Prostate%20cancer Treatment

• 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
• 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 may be considered in cases when there are clear contraindications to combination therapy
• May be offered to intermediate- to high-risk and locally advanced prostate cancer patients prior to, during, or after external beam radiation therapy (EBRT) or in combination with radical radiotherapy
  • Long-term ADT (18-36 months duration) is recommended for high-risk to very high-risk disease
  • Short-term ADT (4-6 months duration) is recommended for intermediate-risk disease
• Treatment option for patients with disease progression after observation who require treatment or with life expectancy of ≤5 years
• PSA levels should be measured every 3 months for patients under intermittent ADT
  • Restart ADT if PSA measurements reach >10 ng/mL or if patients becomes symptomatic
• Bone mineral density (BMD), serum calcium and vitamin D levels should be assessed every 2 years
• Advise patients on ADT 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

Treatment Strategies for ADT

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

Recommended ADT Options for Clinically Localized Prostate Cancer

• 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

Recommended ADT Options for Regional Prostate Cancer

• 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

Recommended ADT Options for Castration-Sensitive Prostate Cancer without Metastasis

• If with PSA persistence or recurrence after radical prostatectomy: EBRT with or without neoadjuvant/concurrent and/or adjuvant ADT, or EBRT + 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 anti-androgen (ie Nilutamide, Flutamide, Bicalutamide)
  • LHRH antagonist (ie Degarelix, Relugolix)

Recommended ADT Options for Castration-Sensitive Metastatic Prostate Cancer

• 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 Abiraterone or Darolutamide
• Degarelix with Abiraterone, Enzalutamide or Apalutamide

Orchiectomy

• Also called surgical castration, total or subcapsular pulpectomy, where one or both testicles (bilateral orchiectomy) are removed
• Surgical option of ADT, to be done with or without Abiraterone therapy
• Recommended castration method for patients with intermediate- to very high-risk prostate cancer and those with treatment-naive locally advanced and metastatic prostate cancer
• Treatment option for patients with disease progression after observation of localized disease who require treatment or with life expectancy of ≤5 years

Luteinizing Hormone-Releasing Hormone (LHRH) Analogs

• Efficacy for castration is the same as orchiectomy
• First-line agents used for ADT in prostate cancer
• Treatment option for patients with disease progression after observation of localized disease who require treatment or with life expectancy of ≤5 years

LHRH Agonists

• Eg Goserelin, Histrelin, Leuprorelin (Leuprolide), Triptorelin
• Mechanism of action: Stimulates luteinizing hormone-releasing hormone receptors, inducing a transient leutenizing hormone (LH) and follicle-stimulating hormone (FSH) surge, leading to androgen release inhibition
• Induces the flare-up phenomenon, a sudden increase in testosterone, which may lead to increased bone pain, urethral obstruction, renal failure, spinal cord compression
• 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 device are preferred over vial-ampoule presentation, due to fewer reported medication errors with dual devices compared to products with complex reconstitution steps for preparation and administration

LHRH Antagonist

• Eg Degarelix, Relugolix
• Mechanism of action: Rapidly and directly inhibits androgen release thereby suppressing testicular androgen activity without the flare-up phenomenon

Secondary Hormone Therapy/Androgen Pathway Targeting Agents

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

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
• Also used in combination with EBRT and ADT 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
• Fine-particle formulation can be used instead of the standard form
• Administered together with Prednisone; fine-particle Abiraterone is given with Methylprednisolone
  • Combination should not be given with anti-androgen agents
  • 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 mCRPC who were given Docetaxel-containing regimens
• Studies showed that addition of Abiraterone to ADT in patients with high-risk metastatic prostate cancer improved overall survival compared with ADT alone
• Mechanism of action: Inhibits the enzyme CYP17 in turn suppressing testosterone production

Apalutamide

• Treatment option for patients with non-metastatic CRPC if PSADT is ≤10 months and metastatic, castration-sensitive prostate cancer
• Mechanism of action: Acts as an androgen receptor inhibitor thereby inhibiting AR nuclear translocation, DNA binding and androgen receptor-mediated transcription

Darolutamide

• Treatment option for patients with non-metastatic CRPC if PSADT is ≤10 months
• Mechanism of action: Competitively inhibits androgen binding to androgen receptors thereby inhibiting nuclear translocation and DNA interaction

