Management of castration-resistant prostate cancer, non-metastatic, pretreatment evaluation: As per ISUP/SIOG/ESUR/ESTRO/EANM/EAU 2022 guidelines, confirm testosterone levels to be < 50 ng/dL before diagnosing castration-resistant prostate cancer. A As per ASCO 2020 guidelines, consider obtaining next-generation imaging in patients with non-metastatic castration-resistant prostate cancer only if a change in clinical care is contemplated. Consider obtaining next-generation imaging to clarify the presence or absence of metastatic disease, assuming patients have received or are ineligible for local salvage treatment options. C Management of castration-resistant prostate cancer, non-metastatic, surveillance: As per SUO/AUA 2023 guidelines, obtain conventional imaging or prostate-specific membrane antigen positron emission tomography at intervals of 6-12 months to assess for https://web.pathway.md/diseases/recXj11agry4hkwmf 13/24 6/29/23, 11:31 PM Prostate cancer Pathway the development of metastatic disease in patients with non-metastatic castration-resistant prostate cancer. E As per CUOG/CUA 2022 guidelines, obtain regular imaging every 6-12 months, depending on the PSA-doubling time values, in patients not treated for non-metastatic castration- resistant prostate cancer. B As per SUO/ASTRO/AUA 2021 guidelines, obtain serial PSA measurements at 3-6-month intervals and calculate a PSA-doubling time starting at the time of development of castration resistance in patients with non-metastatic castration-resistant prostate cancer. B Management of castration-resistant prostate cancer, non-metastatic, observation and androgen deprivation therapy: As per CUOG/CUA 2022 guidelines, maintain androgen deprivation therapy in the non- metastatic castration-resistant prostate cancer state. Discontinue first-generation androgen receptor antagonists (such as bicalutamide, flutamide). B Show 2 more As per SUO/ASTRO/AUA 2021 guidelines, consider offering observation with continued androgen deprivation therapy in patients with non-metastatic castration-resistant prostate cancer, particularly at lower risk (PSA-doubling time > 10 months) for developing metastatic disease. C Management of castration-resistant prostate cancer, non-metastatic, nonsteroidal antiandrogens: As per CUOG/CUA 2022 guidelines, offer apalutamide, enzalutamide, or darolutamide in patients with high-risk non-metastatic castration-resistant prostate cancer (defined as a PSA- doubling time < 10 months) with an estimated life expectancy of > 5 years. A As per ISUP/SIOG/ESUR/ESTRO/EANM/EAU 2022 guidelines, offer apalutamide, darolutamide, or enzalutamide to prolong the time to metastases and overall survival in patients with M0 castration-resistant prostate cancer at high risk of developing metastasis (PSA-doubling time < 10 months). A As per SUO/ASTRO/AUA 2021 guidelines, offer apalutamide, darolutamide, or enzalutamide with continued androgen deprivation therapy in patients with non-metastatic castration- resistant prostate cancer at high risk of developing the metastatic disease (PSA-doubling time 10 months). A As per ESMO 2020 guidelines, consider offering apalutamide, darolutamide, or enzalutamide in patients with M0 (on bone scan and CT) castration-resistant prostate cancer at high risk of disease progression. B Management of castration-resistant prostate cancer (non-metastatic, chemotherapy and immunotherapy): do not offer systemic chemotherapy or immunotherapy in patients with non- metastatic castration-resistant prostate cancer outside a clinical trial. D Management of castration-resistant prostate cancer, metastatic, pretreatment evaluation: As per SUO/AUA 2023 guidelines: Obtain prostate-specific membrane antigen positron emission tomography in patients with metastatic castration-resistant prostate cancer with disease progression (PSA or radiographic progression or new disease-related symptoms) previously received docetaxel https://web.pathway.md/diseases/recXj11agry4hkwmf 14/24 6/29/23, 11:31 PM Prostate cancer Pathway and androgen pathway inhibitor planned for lutetium-177-prostate-specific membrane antigen-617. E Obtain germline (if not already obtained) and somatic genetic testing to identify deoxyRNA repair deficiency, MSI status, tumor mutational burden, and other potential mutations to inform prognosis and familial cancer risk and to direct potential targeted therapies in patients with metastatic castration-resistant prostate cancer. B As per ISUP/SIOG/ESUR/ESTRO/EANM/EAU 2022 guidelines: Confirm testosterone levels to be < 50 ng/dL before diagnosing castration-resistant prostate cancer. A Obtain somatic and/or germline molecular testing as well as testing for mismatch repair deficiencies or MSI in patients with metastatic castration-resistant prostate cancer. A As per SUO/ASTRO/AUA 2021 guidelines, obtain baseline laboratory tests (PSA, testosterone, LDH, Hgb, ALP), review the location of metastatic disease (bone, lymph node, visceral), assess disease-related symptoms and performance