# Background
Prostate cancer is the most common cancer among Canadian men, and is the 3rd leading cause of cancer related death in men in Canada. In 2022, it is estimated that 24,600 men will be diagnosed with prostate cancer in Canada and 4600 men will die from their disease. 1 Many patients with advanced prostate cancers are diagnosed after localized treatment, with disseminated disease being identified by rising PSA post-definitive treatment. However, some men present with de novo metastatic disease.
Guideline Questions 1. How should advanced/ metastatic prostate cancer be staged? 2. How should advanced/ metastatic prostate cancer be treated? 3. How should advanced/ metastatic prostate cancer patients be followed after treatment?

# Search Strategy
For the 2022 guideline update, selected phase III trials were reviewed by the Alberta GU Tumour group (summarized in Appendix A).
For the 2016 guideline, select literature was reviewed by a working group at the Alberta GU Tumour Team meeting. No formal systematic literature review was performed.
For the 2015 update, no formal literature review was conducted.
For the 2014 update of this guideline, the Pubmed database was searched using the search terms Locally Advanced Prostate Cancer and Metastatic Prostate Cancer from 2010 to 2014. Only phase III trials were evaluated for inclusion.
For the 2012 update of this guideline, Ovid Medline was searched using the term Prostatic neoplasms (MeSH term, subheadings drug therapy, surgery, therapy and radiotherapy), limited to clinical trials involving humans published in English, between August 2011 and August 2012. Articles were excluded if they were not phase II-IV trials, did not include survival or recurrence outcomes, was retrospective. Cochrane Database of Systematic Reviews was searched using the term "prostate cancer", published 2011-2012.
Medline & Embase were further searched using the term prostate cancer (keyword), limited to clinical trials related to "therapy (best balance of sensitivity and specificity) involving male humans published in English between August 2011-2012.
Ovid MEDLINE and EMBASE (1965 to August 2011) and clinical practice guideline databases, including the Cochrane Library and the National Guidelines Clearinghouse, were searched in order to obtain evidence relevant to this topic. are viable options. Lower rates of fracture, peripheral arterial disease, and cardiac-related complications have been reported in surgical castration patients when compared to medical castration patients in a large retrospective cohort study. 4 Castrate level serum testosterone (<1.7 nmol/L) can cause a number of undesirable side effects. For this reason intermittent ADT has theoretical advantages. However, in patients with metastatic prostate cancer continuous ADT is recommended unless survival is considered secondary to quality of life. The phase III intergroup trial reported that intermittent ADT cannot be considered non-inferior compared to continuous ADT in terms of overall survival. 5,6 Medical castration: Treatment with an LHRH agonist/GnRH antagonist: - When first introduced, a non-steroidal antiandrogen (e.g. bicalutamide 50 mg daily, flutamide 250 mg three times a day or nilutamide 300mg daily) should be given concurrently with the first administration of leuprolide, goserelin, or buserelin for 2 weeks to 1 month in order to block the potential initial testosterone flare. - The non-steroidal antiandrogen should be administered concurrently with the first LHRH analogue injection and continue for a minimum of 14 days afterward. - Medical and surgical castration is equally effective and the risks, benefits, and economic implications should be discussed with the patient. - Patients who are intolerant to Leuprolide or unable to achieve castrate testosterone should have a trial of Buserelin. - The GnRH antagonist Degarelix is as effective at suppressing testosterone and may achieve testosterone suppression faster 7 than GnRH Agonists. Treatment with a GnRH antagonist (Degarelix) avoids the risk of testosterone 'flare" that occurs with GnRH agonists. 7,8 A non steroidal antiandrogen is not required to be given concurrently with the first dose of GnRH antagonist. 3. Nilutamide 300 mg orally once a day for one month, then decrease to 150 mg daily.
Patients undergoing androgen deprivation therapy for prostate cancer have an improved quality of life if they continue to be physically active. Patients should be counseled on the role of maintaining physical fitness and activity while on hormonal therapy. 9 Ongoing total androgen blockade (e.g. castration with LHRH agonist/antagonist plus a nonsteroidal antiandrogen) is not recommended for patients in this setting.  11 demonstrated a significant overall survival benefit of 14 months in all patients (low and high volume) with metastatic CSPC. o Patients receiving chemotherapy for this indication should be offered 6 cycles of docetaxel chemotherapy at a starting dose of 75 mg/m 2 every 3 weeks (given with or without prednisone). Androgen deprivation therapy as above is continued throughout and after docetaxel completion.

# Abiraterone Acetate:
- Patients should be considered per the LATITUDE trial criteria to qualify for this treatment. The LATITUDE inclusion criteria are 12 : o Adenocarcinoma of the prostate without neuroendocrine differentiation or small cell histology. o Distant metastatic disease documented by positive bone scan or metastatic lesions on CT or MRI. o At least 2 of the following high-risk prognostic factors: Gleason score 8; presence of 3 or more lesions on bone scan; presence of measurable visceral (excluding lymph node disease) metastasis on CT or MRI.
- Docetaxel plus abiraterone acetate with prednisone 5 mg twice a day may be considered for patients, who are chemotherapy candidates with de novo high volume metastatic disease (defined as the presence of visceral metastases or >4 bony lesions with 1 beyond the vertebral bodies and pelvis), as per the PEACE-1 trial. 13 4. Enzalutamide (All risks/volumes). 14,15 5. Apalutamide (All risks/volumes) 16 There is insufficient evidence to recommend one single agent ARAT strategy over another. Clinical decision making should be based on patient factors and access.

