Prostate Cancer Management

Evaluation

Staging  

Staging determines the extent of cancer upon diagnosis. It is also an important factor in the choice of treatment, and it provides information about the prognosis of the disease.  

Tumor, Nodes, and Metastasis (TNM) System  

Developed by the American Joint Committee on Cancer (AJCC) and Union Internationale Contre le Cancer (UICC)

Clinical T (cT)
T - Primary Tumor
TX		Primary tumor cannot be assessed
T0		No evidence of primary tumor
T1		Clinically inapparent tumor not palpable or visible by imaging
	T1a	Tumor incidental histological finding in 5% or less of tissue resected
	T1b	Tumor incidental histological finding in more than 5% of tissue resected
	T1c	Tumor identified by needle biopsy (secondary to elevated PSA level)
T2		Tumor confined within the prostate gland (by needle biopsy)
	T2a	Tumor involves 1/2 of one lobe or less
	T2b	Tumor involves >1/2 of one lobe but not both lobes
	T2c	Tumor involves both lobes
T3		Tumor extends through the prostatic capsule
	T3a	Extracapsular extension (unilateral or bilateral)
	T3b	Tumor invades the seminal vesicle(s)
T4		Tumor fixed or invades adjacent structures other than the seminal vesicles (bladder, rectum, levator muscles, and/or pelvic wall)
Pathological T (pT)
T - Primary Tumor
T2		Confined in the organ
T3		Positive extension extraprostatically
	T3a	Unilateral or bilateral extraprostatic extension
	T3b	Tumor invades seminal vesicle(s)
T4		Fixed tumor or invades adjacent structures other than the seminal vesicles (ie external sphincter, rectum, bladder, levator muscles, and/or pelvic wall)
N - Regional Lymph Nodes
NX		Regional lymph nodes cannot be assessed
N0		No regional lymph node metastasis
N1		Regional lymph node metastasis present
M - Distant metastasis1
M0		No distant metastasis
M1		Distant metastasis
	M1a	Non-regional lymph node(s)
	M1b	Bone(s)
	M1c	Other site(s) with or without bone disease
1The most advanced category (M1c) should be used when >1 metastasis site is present References: TNM Staging System for Prostate Cancer (8th ed, 2017) in National Comprehensive Cancer Network (NCCN). NCCN guidelines: prostate cancer. Version 4.2023. NCCN. Sep 2023; European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Society of Urogenital Radiology (ESUR)-International Society of Urological Pathology (ISUP)-International Society of Geriatric Oncology (SIOG) guidelines on prostate cancer. 2023.

Stage	Tumor	Node	Metastasis	PSA	Grade Group
I	cT1a-c	N0	M0	PSA <10	1
	cT2a	N0	MO	PSA <10	1
	pT2	NO	MO	PSA <10	1
IIA	cT1a-c	N0	M0	PSA  ≥10<20	1
	cT2a	N0	MO	PSA ≥10<20	1
	pT2	NO	MO	PSA ≥10<20	1
	cT2b	NO	MO	PSA <20	1
	cT2c	NO	MO	PSA <20	1
IIB	T1-2	N0	M0	PSA <20	2
IIC	T1-2	N0	MO	PSA <20	3
	T1-2	NO	MO	PSA <20	4
IIIA	T1-2	NO	MO	PSA ≥20	1-4
IIIB	T3-T4	N0	M0	Any PSA	1-4
IIIC	Any T	N0	MO	Any PSA	5
IVA	Any T	N1	M0	Any PSA	Any
IVB	Any T	Any N	M1	Any PSA	Any
References: NCCN. NCCN guidelines: prostate cancer. Version 4.2023. NCCN. Sep 2023; American Cancer Society (ACS).Prostate cancer staging. ACS. Oct 2023.


Risk Stratification  

Based on the PSA level, biopsy, Gleason score, and TNM classification. It helps in decision-making for the management of patients diagnosed with prostate cancer. 

Risk Group	Clinical Stage		PSA		Grade Group or Gleason Pattern		Others
Clinically Localized
Very Low	cT1c	and	<10 ng/mL	and	Grade group 1	and	<3 prostate biopsy fragments/cores positive, with ≤50% cancer in each fragment/core and PSA density <0.15 ng/mL/g
Low	cT1-cT2a	and	<10 ng/mL	and	Grade group 1
Intermediate	cT2b-cT2c	or	10-20 ng/mL	or	Grade group 2-3
Intermediate - Favorable	cT2b-cT2c	or	10-20 ng/mL	or	Grade group 1 or 2	and	1 intermediate risk factor (IRF) and percentage of positive biopsy core <50% (eg <6 of 12 cores)
Intermediate - Unfavorable	cT2b-cT2c	or	10-20 ng/mL	or	Grade group 3	and/or	2 or 3 IRF and/or percentage of positive biopsy cores ≥50% (eg ≥6 of 12 cores)
High	cT3a	or	>20 ng/mL	or	Grade group 4 or Grade group 5		Exactly 1 high-risk feature
Locally Advanced
Very High	cT3b-cT4	or	Any	or	Primary Gleason pattern 5 or Grade group 4 or 5 in >4 cores		2 or 3 high-risk features
Regional	Any T, N1, M0
Metastatic	Any T, any N, M1
References: NCCN. NCCN guidelines: prostate cancer. Version 4.2023. NCCN. Sep 2023; EAU-EANM-ESTRO-ESUR-ISUP-SIOG guidelines on prostate cancer. 2023.; European Society for Medical Oncology (ESMO). Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Jun 2020.

