous junction. The seminal vesicles, ampulla, and vas deferens are also removed. Of the two classic open surgical approaches (retropubic/suprapubic and perineal), the retropubic/suprapubic approach is preferred by many urologists, as this approach facilitates access for pelvic lymph node dissection.

Laparoscopic and robotic-assisted radical prostatectomy are alternative approaches that typically involve five or six small incisions in the abdomen from which the entire prostate is removed, theoretically sparing nerves more easily damaged by a retropubic/suprapubic approach.[160][161] One Cochrane review found that laparoscopic or robotic-assisted radical prostatectomy may result in shorter hospital stays and fewer blood transfusions compared with open surgical radical prostatectomy, but improvements in oncological outcomes (e.g., recurrence or survival) were inconclusive.[162] Complications (e.g., sexual and urinary dysfunction) appear to be similar between these alternative approaches and the open surgical approach.[162][163]

Radical prostatectomy in men with clinically localised prostate cancer that was not detected through PSA screening improves prostate cancer-specific mortality, overall survival, and risk of local disease progression and metastasis, compared with active surveillance.[164][165] These benefits have been shown to continue over the long-term, particularly in those aged ≤65 years.[166][167]

Radical prostatectomy in men with PSA-detected localised prostate cancer does not significantly reduce all-cause mortality or prostate cancer-specific mortality compared with active surveillance or observation.[168][169][170][171] Furthermore, radical prostatectomy is associated with a higher frequency of adverse events than active surveillance and observation.[168][169][170][171][172] [ ]

favourable intermediate-risk disease

life expectancy <10 years

1st line – observation

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1st line –

observation

For favourable intermediate-risk disease, patients have no high-risk or very high-risk features and all of the following: one intermediate risk factor (cT2b-c tumour; Grade Group 2; or prostate-specific antigen [PSA] 10-20 micrograms/L [10-20 nanograms/mL]), Grade Group 1 (if not Grade Group 2), and percentage of positive biopsy cores <50%.[3]

There is no standard approach to managing patients with intermediate-risk disease.

Observation is recommended for patients with favourable intermediate-risk disease and life expectancy <10 years.

Observation involves monitoring the course of the disease with a view to delivering treatment or palliative therapy when symptoms arise or when there is a change in clinical findings that suggest symptoms are imminent.[3]

2nd line – androgen deprivation therapy alone (if symptomatic and life expectancy ≤5 years)

Back

2nd line –

androgen deprivation therapy alone (if symptomatic and life expectancy ≤5 years)

Advise patients about the risk of adverse effects with ADT, including rapid loss of bone mineral density, which increases the risk of osteoporosis and fractures.[147]

Risk assessment for treatment-related bone loss is recommended for all patients starting ADT.[3][148] University of Sheffield: FRAX tool Opens in new window See Complications.

See local specialist protocol for dosing guidelines.

Primary options

leuprorelin

goserelin

triptorelin

degarelix

relugolix

2nd line – brachytherapy (if life expectancy 5-10 years)

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2nd line –

brachytherapy (if life expectancy 5-10 years)

Brachytherapy (given as low-dose rate or as high-dose rate) is a treatment option for patients with favourable intermediate-risk disease and life expectancy 5-10 years (i.e., instead of observation).

Brachytherapy is a definitive treatment. The treatment goal is cure.

2nd line – external beam radiotherapy (if life expectancy 5-10 years)

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2nd line –

external beam radiotherapy (if life expectancy 5-10 years)

External beam radiotherapy (EBRT) is a treatment option for patients with favourable intermediate-risk disease and life expectancy 5-10 years (i.e., instead of observation).

EBRT is a definitive treatment. The treatment goal is cure.

Several EBRT regimens have acceptable efficacy and toxicity, including moderate hypofractionation, conventional fractionation, and ultra-hypofractionation.[3][155][156][157] [ ]

Moderate hypofractionation or ultra-hypofractionation may be options across all risk groups; conventional fractionation is not recommended for low-risk or favourable intermediate-risk disease.[3]

Biocompatible and biodegradable perirectal spacer materials can be implanted between the prostate and rectum in patients with organ-confined disease to reduce toxicity to the rectum.[3][153][154]

Patients with significant baseline urinary symptoms may not be suitable for EBRT due to increased risk of urinary obstruction.

life expectancy ≥10 years

1st line – active surveillance

Back

1st line –

active surveillance

There is no standard approach to managing patients with intermediate-risk disease. Adverse effects of treatment may influence treatment choice.[180][181][182][183]

Patients with favourable intermediate-risk disease and life expectancy ≥10 years can delay definitive treatments (e.g., brachytherapy or external beam radiotherapy) and undergo active surveillance instead, depending on the patient's wish to avoid treatment-related adverse effects (e.g., gastrointestinal and genitourinary toxicity).[164][165][166][180][181][182][183]

PSA level and digital rectal examination are checked no more than every 6 and 12 months unless clinically indicated.[3][143]

1st line – brachytherapy

Back

1st line –

brachytherapy

Brachytherapy is a treatment option for patients with favourable intermediate-risk disease and life expectancy ≥10 years.

Brachytherapy (low-dose rate or high-dose rate) is a definitive treatment. The treatment goal is cure.

Brachytherapy may achieve similar control (5-year freedom from progression) in patients with intermediate-risk disease compared with EBRT plus brachytherapy boost, but with lower toxicity.[207]

1st line – external beam radiotherapy

Back

1st line –

external beam radiotherapy

External beam radiotherapy (EBRT) is a treatment option for patients with favourable intermediate-risk disease and life expectancy ≥10 years.

EBRT is a definitive treatment. The treatment goal is cure.

Several EBRT regimens have acceptable efficacy and toxicity, including moderate hypofractionation, conventional fractionation, and ultra-hypofractionation.[3][155][156][157] [ ]

Biocompatible and biodegradable perirectal spacer materials can be implanted between the prostate and rectum in patients with organ-confined disease to reduce toxicity to the rectum.[3][153][154]

Patients with significant baseline urinary symptoms may not be suitable for EBRT due to increased risk of urinary obstruction.

Prophylactic pelvic nodal irradiation may be considered in highly selected patients with intermediate-risk disease who are undergoing radiotherapy, but only if further risk assessment (e.g., nomograms, biomarker testing) indicates aggressive disease.[3]

1st line – radical prostatectomy ± lymph node dissection

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1st line –

radical prostatectomy ± lymph node dissection

Radical prostatectomy is a treatment option for patients with favourable intermediate-risk disease and life expectancy ≥10 years (depending on patient preference and suitability for surgery). Pelvic lymph node dissection may be carried out (depending on nomogram assessment).[3]

Radical prostatectomy is a definitive treatment. The treatment goal is cure.

Radical prostatectomy in men with PSA-detected localised prostate cancer does not significantly reduce all-cause mortality or prostate cancer-specific mortality, compared with active surveillance or observation.[168][169][170][171] Furthermore, radical prostatectomy is associated with a higher frequency of adverse events than active surveillance and observation.[168][169][170][171][172] [ ]

unfavourable intermediate-risk disease

life expectancy ≤5 years

1st line – observation

Back

1st line –

observation

For unfavourable intermediate-risk disease, patients have no high-risk or very high-risk features and one or more of the following: two or three intermediate risk factors (cT2b-c tumour; Grade Group 2 or 3; and/or prostate-specific antigen [PSA] 10-20 micrograms/L [10-20 nanograms/mL]); and/or Grade Group 3 alone; and/or percentage of positive biopsy cores ≥50%.[3]

Observation is recommended for patients with unfavourable intermediate-risk disease and life expectancy ≤5 years.