# Radiation therapy:
Referral to RO for consideration of radiation therapy to the prostate for patients with de novo low volume metastatic disease (see Management of Oligometastatic Disease below), as per STAMPEDE. 17

# Follow-up Frequency
If on either docetaxel chemotherapy or ARAT (eg: abiraterone acetate, enzalutamide, apalutamide), patients should be evaluated as per standard protocol.
If on ADT alone: q3-6 months following the initiation of therapy to evaluate and then as clinically indicated.
Patients should be treated until development of castrate resistant disease, which is defined as either clinical, biochemical, or radiographic disease progression in the presence of castrate level (<1.7nmol/L) testosterone levels.

# IV. Non-Metastatic Castration Resistant Disease (Stage M0, M+)
Castrate resistant disease is defined as either clinical, biochemical, or radiographic disease progression in the presence of castrate level (<1.7nmol/L) testosterone levels.

# Staging
- Bone scan.
- CT scan of chest, abdomen, and pelvis. 3. Serum PSA, serum testosterone (to ensure that testosterone is in the castrate range). 4. Other imaging may be required as clinically indicated.

# Management of M0 CRPC Disease
Monitoring:
- Baseline ECG recommended. PSA, testosterone, and TSH should be monitored q3-6monthly.
- Systemic therapy may be considered in patients with high-risk disease, where a PSA doubling time is < 10 months and no measurable disease on conventional imaging (bone scan and CT chest, abdomen, and pelvis). A PSA doubling time calculator is recommended for calculation (e.g. MSKCC).  23 1. First line options: a. Abiraterone acetate 1000 mg oral daily in combination with prednisone 5 mg oral twice daily (COUGAR 302) can be used prior to docetaxel. 24,25 b. Docetaxel 75mg/m 2 IV every 3 weeks in combination with prednisone at a dose of 5 mg twice daily. c. Enzalutamide 160mg oral daily can be used prior to docetaxel (PREVAIL). 26 

# Second line options:
a. Post progression on docetaxel chemotherapy: i. Cabazitaxel IV every 3 weeks in combination with prednisone 10 mg oral daily.20 mg or 25 mg can be considered, as the PROSELICA trial. 27 demonstrated that 20 mg dose was non-inferior to the 25 mg dose and was associated with decreased toxicity. Per the CARD trial, cabazitaxel is shown to improve overall survival, in contrast to another ARAT. 28 ii. Abiraterone acetate 29 or enzalutamide. 30 iii. Radium 223 is not funded or available in Alberta. Radium 223 can be given to patients with symptomatic bony metastatic CRPC without visceral metastases (ALSYMPCA). 31,32 Ra 223 is administered upon referral to nuclear medicine and given at a dose of 50 kBq (1.35 microcurie) per kg body weight at 4 week intervals for a total of 6 injections. b. Post progression on abiraterone, apalutamide, darolutamide or enzalutamide: i. Docetaxel chemotherapy.
ii. Olaparib -for patients with BRCA1/2 or ATM alterations. 33 ATM mutations may require strong consideration of chemotherapy prior to PARP inhibitors. Hence, medical oncology should be involved in the care of these patients prior to initiation of PARP inhibitor. Other DNA damage repair alterations do not qualify for Olaparib therapy. iii. Platinum-based chemotherapy options should be considered for patients with DNA damage repair mutations (e.g. BRCA1/2, ATM, etc.), and discussion at multidisciplinary tumour board rounds is encouraged. 23 3. Subsequent lines: a. Sequencing with another agent listed above not previously used. Optimal sequencing of these agents is unknown. b. If a patient has already received docetaxel and one ARAT, the CARD trial would suggest that cabazitaxel would be the preferred subsequent agent provided the patient is medically fit for therapy. 

# Management of Oligometastatic Disease

# Radiotherapy to the prostate:
- The STAMPEDE trial 17 failed to demonstrate improvement in overall survival after radiotherapy in newly diagnosed metastatic prostate cancer. However, pre-specified subgroup analysis of patients with low metastatic burden (by CHAARTED clinical trial criteria) demonstrated an improvement in overall survival with radiotherapy to the prostate compared to standard of care (81% vs. 73% OS at 3 years; HR:0.68, 95%CI: 0.52-0.90). Discussion in multidisciplinary tumour group meetings is advised if radiotherapy is being considered.
- SBRT is an investigational option and may be considered for some patients.
- PSMA PET/CT is an investigational option and is not currently standard of care. Patient results of PSMA PET/CT should be reviewed at multidisciplinary tumour board rounds to determine best course of action in patient management.

# Follow-up:
- Patients on docetaxel, abiraterone, enzalutamide, apalutamide, darolutamide, or cabazitaxel should be monitored as per standard protocols.
- Once therapy with one of these agents has been discontinued, patients should be assessed for further therapy.    

# Appendix A: Clinical Trial Summaries

# Development and Revision History
This guideline was developed by a multidisciplinary working group comprised of members from the Alberta Provincial GU Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. The draft guideline was externally reviewed and endorsed by members of the Alberta Provincial GU Tumour Team who were not involved in the guideline's development, including urologists, radiation oncologists, medical oncologists, nurses, pathologists, and pharmacists. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2019.

# Maintenance
A formal review of the guideline will be conducted in 2023. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.

# Abbreviations
ADT Androgen deprivation therapy, ALT Alanine transamine, AST Aspartate transaminase, BUN Blood urea nitrogen, CBC Complete blood count, CT Computed tomography, EBRT External beam radiotherapy, GnRH Gonadotropin-releasing hormone agonist, LHRH Luteinizing hormone-releasing hormone, PSA Prostate-specific antigen