• Small cell or neuroendocrine prostate carcinoma histology
• Exclusive visceral metastases
• Predominant lytic bone metastases
• Bulky (>5 cm) lymphadenopathy or Gleason score of ≥8 at diagnosis 
• PSA of <10 ng/mL with ≥20 bone metastases
• ≥2 times elevated lactate dehydrogenase (LDH) or carcinoembryonic antigen (CEA) 
• <6 months interval response to androgen deprivation therapy

Aggressive variant prostate cancer contains defects in at least two of the three tumor suppressors: Tumor protein 53 (TP53), retinoblastoma protein 1 (RB1), and phosphatase and tensin homolog (PTEN). 

Small Cell/Neuroendocrine Prostate Carcinoma  

Small cell or neuroendocrine prostate carcinoma is characterized by small, blue neuroendocrine cells which do not secrete PSA but express neuroendocrine markers (chromogranin A, synaptophysin, and neuron-specific enolase [NSE]). It metastasizes to visceral organs and responds temporarily to chemotherapy.

Principles of therapy

Treatment Strategies for Androgen Deprivation Therapy (ADT)  

Luteinizing hormone-releasing hormone (LHRH) analogs (medical castration) and bilateral orchiectomy (surgical castration) are equally effective.  

The recommended androgen deprivation therapy options for clinically localized prostate cancer include the following:

• LHRH agonist monotherapy (ie Goserelin, Leuprolide, Triptorelin)
• LHRH agonist with first-generation anti-androgen (ie Nilutamide, Flutamide, Bicalutamide)
• LHRH antagonist (ie Degarelix, Relugolix)
• Very high-risk disease: LHRH agonist or Degarelix with Abiraterone 

The recommended ADT options for regional prostate cancer include the following:

• Orchiectomy with or without Abiraterone
• LHRH agonist monotherapy (ie Goserelin, Leuprolide, Triptorelin)
• LHRH agonist (ie Goserelin, Leuprolide, Triptorelin) with first-generation anti-androgen (ie Nilutamide, Flutamide, Bicalutamide) or Abiraterone
• LHRH antagonist (ie Degarelix, Relugolix)
• Degarelix with Abiraterone
• LHRH agonist, LHRH antagonist, or orchiectomy for patients with life expectancy of <5 years

The recommended ADT options for castration-sensitive prostate cancer without metastasis include the following:

• If with PSA persistence or recurrence after radical prostatectomy: EBRT with or without neoadjuvant or concurrent and/or adjuvant ADT, or EBRT plus LHRH agonist or Degarelix with Abiraterone (if positive for pelvic recurrence)
• If with PSA persistence or recurrence after EBRT, TRUS-biopsy negative, or with disease progression after salvage EBRT:
  • Orchiectomy
  • LHRH agonist monotherapy (ie Goserelin, Leuprolide, Triptorelin)
  • LHRH agonist (ie Goserelin, Leuprolide, Triptorelin) with first-generation ant-androgen (ie Nilutamide, Flutamide, Bicalutamide)
  • LHRH antagonist (ie Degarelix, Relugolix)

The recommended ADT options for castration-sensitive metastatic prostate cancer include the following:

• Orchiectomy with or without Docetaxel and Abiraterone or Darolutamide
• Orchiectomy with Abiraterone, Apalutamide, or Enzalutamide
• LHRH agonist monotherapy (ie Goserelin, Leuprolide, Triptorelin)
• LHRH agonist or with Docetaxel and Abiraterone or Darolutamide
• LHRH agonist with first-generation anti-androgen (ie Nilutamide, Flutamide, Bicalutamide) with or without Docetaxel
• LHRH agonist with Abiraterone, Apalutamide or Enzalutamide
• LHRH antagonist with or without Docetaxel for patients given EBRT with ADT
• Degarelix with Docetaxel and Abiraterine or Darolutamide
• Degarelix with Abiraterone, Enzalutamide or Apalutamide

Treatment Strategies for Castration-Resistant Prostate Cancer  

CRPC without Metastasis (M0)  

For CRPC without metastasis (M0), observation with ADT if PSADT of >10 months may be considered. Apalutamide, Darolutamide, or Enzalutamide with ADT if PSADT ≤10 months may be offered.  

CRPC with Metastasis (M1)  

Patients with mCRPC should continue ADT with additional secondary hormone therapies, chemotherapies, or immunotherapies.  

Treatment Strategies for Adenocarcinoma-type Metastatic CRPC  

Novel hormone therapy includes Abiraterone, Apalutamide, Darolutamide, or Enzalutamide received for metastatic castration-sensitive prostate cancer, M0 CRPC, or previous lines of treatment for M1CRPC.  

The recommended options for patients without prior Docetaxel and novel hormone therapy use includes Abiraterone, Docetaxel, and Enzalutamide as preferred treatment options. Regimens that can be used depending on the patient's status include the following:

• BRCA1/2 mutations: Niraparib/Abiraterone, Olaparib/Abiraterone
• Recommended only for asymptomatic or minimally symptomatic patients, with no liver metastases, with a life expectancy of >6 months, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1: Sipuleucel-T
• HRRm positive previously patients: Talazoparib/Enzalutamide
• Symptomatic bone metastases: Radium-223

Other recommended therapies include other secondary hormone therapy. 