2nd line – androgen deprivation therapy alone (if symptomatic)

Back

2nd line –

androgen deprivation therapy alone (if symptomatic)

See local specialist protocol for dosing guidelines.

Primary options

leuprorelin

goserelin

triptorelin

degarelix

relugolix

life expectancy >5 years

1st line – observation (if life expectancy 5-10 years)

Back

1st line –

observation (if life expectancy 5-10 years)

For unfavourable intermediate-risk disease, patients have no high-risk or very high-risk features and one or more of the following: two or three intermediate risk factors (cT2b-c tumour; Grade Group 2 or 3; and/or prostate-specific antigen [PSA] 10-20 micrograms/L [10-20 nanograms/mL]), and/or Grade Group 3 alone, and/or percentage of positive biopsy cores ≥50%.[3]

1st line – external beam radiotherapy (± brachytherapy boost) or brachytherapy (if life expectancy >5 years)

Back

1st line –

external beam radiotherapy (± brachytherapy boost) or brachytherapy (if life expectancy >5 years)

For unfavourable intermediate-risk disease, patients have no high-risk or very high-risk features and one or more of the following: two or three intermediate risk factors (cT2b-c tumour; Grade Group 2 or 3; and/or prostate-specific antigen [PSA] 10-20 micrograms/L [10-20 nanograms/mL]), and/or Grade Group 3 alone, and/or percentage of positive biopsy cores ≥50%.[3]

Treatment options for patients with unfavourable intermediate-risk disease and life expectancy >5 years are:

external beam radiotherapy (EBRT), with or without brachytherapy boost, plus androgen deprivation therapy (ADT), or

brachytherapy plus ADT.

EBRT and brachytherapy are definitive treatments. The treatment goal is cure.

Several EBRT regimens have acceptable efficacy and toxicity, including moderate hypofractionation, conventional fractionation, and ultra-hypofractionation.[3][155][156][157] [ ]

Moderate hypofractionation or ultra-hypofractionation may be options across all risk groups.[3]

Biocompatible and biodegradable perirectal spacer materials can be implanted between the prostate and rectum in patients with organ-confined disease to reduce toxicity to the rectum.[3][153][154]

Patients with significant baseline urinary symptoms may not be suitable for EBRT due to increased risk of urinary obstruction.

Brachytherapy boost (low-dose rate or high-dose rate) may be added to EBRT if there is concern about the ability to achieve local control with EBRT.[371] Brachytherapy alone may be an alternative option to EBRT for these patients.

High-dose radiation to the prostate and periprostatic tissue is recommended for patients who are candidates for radiotherapy plus ADT.[199][200][201][202][203] Dose escalation with EBRT alone or with the addition of brachytherapy boost to EBRT improves biochemical control, but increases toxicity.[204][205][206] Brachytherapy alone may achieve similar control (5-year freedom from progression) to EBRT plus brachytherapy boost in patients with intermediate-risk disease, but with lower toxicity.[207]

Targeted dose escalation techniques, using EBRT plus a micro-boost to the MRI-dominant lesion or an SBRT boost, may be a further option for select patients to improve biochemical control without increased toxicity.[3][208][209][210][211]

Plus – androgen deprivation therapy ± first-generation anti-androgen

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Plus –

androgen deprivation therapy ± first-generation anti-androgen

Treatment recommended for ALL patients in selected patient group

Androgen deprivation therapy (ADT) (e.g., a luteinising hormone-releasing hormone [LHRH] agonist or antagonist) may be given before, during, and/or after radiotherapy, for a total of 4-6 months.[3] ADT greater than 6 months duration is not recommended in patients with intermediate-risk disease.[189][190]

Addition of a first-generation anti-androgen (e.g., nilutamide, flutamide, bicalutamide) to an LHRH agonist may be considered to achieve adequate testosterone suppression in unfavourable intermediate-risk disease (life expectancy >5 years).[3]

ADT may have multiple synergistic effects when combined with radiotherapy, and is associated with significant clinical benefit.[191][192][193][194][195][196][197][198]

See local specialist protocol for dosing guidelines.

Primary options

leuprorelin

goserelin

triptorelin

degarelix

relugolix

leuprorelin

goserelin

triptorelin

-- AND --

nilutamide

flutamide

bicalutamide

1st line – radical prostatectomy + lymph node dissection (if life expectancy >10 years)

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1st line –

radical prostatectomy + lymph node dissection (if life expectancy >10 years)

For unfavourable intermediate-risk disease, patients have no high-risk or very high-risk features and one or more of the following: two or three intermediate risk factors (cT2b-c tumour; Grade Group 2 or 3; and/or prostate-specific antigen [PSA] 10-20 micrograms/L [10-20 nanograms/mL]), and/or Grade Group 3 alone, and/or percentage of positive biopsy cores ≥50%.[3]

Radical prostatectomy is a treatment option for patients with unfavourable intermediate-risk disease and life expectancy >10 years (depending on patient preference and suitability for surgery). Pelvic lymph node dissection is also recommended.

Radical prostatectomy is a definitive treatment. The treatment goal is cure.

high-risk or very high-risk disease

asymptomatic and life expectancy ≤5 years

1st line – observation

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1st line –

observation

For high-risk disease, patients have one or more of the following high-risk features, but do not meet the criteria for very high-risk: cT3-cT4 tumour; Grade Group 4 or 5; or prostate-specific antigen (PSA) >20 micrograms/L (>20 nanograms/mL).[3]

For very high-risk (locally advanced) disease, patients have at least two of the following: cT3-cT4 tumour; Grade Group 4 or 5; or PSA >40 nanograms/mL.[3]

Observation is the usual approach for asymptomatic high-risk and very high-risk patients with life expectancy ≤5 years.[3] However, androgen deprivation therapy and/or external beam radiotherapy may be considered if symptoms or complications (e.g., hydronephrosis) of untreated disease or metastases are expected within 5 years.

Observation involves monitoring the course of the disease with a view to delivering treatment or palliative therapy when symptoms aris, or when there is a change in clinical findings that suggest symptoms are imminent.[3]

2nd line – androgen deprivation therapy ± external beam radiotherapy

Back

2nd line –

androgen deprivation therapy ± external beam radiotherapy

Androgen deprivation therapy (ADT) alone (a luteinising hormone-releasing hormone [LHRH] agonist or antagonist, or orchiectomy) or with external beam radiotherapy (EBRT) can be considered in asymptomatic high-risk and very high-risk patients with life expectancy ≤5 years if symptoms or complications (e.g., hydronephrosis) of untreated disease or metastases are expected within 5 years.[3]

ADT alone is not curative, but it may slow progression and help control symptoms. ADT on an intermittent rather than a continuous basis may be considered, although whether this approach improves quality of life is controversial.[233][234][235]

Advise patients about the risk of adverse effects with ADT, including rapid loss of bone mineral density, which increases the risk of osteoporosis and fractures.[147]

Risk assessment for treatment-related bone loss is recommended for all patients starting ADT.[3][148] University of Sheffield: FRAX tool Opens in new window See Complications.

Several EBRT regimens have acceptable efficacy and toxicity, including moderate hypofractionation, conventional fractionation, and ultra-hypofractionation.[3][155][156][157] [ ]

Moderate hypofractionation or ultra-hypofractionation may be options across all risk groups.[3]

Prophylactic pelvic nodal irradiation should also be considered in patients with high-risk or very high-risk disease who are undergoing radiotherapy.[3][212]

Biocompatible and biodegradable perirectal spacer materials can be implanted between the prostate and rectum in patients with organ-confined disease to reduce toxicity to the rectum.[3][153][154]

Patients with significant baseline urinary symptoms may not be suitable for EBRT due to increased risk of urinary obstruction.