Enzalutamide

• May be used for patients with both metastatic and non-metastatic CRPC if PSADT is ≤10 months and metastatic, castration-sensitive prostate cancer
  • Treatment option for patients with mCRPC pre- or post-Docetaxel
  • Compared with placebo, treatment with Enzalutamide showed significant lower risk of metastasis or death in patients with non-metastatic CRPC with a rapidly increasing level of PSA
• Mechanism of action: Potent competitive inhibitor of androgen binding to androgen receptors, inhibits 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/Paracrine Androgen Synthesis Inhibitors

• Eg Ketoconazole
• Treatment option for patients with castration-resistant prostate cancer (CRPC) with or without visceral metastases
• May be given with Hydrocortisone
• Not to be used if positive for disease progression after Abiraterone therapy
• Mechanism of action: Anti-androgenic properties that block androgen production

Anti-Androgen Therapy

• Eg steroidal (Cyproterone acetate, Dexamethasone, Hydrocortisone, Megestrol acetate, Medroxyprogesterone acetate, Prednisone); nonsteroidal or first-generation anti-androgens (Bicalutamide, Flutamide, Nilutamide)
• Treatment option for patients with advanced disease, metastatic, or non-metastatic CRPC
  • May be given concomitantly with luteinizing hormone-releasing hormone (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)
  • May be offered to patients with metastatic disease who prefer their sexual function restored even with more side effects

• Mechanism of action: Blocks androgen receptors, thereby reducing the effect of endogenous hormones
• Bicalutamide monotherapy may also help prevent non-metastatic bone fractures with its bone-protective properties, though monotherapy use is rare

Estrogens

• Eg Diethylstilbestrol (DES)
• Should only be considered if other first- and subsequent-line treatments have been exhausted
• Mechanism of action: Inactivates androgens, down-regulates LHRH secretion, Leydig cell function direct suppression
• Studies have shown that oral estrogen therapy has the same efficacy for castration as bilateral orchiectomy

Docetaxel

• Non-hormonal systemic treatment added to ADT 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 addition of Docetaxel to ADT in patients with metastasis significantly improved overall survival compared with ADT alone
• Mechanism of action: Promotes the assembly of microtubules from tubulin dimers, and inhibits the depolymerization of tubulin which stabilizes microtubules in the cell, resulting in inhibition of DNA, RNA, and protein synthesis

• First-line and subsequent therapy options for small cell/neuroendocrine prostate cancer include 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

• Eg Cabazitaxel, Carboplatin, Cisplatin, Docetaxel, Doxorubicin, Etoposide, Estramustine, Mitoxantrone, Paclitaxel, Vinblastine, Vinorelbine
• Recommended for patients with progressive disease despite medical and surgical castration (both hormone-resistant and/or mCRPC)

Cabazitaxel

• Alternative treatment to those intolerant or unresponsive to Docetaxel therapy in patients with symptomatic mCRPC
• 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 progression-free survival (PFS), PSA response rate and overall survival in several studies
• Given with concomitant steroids (daily Prednisone or Dexamethasone on day of chemotherapy)

Docetaxel

• Recommended first-line treatment for men with symptomatic mCRPC
• Given concomitantly with a corticosteroid (daily Prednisone or Dexamethasone on day of chemotherapy)
• Proven to improve PSA response and time to recurrence and clinical progression
• Should be reserved for prostate cancer patients with confirmed metastatic disease

Mitoxantrone

• May be used for palliative therapy of the pain caused by bone metastasis of CRPC in patients who cannot tolerate other therapies
• Given concomitantly with Prednisone

Targeted Therapy

Niraparib

• Combination 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

• 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 mutation (HRRm) gene (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D or RAD54L), with history of androgen receptor-directed therapy
• Combination with Abiraterone is a treatment option for patients with pathogenic BRCA1 or BRCA2 mutation (germline and/or somatic) who have not yet received a novel hormone therapy or Docetaxel

Rucaparib

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

Talazoparib

• Combination with Enzalutamide is a treatment option for patients with 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

• Anti-PD1 antibody used for patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair-deficient (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

• Cancer vaccine produced from the combination of autologous antigen-presenting blood mononuclear cells and recombinant human fusion protein
• Studies have shown that Sipuleucel-T may help extend mean survival with reduction in mortality risk
• May be given to mCRPC patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, life expectancy of >6 months, absent hepatic metastases, and minimal or absent symptoms
• Not recommended for patients with small cell/neuroendocrine prostate cancer