The recommended options for patients previously given novel hormone therapy but no prior use of Docetaxel include Docetaxel as the preferred agent. Regimens that can be used depending on the patient's status include the following: 

• BRCA1/2 mutation-positive patients treated with androgen receptor-directed therapy and taxane-based chemotherapy: Rucaparib 
• Fit patients with aggressive variant prostate cancer (eg visceral metastases, low PSA and bulky disease, high LDH, high CEA, lytic bone metastases, neuroendocrine prostate cancer histology) or unfavorable genomics (defects in at least 2 of PTEN, TP53, and RB1): Cabazitaxel/Carboplatin
• BRCA1/2 mutation: Niraparib/Abiraterone
• HRRm positive previously treated androgen receptor-directed therapy: Olaparib
• Symptomatic bone metastases: Radium-223
• Recommended only for asymptomatic or minimally symptomatic patients with no liver metastases, life expectancy >6 months, ECOG performance status of 0-1: Sipuleucel-T
• HRRm positive previously patients: Talazoparib/Enzalutamide

Other recommended therapies include Abiretarone with or without Dexamethasone, Enzalutamide and other secondary hormone therapy. 

The recommended options for patients previously given Docetaxel but no prior novel hormone therapy use include Abiraterone, Cabazitaxel, and Enzalutamide as the preferred regimens. Regimens that can be used depending on the patient's status include the following:

• Fit patients with aggressive variant prostate cancer (eg visceral metastases, low PSA and bulky disease, high LDH, high CEA, lytic bone metastases, neuroendocrine prostate cancer histology) or unfavorable genomics (defects in at least 2 of PTEN, TP53, and RB1): Cabazitaxel/Carboplatin
• BRCA1/2 mutation: Niraparib/Abiraterone, Olaparib/Abiraterone
• Symptomatic bone metastases: Radium-223
• Symptomatic patients with visceral metastases intolerant to other therapies: Mitoxantrone
• Recommended only for asymptomatic or minimally symptomatic patients with no liver metastases, life expectancy >6 months, ECOG performance status of 0-1: Sipuleucel-T
• HRRm positive previously patients: Talazoparib/Enzalutamide

Other recommended agents include other secondary hormone therapy. 

The recommended options for patients previously given Docetaxel and novel hormone therapy includes Cabazitaxel and Docetaxel rechallenge as the preferred regimens. Docetaxel rechallenge is to be given after progression on novel hormone therapy in castration-sensitive patients negative for disease progression on prior Docetaxel therapy. Regimens that can be used depending on the patient's status include: 

• PSMA-positive metastases: Lutetium Lu 177 vipivotide tetraxetan (Lu-177-PSMA-617/177Lu-PSMA-617)
• Fit patients with aggressive variant prostate cancer (eg visceral metastases, low PSA and bulky disease, high LDH, high CEA, lytic bone metastases, neuroendocrine prostate cancer histology) or unfavorable genomics (defects in at least 2 of PTEN, TP53, and RB1): Cabazitaxel/Carboplatin
• Symptomatic patients with visceral metastases intolerant to other therapies: Mitoxantrone 
• HRRm-positive dpatients: Olaparib
• MSI-H, dMMR positive, or TMB-H:Pembrolizumab
• Symptomatic bone metastases: Radium-223
• BRCA1/2 mutation-positive patients treated with androgen receptor-directed therapy and taxane-based chemotherapy: Rucaparib

Other recommended therapies include Abiraterone, Enzalutamide, and other secondary hormone therapy.

Pharmacological therapy

Androgen Deprivation Therapy (ADT)  

ADT is a treatment option for patients with disease progression despite surgical treatments and radiotherapy, or for symptomatic control of symptoms in patients who are against, with contraindications, or cannot tolerate surgical procedures. It is recommended as first-line therapy in high- to very high-risk and metastatic prostate cancer and as adjuvant therapy for patients with low- to intermediate-risk prostate cancer. Combination therapy is strongly recommended for metastatic castration-sensitive disease. Monotherapy mat be considered in cases when there are clear contraindications to combination therapy. It may be offered to intermediate- to high-risk and locally advanced prostate cancer patients prior to, during, or after EBRT or in combination with radical radiotherapy. Long-term ADT (18-36 months duration) is recommended for high-risk to very high-risk disease, whereas short-term androgen deprivation therapy (4-6 months duration) is recommended for intermediate-risk disease. It is also a treatment option for patients with disease progression after observation who require treatment or with a life expectancy of ≤5 years.  

PSA levels should be measured every 3 months for patients under intermittent ADT.  ADT should be restarted if PSA measurements reach >10 ng/mL or if the patient becomes symptomatic.  

Bone mineral density (BMD), serum calcium, and vitamin D levels should be assessed every 2 years. Patients on androgen deprivation therapy should be advised to have a healthy weight and diet, stop smoking, lessen alcohol intake, meet recommended levels of calcium and vitamin D, and have an annual screening for diabetes and dyslipidemia.  

Orchiectomy  

Please see Orchiectomy under Surgery for further information.  

LHRH Analogs  

LHRH analogs’ efficacy for castration is the same as orchiectomy. They are considered first-line agents used for ADT in prostate cancer. LHRH analogs are also treatment options for patients with disease progression after observation of localized disease who require treatment or with a life expectancy of ≤5 years.  