See local specialist protocol for dosing guidelines.

Primary options

leuprorelin

goserelin

triptorelin

degarelix

relugolix

2nd line – external beam radiotherapy

Back

2nd line –

external beam radiotherapy

External beam radiotherapy (EBRT) can be considered in asymptomatic high-risk and very high-risk patients with life expectancy ≤5 years if symptoms or complications (e.g., hydronephrosis) of untreated disease or metastases are expected within 5 years.[3]

EBRT is a definitive treatment. The treatment goal is cure.

Several EBRT regimens have acceptable efficacy and toxicity, including moderate hypofractionation, conventional fractionation, and ultra-hypofractionation.[3][155][156][157] [ ]

Moderate hypofractionation is the preferred approach.[372] Although it shortens treatment duration, it may slightly increase the risk of acute gastrointestinal adverse effects compared with conventional fractionation.[155] Comparable biochemical control and toxicity have been reported with ultra-hypofractionation versus more protracted fractionation schedules, but higher total doses are associated with a greater risk of severe late genitourinary complications.[157]

Moderate hypofractionation or ultra-hypofractionation may be options across all risk groups.[3]

Prophylactic pelvic nodal irradiation should also be considered in patients with high-risk or very high-risk disease who are undergoing radiotherapy.[3][212]

Biocompatible and biodegradable perirectal spacer materials can be implanted between the prostate and rectum in patients with organ-confined disease to reduce toxicity to the rectum.[3][153][154]

Patients with significant baseline urinary symptoms may not be suitable for EBRT due to increased risk of urinary obstruction.

symptomatic or life expectancy >5 years

1st line – external beam radiotherapy ± brachytherapy boost

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1st line –

external beam radiotherapy ± brachytherapy boost

For very high-risk (locally advanced) disease, patients have at least two of the following: cT3-cT4 tumour; Grade Group 4 or 5; or prostate-specific antigen (PSA) >40 nanograms/mL.[3]

External beam radiotherapy (EBRT) with or without brachytherapy boost plus androgen deprivation therapy (ADT) is a treatment option for patients with high-risk or very high-risk disease who are symptomatic or have a life expectancy >5 years.

EBRT and brachytherapy are definitive treatments. The treatment goal is cure.

Several EBRT regimens have acceptable efficacy and toxicity, including moderate hypofractionation, conventional fractionation, and ultra-hypofractionation.[3][155][156][157] [ ]

Moderate hypofractionation or ultra-hypofractionation may be options across all risk groups.[3]

Prophylactic pelvic nodal irradiation should also be considered in patients with high-risk or very high-risk disease who are undergoing radiotherapy.[3][212]

Biocompatible and biodegradable perirectal spacer materials can be implanted between the prostate and rectum in patients with organ-confined disease to reduce toxicity to the rectum.[3][153][154]

Patients with significant baseline urinary symptoms may not be good candidates for EBRT due to increased risk of urinary obstruction.

Brachytherapy boost (low-dose rate or high-dose rate) may be added to EBRT, if there is concern about the ability to achieve local control with EBRT.[371]

The addition of brachytherapy boost to EBRT (with or without ADT) may provide superior disease control compared with EBRT plus ADT for patients with high-risk or very high-risk disease.[204][231][232]

Plus – androgen deprivation therapy

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Plus –

androgen deprivation therapy

Treatment recommended for ALL patients in selected patient group

Androgen deprivation therapy (ADT) (e.g., a luteinising hormone-releasing hormone [LHRH] agonist or antagonist) may be given before, during, and/or after initiation of EBRT, for a total of 1.5 to 3 years.[213][214][215][216][217][218][219][220] A shortened duration of 1 year can be considered for patients having EBRT plus brachytherapy boost.[3][221]

The optimal duration of ADT for these patients remains controversial.[222] A significant improvement in disease-free survival is demonstrated for a longer duration of ADT in patients with high-risk disease.[215][222][223][224]

Use of combined radiotherapy with ADT significantly increases some treatment-related symptoms (e.g., pain with urination and overall urinary and bowel bother), although none are serious. However, given the substantial survival benefit of combined treatment, the increased risk of symptoms seems acceptable and has little extra effect on quality of life after 4 years compared with ADT alone.[225][226][227][228][229][230]

Advise patients about the risk of adverse effects with ADT, including rapid loss of bone mineral density, which increases the risk of osteoporosis and fractures.[147]

Risk assessment for treatment-related bone loss is recommended for all patients starting ADT.[3][148] University of Sheffield: FRAX tool Opens in new window See Complications.

See local specialist protocol for dosing guidelines.

Primary options

leuprorelin

goserelin

triptorelin

degarelix

relugolix

1st line – external beam radiotherapy ± brachytherapy boost

Back

1st line –

external beam radiotherapy ± brachytherapy boost

For very high-risk (locally advanced) disease, patients have at least two of the following: cT3-cT4 tumour; Grade Group 4 or 5; or PSA >40 nanograms/mL.[3]

External beam radiotherapy (EBRT) with or without brachytherapy boost combined with 2 years of androgen deprivation therapy (ADT) and abiraterone is recommended for selected patients with very high-risk (non-metastatic) disease.[3]

EBRT and brachytherapy are definitive treatments. The treatment goal is cure.

Several EBRT regimens have acceptable efficacy and toxicity, including moderate hypofractionation, conventional fractionation, and ultra-hypofractionation.[3][155][156][157] [ ]

Moderate hypofractionation or ultra-hypofractionation may be options across all risk groups.[3]

Prophylactic pelvic nodal irradiation should also be considered in patients with high-risk or very high-risk disease who are undergoing radiotherapy.[3][212]

Biocompatible and biodegradable perirectal spacer materials can be implanted between the prostate and rectum in patients with organ-confined disease to reduce toxicity to the rectum.[3][153][154]

Patients with significant baseline urinary symptoms may not be good candidates for EBRT due to increased risk of urinary obstruction.

Brachytherapy boost (low-dose rate or high-dose rate) may be added to EBRT, if there is concern about the ability to achieve local control with EBRT.[371]

Targeted dose escalation techniques, using EBRT plus a micro-boost to the MRI-dominant lesion or an SBRT boost, may be a further option to improve biochemical control without increased toxicity.[3][208][209][210][211]

Plus – androgen deprivation therapy + abiraterone (for very high-risk disease)

Back

Plus –

androgen deprivation therapy + abiraterone (for very high-risk disease)

Treatment recommended for ALL patients in selected patient group

Abiraterone (a second-generation anti-androgen) is approved for use in metastatic disease. However, off-label use in combination with ADT (e.g., an LHRH agonist or antagonist) for 2 years, plus EBRT, is recommended for selected patients with very high-risk (non-metastatic) disease.[3][236][237]

Abiraterone should not be used concurrently with another anti-androgen (e.g., nilutamide, bicalutamide, flutamide), and it should always be given with prednisolone or methylprednisolone (depending on the formulation of abiraterone).

The addition of abiraterone to primary ADT has been shown to improve overall and failure-free survival in a randomised study of men with locally advanced prostate cancer (radiotherapy was required if node negative, and encouraged if node positive) or metastatic disease.[236] Overall survival data for the subgroup of patients with non-metastatic disease at randomisation are immature.[236] However, there are data showing improved metastasis-free survival in this subgroup.[238]

See local specialist protocol for dosing guidelines.