• Also known as castration-recurrent prostate cancer 
• Recurrence or disease progression (clinical, radiographical or biochemical) despite medical or surgical castration
• Criteria for defining CRPC:
  • PSA progression (PSA level >2 ng/mL, listed 3 consecutive increases 1 week apart, resulting in 25% increase over the nadir value)
  • Serum testosterone levels <50 ng/dL or <1.7 nmol/L
  • Anti-androgen withdrawal of >4-6 weeks
  • Radiological progression (new lesions, either ≥2 new bone lesions on bone scan or soft tissue lesion)

CRPC without Metastasis (M0)

• May consider observation with ADT if PSADT >10 months
• Offer Apalutamide, Darolutamide or Enzalutamide with ADT if PSADT ≤10 months

CRPC with Metastasis (M1)

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

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

Second-Generation Anti-androgen

• Apalutamide (for M0 and PSADT ≤10 months)
• Darolutamide (for M0 and PSADT ≤10 months)
• Enzalutamide (for M0 and PSADT ≤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

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

Aggressive Variant Prostate Cancer

• Prostate cancer may be classified as aggressive variant if at least 1 of the following criteria are met:
  • Small cell/neuroendocrine prostate carcinoma histology
  • Exclusive visceral metastases
  • Predominant lytic bone metastases
  • Bulky (>5 cm) lymphadenopathy or Gleason score ≥8 at diagnosis
  • PSA <10 ng/mL with ≥20 bone metastases
  • ≥2 times elevated lactate dehydrogenase (LDH) or carcinoembryonic antigen (CEA)
  • <6 months interval response to ADT
• Contains defects in at least 2 of 3 tumor suppressors: Tumor protein 53 (TP53), retinoblastoma protein 1 (RB1), and phosphatase and tensin homolog (PTEN)

Small Cell/Neuroendocrine Prostate Carcinoma

• Characterized by small, blue neuroendocrine cells which do not secrete PSA but express neuroendocrine markers (chromogranin A, synaptophysin and neuron-specific enolase [NSE])
• Metastasizes to visceral organs and responds temporarily to chemotherapy

• Novel hormone therapy includes Abiraterone, Apalutamide, Darolutamide, or Enzalutamide received for metastatic castration-sensitive prostate cancer, M0 CRPC, or previous lines of treatment for M1 CRPC

• Preferred treatment options include Abiraterone, Docetaxel and Enzalutamide
• Regimens that can be used depending on patient's status include:
  • BRCA1/2 mutation: Niraparib/Abiraterone, Olaparib/Abiraterone
  • Recommended only for asymptomatic or minimally symptomatic patients, no liver metastases, with life expectancy >6 months, and ECOG performance status 0–1: Sipuleucel-T
  • HRRm-positive patients: Talazoparib/Enzalutamide
  • Symptomatic bone metastases: Radium-223
• Other recommended therapies include other secondary hormone therapy

• Docetaxel is the preferred agent
• Regimens that can be used depending on patient's status include:
  • BRCA1/2 mutation-positive patients treated with androgen receptor-directed therapy and a taxane-based chemotherapy: Rucaparib
  • Fit patients with aggressive variant prostate cancer (eg visceral metastases, low PSA and bulky disease, high lactate dehydrogenase, high carcinoembryonic antigen, 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, no liver metastases, with life expectancy >6 months, and ECOG performance status 0–1: Sipuleucel-T
  • HRRm-positive patients: Talazoparib/Enzalutamide
• Other recommended therapies include Abiraterone with or without Dexamethasone, Enzalutamide and other secondary hormone therapy

• Preferred regimens include Abiraterone, Cabazitaxel and Enzalutamide
• Regimens that can be used depending on patient's status include:
  • Fit patients with aggressive variant prostate cancer (eg visceral metastases, low PSA and bulky disease, high lactate dehydrogenase, high carcinoembryonic antigen, 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, no liver metastases, with life expectancy >6 months, and ECOG performance status 0–1: Sipuleucel-T
  • HRRm-positive patients: Talazoparib/Enzalutamide
• Other recommended agent include other secondary hormone therapy

• Preferred regimens include Cabazitaxel and Docetaxel rechallenge
  • Docetaxel rechallenge to be given after progression on novel hormone therapy in castration-naive patients negative for disease progression on prior Docetaxel therapy
• Regimens that can be used depending on patient's status include the following:
  • 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 patients: 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 a taxane-based chemotherapy: Rucaparib
• Other recommended therapies include Abiraterone, Enzalutamide and other secondary hormone therapy