LHRH Agonists
Example drugs: Goserelin, Histrelin, Leuprorelin (Leuprolide), Triptorelin  

The mechanism of action of LHRH agonists is that they stimulate luteinizing hormone-releasing hormone receptors, inducing a transient luteinizing hormone (LH) and follicle-stimulating hormone (FSH) surge, leading to androgen release inhibition. They induce the flare-up phenomenon, a sudden increase in testosterone, which may lead to increased bone pain, urethral obstruction, renal failure, and spinal cord compression.  

The efficacy of Leuprorelin may be affected by handling errors during preparation and administration. Based on the recommendation by the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA), Leuprorelin-containing depot medicinal products using dual-chamber prefilled syringe devices are preferred over vial-ampoule presentations, due to fewer reported medication errors with dual devices compared to products with complex reconstitution steps for preparation and administration.  

LHRH Antagonists
Example drugs: Degarelix, Relugolix  

The mechanism of action of LHRH antagonists is that they rapidly and directly inhibit androgen release thereby suppressing testicular androgen activity without the flare-up phenomenon.  

Secondary Hormone Therapy or Androgen Pathway Targeting Agents  

Second-generation anti-androgens such as Abiraterone acetate, Apalutamide, Darolutamide, and Enzalutamide are given in combination with ADT for patients with castration-sensitive prostate cancer or as monotherapy in CRPC. They are recommended for patients with progressive disease despite medical and surgical castration.  

Abiraterone acetate  

Abiraterone acetate may be used for patients with metastatic, high-risk, castration-sensitive prostate cancer together with LHRH analogs or orchiectomy, and mCRPC pre- or post-Docetaxel therapy. It is also used in combination with EBRT and AFT for very high-risk locally advanced disease. Combination with ADT should be considered for a total of 2 years for patients with N1 disease given radiation to the prostate and pelvic nodes.  

The fine-particle formulation can be used instead of the standard form. It is administered together with Prednisone. The fine-particle Abiraterone is given with Methylprednisolone and this combination should not be given with anti-androgen agents. One may consider switching Prednisone to Dexamethasone 1 mg/day for patients with disease progression on either formulation of Abiraterone.  

Increased median survival, provided pain palliation, showed PSA level decrease, and delayed radiographic progression in studies done to prove the efficacy of Abiraterone in patients with metastatic castration-resistant prostate cancer who were given Docetaxel-containing regimens. Furthermore, studies showed that the addition of Abiraterone to androgen deprivation therapy in patients with high-risk metastatic prostate cancer improved overall survival compared with ADT alone. Its mechanism of action is to inhibit the enzyme cytochrome P450 (CYP)-17, in turn suppressing testosterone production.  

Apalutamide  

Apalutamide is the treatment option for patients with non-metastatic CRPC if PSADT is ≤10 months and metastatic, castration-sen­sitive prostate cancer. Its mechanism of action is to act as an androgen receptor inhibitor thereby inhibiting AR nuclear translocation, DNA binding, and androgen receptor-mediated transcription.  

Darolutamide  

Darolutamide is the treatment option for patients with non-metastatic CRPC if PSADT is ≤10 months. Its mechanism of action is to competitively inhibit androgen binding to androgen receptors thereby inhibiting nuclear translocation and DNA interaction.  

Enzalutamide  

Enzalutamide may be used for patients with both metastatic and non-metastatic CRPC if PSADT is ≤10 months and metastatic, castration-sensitive prostate cancer. It is also a treatment option for patients with mCRPC pre- or post-Docetaxel. Compared with a placebo, treatment with Enzalutamide showed a significantly lower risk of metastasis or death in patients with non-metastatic CRPC with a rapidly increasing level of PSA.  

Its mechanism of action is that is it a potent competitive inhibitor of androgen binding to androgen receptors, inhibiting nuclear translocation of activated receptors and the association of the activated androgen receptor with DNA despite androgen receptor over-expression and prostate cancer cell resistance to anti-androgens.  

Other Secondary Hormone Therapy  

Adrenal or Paracrine Androgen Synthesis Inhibitors
Example drug: Ketoconazole  

Ketoconazole is the treatment option for patients with CRPC with or without visceral metastases. It may be given with Hydrocortisone. It should not be used if the patient is positive for disease progression after Abiraterone therapy. Its mechanism of action is that it has anti-androgenic properties that block androgen production.  

Anti-Androgen Therapy
Example drugs: Steroidal (Cyproterone acetate, Dexamethasone, Hydrocortisone, Megestrol acetate, Medroxyprogesterone acetate, Prednisone); non-steroidal or first-generation anti-androgens (Bicalutamide, Flutamide, Nilutamide)  

Anti-androgen therapy is a treatment option for patients with advanced disease, metastatic, or non-metastatic CRPC. It may be given concomitantly with LHRH analogs for at least 7 days in patients with overt metastases who are at risk of developing symptoms associated with testosterone flare with initial LHRH agonist alone or orchiectomy for better androgen blockade (combined androgen blockade). It may be offered to patients with metastatic disease who prefer their sexual function restored even with more side effects.  

Bicalutamide monotherapy may also help prevent non-metastatic bone fractures with its bone-protective properties, though monotherapy use is rare. Their mechanism of action is that they block androgen receptors, thereby reducing the effect of endogenous hormones.  