Primary options

leuprorelin

goserelin

triptorelin

degarelix

relugolix

-- AND --

abiraterone acetate

1st line – radical prostatectomy + pelvic lymph node dissection (for fit patients without tumour fixation to the pelvic musculature or skeleton)

Back

1st line –

radical prostatectomy + pelvic lymph node dissection (for fit patients without tumour fixation to the pelvic musculature or skeleton)

For very high-risk (locally advanced) disease, patients have at least two of the following: cT3-cT4 tumour; Grade Group 4 or 5; or PSA >40 nanograms/mL.[3]

Radical prostatectomy with pelvic lymph node dissection is a treatment option for highly selected patients with high-risk or very high-risk disease who are symptomatic or have a life expectancy >5 years (e.g., fit patients without tumour fixation to the pelvic musculature or skeleton), depending on patient preference and suitability for surgery.[3]

Radical prostatectomy is a definitive treatment. The treatment goal is cure.

2nd line – androgen deprivation therapy alone (for patients unsuitable for surgery or radiotherapy)

Back

2nd line –

androgen deprivation therapy alone (for patients unsuitable for surgery or radiotherapy)

Where possible, patients with high-risk or very high-risk disease should receive definitive treatment.[226] However, androgen deprivation therapy (ADT) alone (a luteinising hormone-releasing hormone [LHRH] agonist or antagonist, or orchiectomy) may be an option for patients who are unsuitable for definitive treatment due to medical comorbidities (e.g., inflammatory bowel disease or prior pelvic irradiation).[229]

ADT alone is not curative, but it may slow progression and help control symptoms.

ADT on an intermittent rather than a continuous basis may be considered, although whether this approach improves quality of life is controversial.[233][234][235]

See local specialist protocol for dosing guidelines.

Primary options

leuprorelin

goserelin

triptorelin

degarelix

relugolix

ONGOING

non-metastatic disease: post-radical prostatectomy

with PSA persistence or recurrence: negative pelvic nodes and no distant metastases

1st line – salvage external beam radiotherapy (± androgen deprivation therapy) or monitoring

Back

1st line –

salvage external beam radiotherapy (± androgen deprivation therapy) or monitoring

Post-operative salvage therapy is indicated for patients with life expectancy >5 years if there is prostate-specific antigen (PSA) persistence (PSA does not fall to undetectable levels) or recurrence (increase of previously undetectable PSA on two or more measurements or to PSA >0.1 micrograms/L [>0.1 nanograms/mL]).[3][242]

Evaluation for distant metastases should be carried out (e.g., if the patient develops symptoms or PSA is increasing rapidly), which may include bone and soft-tissue imaging and prostate bed biopsy.[3]

Risk assessment (including use of nomograms) should be carried out to inform decision-making after radical prostatectomy. The Decipher (22-gene genomic classifier) molecular assay may be considered to aid decision-making discussions, along with clinical and pathological information, PSA level, and PSA doubling time.[3][103][239][240][241]

Salvage external beam radiotherapy (EBRT) with or without androgen deprivation therapy (ADT) (e.g., a luteinising hormone-releasing hormone [LHRH] agonist or antagonist) is the preferred treatment option for post-operative salvage therapy.[3][243][244][245]

Combining ADT with salvage EBRT reduces the likelihood of progression and may improve survival outcomes compared with salvage EBRT alone, but decisions (including duration of ADT) should be individualised.[243][244][245][246]

Following a careful review of the balance of risks and benefits, monitoring for progression (physical examination and PSA every 3-6 months, and imaging for symptoms or increasing PSA) may be an alternative to salvage therapy in patients with PSA persistence or recurrence after radical prostatectomy (and in whom post-operative imaging studies for pelvic nodal recurrence and distant metastases were negative).[3][241]

Salvage radiotherapy is more effective when given at lower levels of PSA (≥0.1 to 0.2 nanograms/mL), and should be considered for detectable, rising PSA, and before PSA levels reach 0.5 nanograms/mL.[242][255]

Observation is recommended (instead of salvage therapy) in patients with life expectancy ≤5 years.[3][373]

See local specialist protocol for dosing guidelines.

Primary options

leuprorelin

goserelin

triptorelin

degarelix

relugolix

with PSA persistence or recurrence: positive pelvic nodes and no distant metastases

1st line – salvage external beam radiotherapy + androgen deprivation therapy ± abiraterone

Back

1st line –

salvage external beam radiotherapy + androgen deprivation therapy ± abiraterone

Risk assessment (including use of nomograms) should be carried out to inform decision- making after radical prostatectomy. The Decipher (22-gene genomic classifier) molecular assay may also be considered to aid decision-making discussions, along with clinical and pathological information, PSA level, and PSA doubling time.[3][103][239][240][241]

Salvage external beam radiotherapy (EBRT) plus androgen deprivation therapy (ADT) (e.g., a luteinising hormone-releasing hormone [LHRH] agonist or antagonist) with or without abiraterone (plus prednisolone or methylprednisolone) is the preferred treatment option for post-operative salvage therapy in patients with positive pelvic node recurrence.[3][243]

Abiraterone (a second-generation anti-androgen) is approved for use in metastatic disease. However, off-label use in combination with EBRT and ADT (e.g., an LHRH agonist or antagonist) for selected patients with positive pelvic node recurrence may be considered.[3][236]

Observation is recommended (instead of salvage therapy) in patients with life expectancy ≤5 years.[3][373]

See local specialist protocol for dosing guidelines.

Primary options

leuprorelin

goserelin

triptorelin

degarelix

relugolix

leuprorelin

goserelin

triptorelin

degarelix

relugolix

-- AND --

abiraterone acetate

without PSA persistence or recurrence: adverse pathological features or detectable PSA

1st line – adjuvant external beam radiotherapy (± androgen deprivation therapy) or monitoring

Back

1st line –

adjuvant external beam radiotherapy (± androgen deprivation therapy) or monitoring

Decisions about adjuvant treatment for patients with adverse pathological features or detectable PSA, but without PSA persistence or recurrence, should be individualised based on risk assessment and patient preferences.

Risk assessment (including use of nomograms) should be carried out to inform decision-making after radical prostatectomy. The Decipher molecular assay (22-gene genomic classifier) may also be considered to aid decision-making discussions, along with clinical and pathological information, PSA level, and PSA doubling time.[3][103][239][240][241]

Adjuvant radiotherapy may be considered for patients with positive margins, extracapsular extension (pT3 disease), seminal vesicle invasion, or detectable PSA, and with no lymph node metastases.[247][248][249][250]

Patients with multiple adverse features or lymph node metastases (regardless of PSA levels) may be offered salvage EBRT (with or without ADT) as for PSA persistence or recurrence.[3]

Randomised controlled trials have shown that early salvage EBRT results in similar biochemical control and event-free survival rates, and lower genitourinary toxicity, compared with immediate adjuvant EBRT.[251][252][253][254]

Observation is recommended (instead of adjuvant therapy) in patients with life expectancy ≤5 years.[3]

See local specialist protocol for dosing guidelines.

Primary options

leuprorelin

goserelin

triptorelin

degarelix

relugolix

non-metastatic disease: post-radiotherapy

with PSA recurrence or positive digital rectal examination: negative lymph nodes

1st line – monitoring or androgen deprivation therapy or local secondary therapy

Back

1st line –

monitoring or androgen deprivation therapy or local secondary therapy

Salvage therapy is indicated for patients with life expectancy >5 years if there is prostate-specific antigen (PSA) recurrence or positive digital rectal examination after primary radiotherapy.

PSA recurrence after radiotherapy is defined as PSA increase of ≥2 micrograms/L (≥2 nanograms/mL) above the nadir PSA.[256] Evaluation for salvage therapy can also be considered if the PSA is increasing but has not reached 2 micrograms/L (2 nanograms/mL) above nadir.

Treatment decisions should be individualised, guided by risk stratification; PSA density, and bone and soft-tissue imaging should be performed.[3][257]

If negative for regional lymph nodes and distant metastases, consider prostate/seminal vesicle biopsy and:[3][257][258][259][260]

monitoring for progression;

androgen deprivation therapy (based on PSA density); or

local secondary therapy (which may include salvage prostatectomy plus pelvic lymph node dissection, salvage cryotherapy, re-irradiation [low- or high-dose rate brachytherapy, or stereotactic body radiotherapy], high-intensity focused ultrasound).

Salvage brachytherapy provides precise treatment for pathologically confirmed (e.g., using magnetic resonance imaging-guided biopsy) locally recurrent disease, therefore minimising toxicity to adjacent organs. Use of salvage prostatectomy and salvage cryotherapy is limited by treatment-related adverse effects (e.g., erectile dysfunction).[260][261][262][263][264][265][266]

Observation is recommended instead of salvage therapy in patients with life expectancy ≤5 years.[3]

See local specialist protocol for dosing guidelines.

Primary options

leuprorelin

goserelin

triptorelin

degarelix

relugolix

with PSA recurrence or positive digital rectal examination: positive lymph nodes

1st line – monitoring or androgen deprivation therapy (± abiraterone) or local secondary therapy (± androgen deprivation therapy)

Back

1st line –

monitoring or androgen deprivation therapy (± abiraterone) or local secondary therapy (± androgen deprivation therapy)

Salvage therapy is indicated for patients with life expectancy >5 years if there is prostate-specific antigen (PSA) recurrence or positive digital rectal examination after primary radiotherapy.

Treatment decisions should be individualised, guided by risk stratification; PSA density, and bone and soft-tissue imaging should be performed.[3][257]

If positive for regional lymph nodes and negative for distant metastases, consider prostate/seminal vesicle biopsy and:[3][257][258][259][260]

monitoring for progression

androgen deprivation therapy (ADT) with or without abiraterone (plus prednisolone or methylprednisolone);

consideration of local secondary therapy (e.g., pelvic lymph node dissection, pelvic lymph node radiation or re-irradiation [low- or high-dose rate brachytherapy, or stereotactic body radiotherapy]) with or without ADT.

Abiraterone (a second-generation anti-androgen) is approved for use in metastatic disease. However, off-label use in combination with EBRT and ADT for selected patients with positive pelvic node recurrence may be considered.[3][236] Abiraterone should not be used concurrently with another anti-androgen (e.g., nilutamide, bicalutamide, flutamide), and it should always be given with prednisolone or methylprednisolone (depending on the formulation of abiraterone).

Observation is recommended (instead of salvage therapy) in patients with life expectancy ≤5 years.[3]

See local specialist protocol for dosing guidelines.

Primary options

leuprorelin

goserelin

triptorelin

degarelix

relugolix

leuprorelin

goserelin

triptorelin

degarelix

relugolix

-- AND --

abiraterone acetate

non-metastatic disease: castration-resistant

PSA doubling time >10 months

1st line – continue androgen deprivation therapy + monitoring or secondary hormone therapy

Back

1st line –

continue androgen deprivation therapy + monitoring or secondary hormone therapy

Patients with non-metastatic castration-resistant prostate cancer are those with clinical, radiographic, or biochemical (PSA) progression despite treatment with androgen deprivation therapy (ADT), but who do not have metastases. These patients are at high risk for developing metastases, particularly if PSA doubling time (PSADT) is short (e.g., ≤10 months).

ADT with a luteinising hormone-releasing hormone (LHRH) agonist or antagonist should continue in these patients to maintain castrate serum levels of testosterone, but further hormonal treatment may be added depending on the PSADT.[3]

If PSADT is >10 months, monitoring with continued ADT is the preferred option. A secondary hormone therapy can be added to ADT (if not previously used), although evidence of survival benefit is lacking. Secondary hormone therapy may include: ketoconazole plus hydrocortisone; a first-generation anti-androgen (e.g., nilutamide, bicalutamide, flutamide); or a corticosteroid (e.g., hydrocortisone, prednisolone, dexamethasone).[3]

Ketoconazole may cause severe liver injury and adrenal insufficiency. It is contraindicated in patients with liver disease and expert guidance should be sought if used. Liver and adrenal function should be monitored before and during treatment.[270]

ADT alone or observation is recommended for asymptomatic patients with life expectancy ≤5 years.[3]

See local specialist protocol for dosing guidelines.

Primary options

ketoconazole

and

hydrocortisone

nilutamide

bicalutamide

flutamide

hydrocortisone

prednisolone

dexamethasone

2nd line – continue androgen deprivation therapy + anti-androgen withdrawal

Back

2nd line –

continue androgen deprivation therapy + anti-androgen withdrawal

Anti-androgen withdrawal (i.e., to exclude an anti-androgen withdrawal effect) may be an option for non-metastatic castration-resistant disease.[3][267][268][269]

PSA doubling time ≤10 months

1st line – continue androgen deprivation therapy + second-generation anti-androgen or monitoring

Back

1st line –

continue androgen deprivation therapy + second-generation anti-androgen or monitoring

If PSADT is ≤10 months, a second-generation anti-androgen (e.g., apalutamide, darolutamide, or enzalutamide) can be added to ADT.[3]

Randomised studies of second-generation anti-androgens in patients with non-metastatic castration-resistant prostate cancer and PSADT ≤10 months have demonstrated improved overall survival, metastasis-free survival, and time to progression compared with placebo, without compromising quality of life.[271][272][273][274][275][276][277][278][279] It is not known if similar benefit would be achieved in men with a PSADT >10 months.

ADT alone or observation is recommended for asymptomatic patients with life expectancy ≤5 years.[3]

See local specialist protocol for dosing guidelines.

Primary options

apalutamide

darolutamide

enzalutamide

2nd line – continue androgen deprivation therapy + secondary hormone therapy or anti-androgen withdrawal

Back

2nd line –

continue androgen deprivation therapy + secondary hormone therapy or anti-androgen withdrawal

Alternative options for patients with non-metastatic castration-resistant disease and PSADT ≤10 months include other secondary hormone options or anti-androgen withdrawal (as described for PSADT >10 months).[3][267][268][269][374]

metastatic disease: castration-sensitive

1st line – androgen deprivation therapy + second-generation anti-androgen ± docetaxel

Back

1st line –

androgen deprivation therapy + second-generation anti-androgen ± docetaxel

The main treatment goals for metastatic disease are prolongation of survival while maintaining quality of life, and palliation of symptoms that may arise from metastatic tumour deposits.

Patients with castration-sensitive metastatic disease include those with metastatic disease at presentation, and those who are not receiving androgen deprivation therapy (ADT) when metastatic disease develops (i.e., castration-naive).

Genetic testing (germline and somatic) should be carried out in all patients with metastatic disease (if not done previously) to inform prognosis and guide treatment decisions, including eligibility for clinical trials and suitability for novel targeted therapies.[280][281] See Diagnosis approach.

Combination therapy with ADT (e.g., a luteinising hormone-releasing hormone [LHRH] agonist or antagonist) plus a second-generation anti-androgen with or without docetaxel is recommended.[236][281][282][283][284][285][286][287][288][289][290][291][292][293] Decisions about treatment should take into account toxicity, disease volume, and timing of metastases.