Estrogens
Example drug: Diethylstilbestrol (DES)  

DES should only be considered if other first- and subsequent-line treatments have been exhausted. Studies have shown that oral estrogen therapy has the same efficacy for castration as bilateral orchiectomy. Its mechanism of action is to inactivate androgens, down-regulate LHRH secretion, and directly suppress Leydig cell function.  

Docetaxel  

Docetaxel is a non-hormonal systemic treatment added to androgen deprivation therapy for patients with metastatic, castration-sensitive prostate cancer. ADT with Docetaxel with either Abiraterone or Darolutamide is encouraged for patients with high-volume disease who are fit for chemotherapy. Studies showed that the addition of Docetaxel to androgen deprivation therapy in patients with metastasis significantly improved overall survival compared with ADT alone. Its mechanism of action is to promote the assembly of microtubules from tubulin dimers, and to inhibit the depolymerization of tubulin which stabilizes microtubules in the cell, resulting in the inhibition of DNA, RNA, and protein synthesis. 

Non-hormonal Systemic Therapy  

Non-hormonal systemic therapy is considered a first-line and subsequent therapy option for small cell or neuroendocrine prostate cancer. This includes Cisplatin/Etoposide, Carboplatin/Etoposide, Docetaxel/Carboplatin, and Cabazitaxel/Carboplatin. Cabazitaxel/Carboplatin can be considered for fit patients with aggressive variant prostate cancer or unfavorable genomics.  

Chemotherapy
Example drugs: Cabazitaxel, Carboplatin, Cisplatin, Docetaxel, Doxorubicin, Etoposide, Estramustine, Mitoxantrone, Paclitaxel, Vinblastine, Vinorelbine  

Chemotherapy drugs are recommended for patients with progressive disease despite medical and surgical castration (both hormone-resistant and/or mCRPC).  

Cabazitaxel  

Cabazitaxel is an alternative treatment to those intolerant or unresponsive to Docetaxel therapy in patients with symptomatic mCRPC.  It may be given together with Carboplatin and concurrent twice-daily Prednisone, especially for fit patients with aggressive variant prostate cancer or unfavorable genomics. Patients given Cabazitaxel exhibited improvement in PFS, PSA response rate, and overall survival in several studies. It is given with concomitant steroids (daily Prednisone or Dexamethasone the on day of chemotherapy).  

Docetaxel  

Docetaxel is the recommended first-line treatment for men with symptomatic mCRPC. It is given concomitantly with a corticosteroid (daily Prednisone or Dexamethasone on the day of chemotherapy). It is proven to improve PSA response and the time to recurrence, and clinical progression. It should be reserved for prostate cancer patients with confirmed metastatic disease.  

Mitoxantrone  

Mitoxantrone may be used for palliative therapy of the pain caused by bone metastasis of CRPC in patients who cannot tolerate other therapies. It is given concomitantly with Prednisone.  

Targeted Therapy  

Niraparib  

The combination of Niraparib with Abiraterone is a treatment option for patients with mCRPC and a pathogenic BRCA1 or BRCA2 mutation (germline and/or somatic) without any history of treatment for mCRPC, depending on prior treatment in other disease settings.  

Olaparib  

Olaparib is a poly-ADP ribose polymerase (PARP) inhibitor used as a treatment option for patients with mCRPC and a pathogenic mutation (germline and/or somatic) in a homologous recombination repair (HRRm) gene (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D or RAD54L), with a history of androgen receptor-directed therapy. Combination therapy with Abiraterone is a treatment option for patients with pathogenic BRCA1 or BRCA2 mutation (germline or somatic) who have not yet received a novel hormone therapy or Docetaxel.  

Rucaparib  

Rucaparib is also a PARP inhibitor used as a treatment option for patients with mCRPC and a pathogenic BRCA1 or BRCA2 mutation (germline and/or somatic) with a history of androgen receptor-directed therapy and a taxane-based chemotherapy. It may be considered for patients unfit for chemotherapy regardless if the patient was previously given taxane-based therapy.  

Talazoparib  

A combination with Enzalutamide is a treatment option for patients w/ mCRPC and a pathogenic mutation (germline and/or somatic) in a HRRm gene (BRCA1, BRCA2, ATM, ATR, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C) without any history of treatment for CRPC, depending on prior treatment in other disease settings.  

Immunotherapy

Pembrolizumab  

Pembrolizumab is an anti-PD1 antibody used for patients with unresectable or metastatic MSI-H, dMMR positive, or tumor mutational burden-high (TMB-H) (≥10 mutations/megabase [mut/Mb]) that have progressed on prior treatment and with no satisfactory alternative treatment options.  

Sipuleucel-T  

Sipuleucel-T is a cancer vaccine produced from the combination of autologous antigen-presenting blood mononuclear cells and the recombinant human fusion protein. Studies have shown that Sipuleucel-T may help extend mean survival with a reduction in mortality risk. It may be given to mCRPC with ECOG performance status of 0 to 1, life expectancy of >6 months, absent hepatic metastasis, and minimal or absent symptoms. It is not recommended for patients with small cell or neuroendocrine prostate cancer.  