Specific treatment options include:

ADT plus docetaxel and one of: abiraterone, apalutamide, darolutamide, or enzalutamide; or

ADT plus one of: abiraterone, apalutamide, darolutamide, or enzalutamide.[3][237][293][296][297][298]

Abiraterone should always be given with prednisolone or methylprednisolone (depending on the formulation of abiraterone).

For patients with high-volume disease (i.e., visceral metastases and/or ≥4 bone metastases with ≥1 beyond the vertebral bodies and pelvis) or low-volume disease (i.e., non-regional lymph-node-only disease, or presence of <4 bone metastases without visceral/other metastasis) with synchronous metastases, ADT plus a second-generation anti-androgen with docetaxel should be considered.[3] Triplet combination therapy may improve survival compared with ADT plus docetaxel alone, particularly in those with high-volume castration-sensitive disease.[297][298][299][300][301]

For low-volume disease (i.e., non-regional lymph-node-only disease, or presence of <4 bone metastases without visceral/other metastasis) with metachronous metastases, ADT plus abiraterone, apalutamide, or enzalutamide is preferred.[3][302]

ADT is usually given continuously, but intermittent ADT may be considered if adverse effects occur with continuous ADT.[72][306][307][308][309][310]

A PSA level ≤0.2 micrograms/L (≤0.2 nanograms/mL) after 7 months of ADT is a strong predictor for longer overall survival in patients with castration-sensitive metastatic disease.[311]

ADT alone is not recommended for patients with castration-sensitive metastatic disease unless combination treatment is clearly contraindicated.[3]

Bilateral orchiectomy is an option for patients with castration-sensitive metastatic disease, but is rarely used.

LHRH agonists may cause an increase in testosterone levels during the first week of treatment (testosterone flare), which may exacerbate symptoms in patients with metastatic disease.[149][150][151] If an LHRH agonist is used in the metastatic setting, it should be combined with a first-generation anti-androgen for ≥7 days to avoid testosterone flare or, alternatively, an LHRH antagonist can be used for 1 month before transitioning to an LHRH agonist.[3][152]

See local specialist protocol for dosing guidelines.

Primary options

leuprorelin

goserelin

triptorelin

degarelix

relugolix

-- AND --

abiraterone acetate

apalutamide

darolutamide

enzalutamide

leuprorelin

goserelin

triptorelin

degarelix

relugolix

-- AND --

docetaxel

-- AND --

abiraterone acetate

apalutamide

darolutamide

enzalutamide

Secondary options

leuprorelin

goserelin

triptorelin

degarelix

relugolix

Consider – supportive care

Back

Consider –

supportive care

Additional treatment recommended for SOME patients in selected patient group

Supportive care should be considered to manage complications and symptoms related to metastatic disease.

Systemic radiotherapy with the beta-particle emitters strontium-89 or samarium-153 can be considered for palliation in patients with symptomatic bone metastases without visceral metastases. Their use is purely palliative and has largely been superseded by radium-223, which confers a survival advantage.

Radiotherapy in palliative doses can be given to sites of painful bony metastasis. Radiation may include a single treatment or a 1- or 2-week course depending on normal tissue toxicity and patient convenience.[364] Studies do not show a consistent difference between regimens for pain control, but some have reported higher rates of reirradiation in patients receiving single-fraction regimens (although the reason for this is unclear).[364][365][366][367] Stereotactic body radiotherapy (SBRT) may be considered instead of conventional palliative radiotherapy for some patients with painful bony metastases (e.g., with an Eastern Cooperative Oncology Group performance status 0 to 2, without neurological symptoms, and not receiving surgery).[364][368] Radiation may also be given to the pelvis, if previously untreated, in palliative doses to relieve obstructive symptoms or bleeding.

1st line – androgen deprivation therapy + external beam radiotherapy ± second-generation anti-androgen or docetaxel

Back

1st line –

androgen deprivation therapy + external beam radiotherapy ± second-generation anti-androgen or docetaxel

The main treatment goals for metastatic disease are prolongation of survival while maintaining quality of life, and palliation of symptoms that may arise from metastatic tumour deposits.

Androgen deprivation therapy (ADT) plus external beam radiotherapy (EBRT) to the primary tumour (with or without abiraterone, apalutamide, docetaxel, or enzalutamide) may be an option for some patients with castration-sensitive metastatic disease.[3][294][295] Decisions about treatment should take into account toxicity, disease volume, and timing of metastases.

Abiraterone should always be given with prednisolone or methylprednisolone (depending on the formulation of abiraterone).

Improved survival has been demonstrated with EBRT plus ADT versus ADT alone in patients with low-volume castration-sensitive disease (i.e., non-regional lymph-node-only disease, or presence of <4 bone metastases without visceral/other metastasis).[301][303][304][305]

Moderate hypofractionation and ultra-hypofractionation are the preferred approaches for EBRT.[3][303]

Patients with significant baseline urinary symptoms may not be suitable for EBRT due to increased risk of urinary obstruction.

Luteinising hormone-releasing hormone (LHRH) agonists may cause an increase in testosterone levels during the first week of treatment (testosterone flare), which may exacerbate symptoms in patients with metastatic disease.[149][150][151] If an LHRH agonist is used in the metastatic setting, it should be combined with a first-generation anti-androgen for ≥7 days to avoid testosterone flare or, alternatively, an LHRH antagonist can be used for 1 month before transitioning to an LHRH agonist.[3][152]

See local specialist protocol for dosing guidelines.

Primary options

leuprorelin

goserelin

triptorelin

degarelix

relugolix

leuprorelin

goserelin

triptorelin

degarelix

relugolix

-- AND --

abiraterone acetate

apalutamide

docetaxel

enzalutamide

Consider – supportive care

Back

Consider –

supportive care

Additional treatment recommended for SOME patients in selected patient group

Supportive care should be considered to manage complications and symptoms related to metastatic disease.

metastatic disease: castration-resistant

no prior treatment with second-generation anti-androgen therapy

1st line – continue androgen deprivation therapy + supportive care

Back

1st line –

continue androgen deprivation therapy + supportive care

The main treatment goals for metastatic disease are prolongation of survival while maintaining quality of life, and palliation of symptoms that may arise from metastatic tumour deposits.

Patients with castration-resistant metastatic disease are those who develop metastatic disease despite achieving castrate levels of testosterone with primary androgen deprivation therapy (ADT) (e.g., a luteinising hormone-releasing hormone [LHRH] agonist or antagonist).

ADT should be continued to maintain castrate levels of testosterone in patients with castration-resistant metastatic disease. Patients should be closely monitored for progression, and treatments added sequentially.[3]

Treatment options for patients with castration-resistant metastatic disease have expanded rapidly. Optimal sequencing of therapies following docetaxel or cabazitaxel and/or second-generation anti-androgen therapy is unclear. Treatment decisions should take into account patient goals and preferences, prior treatment exposures, the presence or absence of symptoms, the location of metastases, potential adverse effects, and the presence of certain biomarkers.[3]

Tumour testing for somatic homologous recombination repair (HRR) mutations, microsatellite instability (MSI)/mismatch repair (MMR) deficiency, and tumour mutational burden (TMB) should be carried out in patients with metastatic disease (if not done previously) to inform prognosis and guide treatment decisions, including eligibility for clinical trials and suitability for novel targeted therapies.[280][281] Re-evaluation of somatic testing may be considered if done previously.[3] Germline testing for HRR mutations is recommended if not done previously. See Diagnosis approach.

Continue supportive care to manage complications and symptoms related to metastatic disease.

Patients with castration-resistant disease who have bone metastases should be offered treatment to prevent skeletal-related events. See Complications.