Castration-Resistant Prostate Cancer

Secondary Hormone Therapy for CRPC without Metastasis (M0) and Metastatic CRPC (M1)  

For patients with CRPC without metastasis (M0) or mCRPC (M1), the following may be offered: 

• Second-Generation Anti-androgen
  • Apalutamide (for M0 and PSADT of ≤10 months) 
  • Darolutamide (for M0 and PSADT of ≤10 months) 
  • Enzalutamide (for M0 and PSADT of ≤10 months or M1)
• Androgen Metabolism Inhibitor
  • Abiraterone with Prednisone (for M1 only)
  • Fine-particle Abiraterone with Methylprednisolone (for M1 only)
• Other Secondary Hormone Therapy (for M0 or M1)
  • Ketoconazole with or without Hydrocortisone
  • First generation anti-androgen (Nilutamide, Flutamide, or Bicalutamide)
  • Corticosteroids (Hydrocortisone, Prednisone, or Dexamethasone)
  • Estrogen with DES 
  • Anti-androgen withdrawal 

Systemic Therapy for Metastatic CRPC

For patients with mCRPC, the following systemic therapy are the treatment options:

• Chemotherapy: Docetaxel with Prednisone or Dexamethasone, Cabazitaxel/Carboplatin with Prednisone or Dexamethasone, Mitoxantrone with Prednisone
• Immunotherapy: Sipuleucel-T, Pembrolizumab
• Radiopharmaceutical Therapy: Radium-223: For symptomatic bone metastases; Lutetium-177: For PSMA-positive metastases

Palliative Therapy  

Palliative ADT can be given to patients who are high-risk, very high-risk, regional, or metastatic prostate cancer with a life expectancy of ≤5 years and men with disease progression during observation. Mitoxantrone may be used for patients with symptomatic mCRPC who have contraindications to Cabazitaxel or Radium-223 therapy. Denosumab and bisphosphonates (eg Alendronate, Pamidronate, Zoledronic acid) may be suggested in patients with mCRPC with bone metastasis to help prevent bone fractures, metastases, and other skeletal complications. Bone antiresportive therapy is indicated for elevated fracture risk based upon FRAC in castration-sensitive mCRPC. Analgesics for painful bone metastases and corticosteroids, if with spinal cord compression, may be used.

Nonpharmacological

Observation and Active Surveillance

Observation or Watchful Waiting  

Observation or watchful waiting is based on the premise that it may be more beneficial to provide palliative therapy at the time when local or metastatic progression occurs, thereby maintaining the quality of life. It also prompts a change in the diagnostic tests when symptoms suggest disease progression. It is the management option for patients who prefer not to undergo treatments, elderly men or immunocompromised patients with comorbidities and/or poor prognostic features, and patients who will not benefit but will only incur harm from definitive treatments. It is also recommended for asymptomatic patients in very-low-, low-, and intermediate-risk groups with a life expectancy of ≤5 years, and asymptomatic patients with very-low- and low-risk prostate cancer with a life expectancy of 5 to 10 years. It may also be considered in asymptomatic patients with favorable and unfavorable intermediate-risk prostate cancer with a life expectancy between 5 to 10 years, and asymptomatic patients with high-risk, very-high risk, regional, and metastatic prostate cancer with a life expectancy of ≤5 years. It is also recommended for patients with non-mCRPC, with continued ADT. This entails monitoring PSA and DRE results every 6 months.  

Its main advantages are the avoidance of potential harm from different unnecessary therapies and the early initiation and/or continuous androgen deprivation therapy (ADT). Whereas its disadvantages include the increased risk of urinary retention and pathologic fracture without prior symptoms or increasing PSA.  

Active Surveillance  

Active surveillance means watchful waiting while actively monitoring the disease course to be able to intervene when the disease progresses, delaying the potential side effects of treatments. It is preferred for patients with very low-risk prostate cancer with a life expectancy of ≥10 years and for patients with low-risk prostate cancer with a life expectancy of ≥10 years. It is considered for patients with favorable intermediate-risk prostate cancer with a life expectancy of >10 years.  

The criteria for the use of active surveillance include the clinical stage T1c or T2a, grade group 1-2, ≤3 positive cores with ≤50% cancer involvement in any core, PSA of <10 ng/mL, and PSA density of <0.15 ng/mL/g. The decision to use active surveillance should not be based solely on the mentioned criteria.  

Active surveillance may also be the treatment option for those with low-risk localized disease and candidates for radical prostatectomy or radiotherapy. It may also be suggested to asymptomatic patients, elderly men, and those with comorbidities.  

The presence of pathologies like predominant ductal carcinoma, sarcomatoid carcinoma, small cell carcinoma, extraprostatic extension (EPE), lymphovascular invasion (LVI) in needle biopsy, or perineal invasion should prompt exclusion for active surveillance. 

The following are the inclusions for active surveillance:

• Initial: mpMRI and/or prostate biopsy if not performed previously
• First year: Monitoring of PSA every 6 months and DRE, prostate biopsy, and mpMRI every 12 months. 
  • A repeat needle biopsy within 6 to 12 months from the initial diagnosis is indicated for patients with <10 cores and once every 3 years for low-risk patients for 10 years 
  • A repeat biopsy may not be performed if the life expectancy is <10 years
• Second to fourth year: PSA monitoring every 3-6 months and DRE every 6 to 12 months
• Fifth year and yearly thereafter: PSA every 6 months and DRE every 12 months
• PSA kinetics (doubling time and velocity) should be monitored all throughout the active surveillance duration

The advantages of active surveillance include eligible patients may avoid or delay treatment, potential harm from different treatment modalities may be avoided, the patient may go back to their normal activities and may retain the present quality of life, smaller or undiagnosed malignancies will remain therapy-naive, thereby preventing future treatment resistance, and expenses may be reserved for more definitive treatments.

The disadvantages of active surveillance include the chance for early treatment and cure may be missed, high propensity for disease progression and metastasis, tumor size may increase, making surgery and medical management more difficult, preservation of function may be more difficult for more aggressive and bigger tumors, increased anxiety due to untreated malignancy and uncertainty of disease progression, and intermittent monitoring with diagnostics and clinic visits are required. 

Surgery

Orchiectomy  

Orchiectomy is the surgical option of ADT, to be done with or without Abiraterone therapy. It is also called surgical castration, total or subcapsular pulpectomy, in which one or both testicles (bilateral orchiectomy) are removed. A surgical option of ADT that can be done with or without Abiraterone therapy. It is recommended castration method for patients with intermediate- to very high-risk prostate cancer and those with treatment-naive locally advanced and metastatic prostate cancer. It is also a treatment option for patients with disease progression after observation of localized disease who require treatment or with a life expectancy of ≤5 years.  

Radical Prostatectomy  

Radical prostatectomy involves the removal of the prostate gland as a whole, including the seminal vesicles, ampulla of the vas deferens, and lymph nodes with preservation of function (continence, potency). It is the first-line treatment for patients with tumors confined to the prostate gland, with very low- to intermediate-risk disease and a life expectancy of ≥10 years. It is a treatment option for patients with high- to very high-risk disease and a salvage therapy option for patients with biochemical recurrence after EBRT, brachytherapy, or cryotherapy if with no metastases, ISUP grade 4 to 5, or PSA of >20 ng/mL. It may also be considered in select patients with locally advanced disease as part of multi-modal therapy. It has a high cure rate for patients with purely localized disease.  

Pelvic Lymph Node Dissection (PLND)  

Pelvic lymph node dissection is recommended for patients with high-risk or locally advanced disease with nodal metastases, done concurrently with radical prostatectomy.  

An extended pelvic lymph node dissection, which involves the removal of the lymph nodes in the area of the external iliac artery and vein, veins within the obturator fossa, and medial and lateral nodes of the internal iliac artery, is preferred due to its completeness of disease staging and is therapeutically more advantageous in patients with microscopic metastases compared to PLND alone. It may be done in patients with intermediate risk with >5% estimated risk of lymph node involvement. It should be done in all high-risk patients.  

Cryosurgery (Cryotherapy or Cryoablation)  

Cryosurgery is a minimally invasive surgical procedure that involves freezing and destruction of tumor tissues. It is a treatment option for patients with high-risk prostate cancer following radiation therapy, low- to intermediate-risk prostate cancer patients who are not a candidate for prostatectomy due to comorbidities, and patients with relative contraindications to radiotherapy. Prostate volume should be <40 mL at the time of therapy. There is a lower risk of damage to nearby structures and complications secondary to radical treatment.  

Studies reported a range of 52-92% biochemical disease-free survival within 5 to 7 years, depending on the criteria used. Discussion with the patient should be made regarding the lack of long-term efficacy comparative outcome data.  

Other Ablative Techniques
Examples: High-intensity focused ultrasound (HIFU), radiofrequency ablation, and electroporation  

High-intensity focused ultrasound is a minimally invasive procedure that uses focused ultrasound waves emitted from a transducer to cause thermal damage to malignant tissues. It is an alternative treatment to localized prostate cancer with disease recurrence after radiotherapy. It may be applicable for low- to intermediate-risk patients but further studies are needed to conclude use. 

Radiation Therapy

Prophylactic lymph node radiation and/or ADT may be considered in patients with favorable or unfavorable intermediate-risk if the risk assessment suggests aggressive tumor behavior. For patients with unfavorable intermediate- or high- and very high-risk, brachytherapy plus androgen deprivation therapy without external beam radiotherapy (EBRT), or stereotactic body radiotherapy (SBRT) plus ADT can be considered if longer courses of external beam radiotherapy would be an issue. Regional radiation with ADT is recommended in patients with regional disease, with additional Abiraterone. Radiation therapy may be considered in patients with low-volume castration-naive metastatic disease, without contraindications to radiotherapy. It is not recommended for high-volume metastatic disease.  

Interstitial Prostate Brachytherapy  

Interstitial prostate brachytherapy is the implantation of small radioactive sources into the prostate gland. It is the recommended initial therapeutic strategy for patients with very low-risk prostate cancer with a life expectancy of >20 years and low-risk prostate cancer with a life expectancy of ≥10 years not suitable for active surveillance. It is difficult to perform in patients with very small or very large prostates, bladder outlet obstruction symptoms, or previous transurethral resection of the prostate (TURP).  

It is recommended for patients with favorable intermediate-risk prostate cancer with a life expectancy of ≥5 years. It is also recommended for patients with unfavorable intermediate- to very high-risk prostate cancer when given in combination with EBRT and ADT as it showed improved biochemical control when given together with androgen deprivation therapy and external beam radiotherapy (45-50 Gy) but with more side effects. The recommended doses are 140 Gy (125I) with postoperative dosimetry and 120 Gy (palladium).  

Low Dose-Rate Brachytherapy  

Low dose-rate brachytherapy uses permanent low-energy seeds (Iodine-125, Palladium-103, Cesium-131) for implantation that delivers adequate doses.