Plus – second-generation anti-androgen or docetaxel or cabazitaxel

Back

Plus –

second-generation anti-androgen or docetaxel or cabazitaxel

Treatment recommended for ALL patients in selected patient group

For patients with no prior treatment with a second-generation anti-androgen therapy (abiraterone, enzalutamide, darolutamide, apalutamide), ADT can be combined with one of the following options:[320][321][322][323][324][325][326][327][328][329][330][331]

abiraterone (with prednisolone or methylprednisolone);

enzalutamide;

docetaxel plus prednisolone (if no prior docetaxel use); or

cabazitaxel plus prednisolone (if prior docetaxel use).

Patients who show signs of progression while taking abiraterone plus prednisolone may benefit from switching from prednisolone to dexamethasone.[337][338]

See local specialist protocol for dosing guidelines.

Primary options

abiraterone acetate

enzalutamide

docetaxel

and

prednisolone

Secondary options

cabazitaxel

and

prednisolone

prior treatment with second-generation anti-androgen therapy: no prior docetaxel treatment

1st line – continue androgen deprivation therapy + supportive care

Back

1st line –

continue androgen deprivation therapy + supportive care

The main treatment goals for metastatic disease are prolongation of survival while maintaining quality of life, and palliation of symptoms that may arise from metastatic tumour deposits.

Tumour testing for somatic homologous recombination repair (HRR) mutations, microsatellite instability (MSI)/mismatch repair (MMR) deficiency, and tumour mutational burden (TMB) should be carried out in patients with castration-resistant metastatic disease (if not done previously) to inform prognosis and guide treatment decisions, including eligibility for clinical trials and suitability for novel targeted therapies.[280][281] Re-evaluation of somatic testing may be considered if done previously.[3] Germline testing for HRR mutations is recommended if not done previously. See Diagnosis approach.

Continue supportive care to manage complications and symptoms related to metastatic disease.

Patients with castration-resistant disease who have bone metastases should be offered treatment to prevent skeletal-related events. See Complications.

Radiotherapy in palliative doses can be given to sites of painful bony metastasis. Radiation may include a single treatment or a 1- or 2-week course depending on normal tissue toxicity and patient convenience.[364] Studies do not show a consistent difference between regimens for pain control, but some have reported higher rates of re-irradiation in patients receiving single-fraction regimens (although the reason for this is unclear).[364][365][366][367] Stereotactic body radiotherapy (SBRT) may be considered instead of conventional palliative radiotherapy for some patients with painful bony metastases (e.g., with an Eastern Cooperative Oncology Group performance status 0 to 2, without neurological symptoms, and not receiving surgery).[364][368] Radiation may also be given to the pelvis, if previously untreated, in palliative doses to relieve obstructive symptoms or bleeding.

Plus – docetaxel or olaparib or rucaparib

Back

Plus –

docetaxel or olaparib or rucaparib

Treatment recommended for ALL patients in selected patient group

For patients with progression following treatment with second-generation anti-androgen therapy, with no prior docetaxel treatment, docetaxel plus prednisolone can be added to ADT.[3]

If the patient has a BRCA1 or BRCA2 mutation, either of the poly (ADP-ribose) polymerase (PARP) inhibitors, olaparib or rucaparib, may be considered as alternative options in this setting.[332][333][334][335]

Anaemia, fatigue, and nausea are commonly reported with PARP inhibitors. Careful monitoring for anaemia and renal and hepatic function is required.[3]

See local specialist protocol for dosing guidelines.

Primary options

docetaxel

and

prednisolone

olaparib

rucaparib

prior treatment with second-generation anti-androgen therapy: prior docetaxel treatment

1st line – continue androgen deprivation therapy + supportive care

Back

1st line –

continue androgen deprivation therapy + supportive care

The main treatment goals for metastatic disease are prolongation of survival while maintaining quality of life, and palliation of symptoms that may arise from metastatic tumour deposits.

Continue supportive care to manage complications and symptoms related to metastatic disease.

Patients with castration-resistant disease who have bone metastases should be offered treatment to prevent skeletal-related events. See Complications.

Plus – cabazitaxel or docetaxel rechallenge

Back

Plus –

cabazitaxel or docetaxel rechallenge

Treatment recommended for ALL patients in selected patient group

For patients with progression following treatment with second-generation anti-androgen therapy and prior docetaxel treatment, cabazitaxel plus prednisolone can be added to ADT.[328][329][330][336]or

Docetaxel rechallenge is a further option for patients with castration-sensitive disease who progressed on prior docetaxel and second-generation anti-androgen therapy.[3]

See local specialist protocol for dosing guidelines.

Primary options

cabazitaxel

and

prednisolone

docetaxel

and

prednisolone

progression on initial/preferred treatments or alternative treatment indicated

1st line – sipuleucel-T + continue androgen deprivation therapy + supportive care

Back

1st line –

sipuleucel-T + continue androgen deprivation therapy + supportive care

The main treatment goals for metastatic disease are prolongation of survival while maintaining quality of life, and palliation of symptoms that may arise from metastatic tumour deposits.

An autologous active cellular immunotherapy, sipuleucel-T may be an option for asymptomatic or minimally symptomatic patients with good functional status (e.g., an Eastern Cooperative Oncology Group performance status of 0 to 1).[3][339][340]

Sipuleucel-T is not recommended for patients with visceral disease and a life expectancy of less than 6 months, or patients with hepatic metastases.[3][339]

Continue supportive care to manage complications and symptoms related to metastatic disease. Patients with castration-resistant disease who have bone metastases should be offered treatment to prevent skeletal-related events. See Complications.

See local specialist protocol for dosing guidelines.

Primary options

sipuleucel-T

1st line – PARP inhibitor ± second-generation anti-androgen + continue androgen deprivation therapy + supportive care

Back

1st line –

PARP inhibitor ± second-generation anti-androgen + continue androgen deprivation therapy + supportive care

The main treatment goals for metastatic disease are prolongation of survival while maintaining quality of life, and palliation of symptoms that may arise from metastatic tumour deposits.

PARP inhibitors are recommended for patients with homologous recombination repair (HRR) gene alterations; response may be greatest for BRCA1 and BRCA2 variants.[3]

Olaparib can be considered for patients with an HRR gene mutation who have had prior second-generation anti-androgen therapy.[3][237][332][333][334] Efficacy may vary depending on the genes involved; in one study, of patients with an alteration in one of 15 pre-specified HRR genes, those with a BRCA1 or BRCA2 mutation appeared to derive the greatest survival benefit.[334]

Rucaparib can be considered for patients with a BRCA1 or BRCA2 mutation who have had prior second-generation anti-androgen therapy.[3][335][341][342] Rucaparib is not recommended for patients without a BRCA1 or BRCA2 mutation.[3][343]

Olaparib or niraparib may be used in combination with abiraterone (plus prednisolone or methylprednisolone) for patients with a BRCA1 or BRCA2 mutation who have not received prior second-generation anti-androgen therapy.[3][344][345][346]

Talazoparib plus enzalutamide may be an option for patients with an HRR mutation who have not been treated in the castration-resistant setting, depending on treatments received before progression.[3][347][348]

Anaemia, fatigue, and nausea are commonly reported with PARP inhibitors. Careful monitoring for anaemia and renal and hepatic function is required.[3]

See local specialist protocol for dosing guidelines.

Primary options

olaparib

rucaparib

olaparib

niraparib

-- AND --

abiraterone acetate

talazoparib

and

enzalutamide

1st line – pembrolizumab + continue androgen deprivation therapy + supportive care

Back

1st line –

pembrolizumab + continue androgen deprivation therapy + supportive care

The main treatment goals for metastatic disease are prolongation of survival while maintaining quality of life, and palliation of symptoms that may arise from metastatic tumour deposits.