It is recommended for patients with the following:

• Stage T1b-T2a N0 M0
• ISUP grade 1 with ≤50% biopsy cores involved or ISUP grade 2 with ≤33% biopsy cores involved
• ≤10 ng/mL initial PSA level
• <50 cm3 prostate volume International Prostatic Symptom Score (IPSS) ≤12 and urinary flow test result of >15 mL/min

Low dose-rate brachytherapy may be given to low-risk patients without recent TURP. It may also be given to patients with favorable intermediate- to high-risk together with EBRT. It may also be given in combination with intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) plus image-guided radiation therapy (IGRT) in patients with good urinary function and high-risk and/or locally advanced disease or patients with good urinary function, unfavorable intermediate-risk disease, ISUP grade 3 and/or PSA of 10 to 20 ng/mL. The recommended dose for Iodine-125 is 145 Gy (110 to 115 Gy with 45 to 50.4 Gy EBRT), for Palladium-103 is 125 Gy (90 to 100 Gy with 45 to 50.4 Gy EBRT), and for Cesium 131 is 115 Gy (85 Gy with 45 to 50.4 Gy EBRT). 

High Dose-Rate Brachytherapy  

High dose-rate brachytherapy uses temporary radioactive sources (eg Iridium-192) inserted into different locations in the prostate gland. It may be given in combination with IMRT or VMAT plus IGRT in patients with good urinary function and high-risk and/or locally advanced disease, or patients with good urinary function, unfavorable intermediate-risk disease, ISUP grade 3 and/or PSA of 10-20 ng/mL. Monotherapy may be considered in patients with low- to intermediate-risk disease. The recommended dose for monotherapy is 13.5 Gy x 2 fractions; 9.5 Gy 12 hrly x 2 fractions. The recommended dose with external beam radiotherapy is 15 Gy x 1 fraction; 10.75 Gy x 2 fractions.  

External Beam Radiotherapy (EBRT)  

EBRT is the recommended initial therapeutic strategy for patients with very low- to high-risk prostate cancer. Limited radiation fields are preferred over extended field radiotherapy for localized and locally advanced prostate cancer.  

EBRT may be given with or without ADT or with brachytherapy with or without ADT in patients with unfavorable intermediate risk. It is recommended to be given concomitantly with ADT as initial therapy in patients with high or very high risk.

The localization of the prostate with IGRT is necessary with either 3-dimensional conformal radiation therapy (3D-CRT) or IMRT for reducing the target margin and ensuring treatment accuracy. Dose-escalated IMRT or VMAT with image-guided radiation therapy (IGRT) is the best available approach due to low toxicity.  

The recommended dose for patients with low-risk prostate cancer is 75.6-79.2 Gy; intermediate- to high-risk and metastatic prostate cancer is 81.0 Gy. For patients opposed to ADT, IMRT or VMAT plus IGRT = 76 to 78 Gy; moderate hypofractionation = 60 Gy/20 fx in 4 weeks or 70 Gy/28 fx in 6 weeks.  

Stereotactic Body Radiotherapy (SBRT)  

SBRT uses high conformal, high-dose radiation delivered precisely using imaging techniques. It may be considered in patients with limited metastatic disease to the vertebra or paravertebral regions when ablation is to be achieved, in oligometastatic progression to achieve progression-free survival, and in symptomatic patients with lesions in or immediately adjacent to a previously irradiated treatment field. It may also be considered an alternative to conventionally fractionated regimens or EBRT in unfavorable intermediate- or high-risk patients when combined with ADT when external beam radiotherapy is medically challenging.  

Proton Beam Therapy  

Proton beam therapy delivers less radiation to surrounding normal tissues thereby decreasing the long-term treatment morbidity. Further studies are needed to prove the efficacy of proton therapy against prostate cancer and its superiority to photon-based radiation therapy.  

Radiopharmaceutical Therapy  

Radiopharmaceutical therapy includes Radium-223 dichloride and ß-emitting agents (Strontium-89, Samarium-153, Lutetium-177 [Lutetium Lu 177 vipivotide tetraxetan, ¹⁷⁷Lu-PSMA-617, Lu-177-PSMA-617]). It eradicates malignant cells using radioactive atoms delivered to tumor-associated targets. It is an option for palliative treatment of patients with metastatic disease.  

Beta-Emitting Radioactive Agents
Examples: Strontium-89 (Sr-89, 89Sr), Samarium-153 (Sm-153, 153Sm), Lutetium-177  

Beta-emitting radioactive agents are used for palliative treatment of painful bone or widespread metastases that are not eligible for chemotherapy. Lutetium-177 is a treatment of option for patients with ≥1 PSMA-positive lesion and/or metastatic disease that is predominantly PSMA-positive and with no dominant PSMA-negative metastatic lesion previously treated with androgen receptor-directed therapy and a taxane-based chemotherapy.  

Radium-223 dichloride  

Radium-223 is an alpha particle-emitting radioactive agent used for mCRPC with symptomatic bone metastases but without visceral involvement. Studies have shown that patients given Radium-223 had better overall survival and time to appearance of symptomatic bone events than those given placebo. 

Palliative Therapy

Single fraction EBRT is recommended for palliation of uncomplicated, painful bone metastasis. The recommended dose for non-vertebral metastases is 800 cGy x 1 fraction and for widespread bone metastases is Sr-89 or Sm-153 with or without focal EBRT.