A programmed death receptor-1 (PD-1)-blocking monoclonal antibody, pembrolizumab may be considered for patients with mismatch repair deficient, (dMMR), microsatellite instability-high (MSI-H), or high tumour mutational burden-high (TMB-H) castration-resistant metastatic prostate cancer.[3][281]

Much of the evidence for this treatment is based on different tumour types; however, early phase trials report antitumour activity among specific subsets of patients with metastatic castration-resistant prostate cancer.[349][350][351][352]

Pembrolizumab may cause severe, life-threatening immune-mediated adverse reactions.[353]

See local specialist protocol for dosing guidelines.

Primary options

pembrolizumab

1st line – lutetium (Lu-177) vipivotide tetraxetan + continue androgen deprivation therapy + supportive care

Back

1st line –

lutetium (Lu-177) vipivotide tetraxetan + continue androgen deprivation therapy + supportive care

The main treatment goals for metastatic disease are prolongation of survival while maintaining quality of life, and palliation of symptoms that may arise from metastatic tumour deposits.

A radioligand therapeutic agent that delivers beta-radiation to prostate-specific membrane antigen (PSMA)-expressing cells and the surrounding microenvironment. Lu-177 vipivotide tetraxetan can be considered for patients with progression after second-generation anti-androgen therapy who have PSMA-positive castration-resistant metastatic disease.[3][237][354][355][356][281]

PSMA-PET imaging is required for patient selection. Gallium (Ga-68) PSMA-11, piflufolastat F-18, or flotufolastat F-18 may be used as radiotracers to detect PSMA expression and determine eligibility.[3][354][357]

See local specialist protocol for dosing guidelines.

Primary options

lutetium Lu 177 vipivotide tetraxetan

1st line – cabazitaxel plus carboplatin + continue androgen deprivation therapy + supportive care

Back

1st line –

cabazitaxel plus carboplatin + continue androgen deprivation therapy + supportive care

The main treatment goals for metastatic disease are prolongation of survival while maintaining quality of life, and palliation of symptoms that may arise from metastatic tumour deposits.

Carbazitaxel plus carboplatin may be considered in combination with prednisolone for patients with aggressive disease or unfavourable genomics (two or more defects in PTEN, TP53, and RB1).[358]

Adverse events may include fatigue, anaemia, neutropenia, and thrombocytopenia.

See local specialist protocol for dosing guidelines.

Primary options

cabazitaxel

and

carboplatin

and

prednisolone

1st line – mitoxantrone + continue androgen deprivation therapy + supportive care

Back

1st line –

mitoxantrone + continue androgen deprivation therapy + supportive care

The main treatment goals for metastatic disease are prolongation of survival while maintaining quality of life, and palliation of symptoms that may arise from metastatic tumour deposits.

Mitoxantrone may be considered in combination with prednisolone for palliative treatment of symptomatic patients who have progressed on prior docetaxel and cannot tolerate other therapies. It has not been shown to improve survival.[3][359][360]

See local specialist protocol for dosing guidelines.

Primary options

mitoxantrone

and

prednisolone

1st line – radium-223 + continue androgen deprivation therapy + supportive care

Back

1st line –

radium-223 + continue androgen deprivation therapy + supportive care

The main treatment goals for metastatic disease are prolongation of survival while maintaining quality of life, and palliation of symptoms that may arise from metastatic tumour deposits.

A calcium mimetic that localises to the bone and delivers radiation directly to bone metastases, radium-223 can be considered for patients with castration-resistant metastatic disease who have symptomatic bone metastases without visceral metastases.[3][361]

Radium-223 is associated with adverse events including anaemia, neutropenia, thrombocytopenia, bone pain, and gastrointestinal disorders. There have also been reports of increased risk of fracture and deaths when used in combination with abiraterone plus prednisolone.[362][363]

The European Medicines Agency (EMA) has restricted the use of radium-223 to symptomatic patients who have received two prior treatments for metastatic prostate cancer, or who cannot receive other treatments. It should not be used with abiraterone and prednisolone or with other systemic cancer therapies (except hormone therapy).[363]

A careful assessment of risk of fractures should be carried out before, during, and after treatment with radium-223. Concomitant bisphosphonate or denosumab is recommended when radium-223 is prescribed.[3][363] See Complications.

See local specialist protocol for dosing guidelines.

Primary options

radium Ra 223 dichloride

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Prostate cancer

Treatment algorithm

Your Organisational Guidance

very low-risk disease

observation

androgen deprivation therapy alone (if symptomatic and life expectancy ≤5 years)

Primary options

active surveillance

low-risk disease

observation

androgen deprivation therapy alone (if symptomatic and life expectancy ≤5 years)

Primary options

active surveillance

brachytherapy

external beam radiotherapy

radical prostatectomy

favourable intermediate-risk disease

observation

androgen deprivation therapy alone (if symptomatic and life expectancy ≤5 years)

Primary options

brachytherapy (if life expectancy 5-10 years)

external beam radiotherapy (if life expectancy 5-10 years)

active surveillance

brachytherapy

external beam radiotherapy

radical prostatectomy ± lymph node dissection

unfavourable intermediate-risk disease

observation

androgen deprivation therapy alone (if symptomatic)

Primary options

observation (if life expectancy 5-10 years)

external beam radiotherapy (± brachytherapy boost) or brachytherapy (if life expectancy >5 years)

androgen deprivation therapy ± first-generation anti-androgen

Primary options

radical prostatectomy + lymph node dissection (if life expectancy >10 years)

high-risk or very high-risk disease

observation

androgen deprivation therapy ± external beam radiotherapy

Primary options

external beam radiotherapy

external beam radiotherapy ± brachytherapy boost

androgen deprivation therapy

Primary options

external beam radiotherapy ± brachytherapy boost

androgen deprivation therapy + abiraterone (for very high-risk disease)

Primary options

radical prostatectomy + pelvic lymph node dissection (for fit patients without tumour fixation to the pelvic musculature or skeleton)

androgen deprivation therapy alone (for patients unsuitable for surgery or radiotherapy)

Primary options

non-metastatic disease: post-radical prostatectomy

salvage external beam radiotherapy (± androgen deprivation therapy) or monitoring

Primary options

salvage external beam radiotherapy + androgen deprivation therapy ± abiraterone

Primary options

adjuvant external beam radiotherapy (± androgen deprivation therapy) or monitoring

Primary options

non-metastatic disease: post-radiotherapy

monitoring or androgen deprivation therapy or local secondary therapy

Primary options

monitoring or androgen deprivation therapy (± abiraterone) or local secondary therapy (± androgen deprivation therapy)

Primary options

non-metastatic disease: castration-resistant

continue androgen deprivation therapy + monitoring or secondary hormone therapy

Primary options

continue androgen deprivation therapy + anti-androgen withdrawal

continue androgen deprivation therapy + second-generation anti-androgen or monitoring

Primary options

continue androgen deprivation therapy + secondary hormone therapy or anti-androgen withdrawal

metastatic disease: castration-sensitive

androgen deprivation therapy + second-generation anti-androgen ± docetaxel

Primary options

Secondary options

supportive care

androgen deprivation therapy + external beam radiotherapy ± second-generation anti-androgen or docetaxel

Primary options

supportive care

metastatic disease: castration-resistant

continue androgen deprivation therapy + supportive care

second-generation anti-androgen or docetaxel or cabazitaxel

Primary options