status to inform discussions of prognosis and treatment decision-making in patients with metastatic castration-resistant prostate cancer. B Management of castration-resistant prostate cancer, metastatic, general principles of management: As per ISUP/SIOG/ESUR/ESTRO/EANM/EAU 2022 guidelines, counsel, manage, and treat patients with metastatic castration-resistant prostate cancer in a multidisciplinary team. A Show 3 more As per SUO/ASTRO/AUA 2021 guidelines, consider taking into account the prior treatment and offering therapy with an alternative mechanism of action in sequencing agents. C Management of castration-resistant prostate cancer, metastatic, hormonal therapy: As per SUO/AUA 2023 guidelines, offer continued androgen deprivation therapy with abiraterone acetate plus prednisone, docetaxel, or enzalutamide in patients with newly diagnosed metastatic castration-resistant prostate cancer not received prior androgen receptor pathway inhibitors. B As per CUOG/CUA 2022 guidelines, offer abiraterone acetate 1,000 mg/day plus prednisone 5 mg BID, or enzalutamide 160 mg/day as first-line therapy in asymptomatic or minimally symptomatic chemotherapy-na ve patients with metastatic castration-resistant prostate cancer. A Show 3 more As per ISUP/SIOG/ESUR/ESTRO/EANM/EAU 2022 guidelines, offer abiraterone or enzalutamide in patients previously treated with 1-2 lines of chemotherapy. A Avoid sequencing of androgen receptor-targeted agents. B As per ESMO 2020 guidelines, offer abiraterone or enzalutamide in asymptomatic/mildly symptomatic patients with chemotherapy-na ve metastatic castration-resistant prostate cancer. A Show 2 more Management of castration-resistant prostate cancer, metastatic, chemotherapy: As per ESMO 2023 guidelines, offer cabazitaxel in patients with metastatic castration- resistant prostate cancer received a novel androgen receptor axis inhibitor (abiraterone, https://web.pathway.md/diseases/recXj11agry4hkwmf 15/24 6/29/23, 11:31 PM Prostate cancer Pathway apalutamide, darolutamide, or enzalutamide) and docetaxel and considered fit enough to receive this treatment. A As per CUOG/CUA 2022 guidelines, offer docetaxel 75 mg/m IV every 3 weeks with 5 mg oral prednisone BID in patients with metastatic castration-resistant prostate cancer. A Show 5 more As per ISUP/SIOG/ESUR/ESTRO/EANM/EAU 2022 guidelines: Offer docetaxel 75 mg/m every 3 weeks in chemotherapy-na ve patients with metastatic castration-resistant prostate cancer eligible for cytotoxic therapy. A Offer chemotherapy in patients previously treated with abiraterone or enzalutamide. Offer cabazitaxel in patients previously treated with docetaxel. Offer cabazitaxel in patients previously treated with docetaxel and progressing within 12 months of treatment with abiraterone or enzalutamide. A As per SUO/ASTRO/AUA 2021 guidelines: Consider offering cabazitaxel in patients with metastatic castration-resistant prostate cancer received prior docetaxel chemotherapy, with or without prior abiraterone acetate plus prednisone or enzalutamide. C Offer cabazitaxel rather than an alternative androgen pathway-directed therapy in patients with metastatic castration-resistant prostate cancer received prior docetaxel chemotherapy and abiraterone acetate plus prednisone or enzalutamide. B As per ESMO 2020 guidelines, offer docetaxel in patients with metastatic castration-resistant prostate cancer. Offer cabazitaxel or abiraterone/enzalutamide in patients with metastatic castration-resistant prostate cancer in the post-docetaxel setting. A Management of castration-resistant prostate cancer, metastatic, PARP inhibitors: As per ESMO 2023 guidelines, consider offering olaparib following novel androgen receptor axis inhibitors (with or without prior taxane treatment) in patients with metastatic castration- resistant prostate cancer with alteration in BRCA1 or BRCA2 genes. B As per CUOG/CUA 2022 guidelines, offer olaparib 300 mg BID in patients with metastatic castration-resistant prostate cancer and homologous recombination repair mutation progressed on a previous androgen receptor-axis-targeted therapy. A As per ISUP/SIOG/ESUR/ESTRO/EANM/EAU 2022 guidelines, offer poly(ADP-ribose) polymerase inhibitors in pre-treated patients with metastatic castration-resistant prostate cancer with relevant deoxyRNA repair gene mutations. A As per SUO/ASTRO/AUA 2021 guidelines, offer a poly(ADP-ribose) polymerase inhibitor in patients with deleterious or suspected deleterious germline or somatic homologous recombination repair gene-mutated metastatic castration-resistant prostate cancer following prior treatment with enzalutamide or abiraterone acetate, and/or taxane-based chemotherapy. Consider offering platinum-based chemotherapy as an alternative in patients unable to use or obtain a poly(ADP-ribose) polymerase inhibitor. B Management of castration-resistant prostate cancer (metastatic, immunotherapy): Consider offering sipuleucel-T in asymptomatic or minimally symptomatic patients with metastatic castration-resistant prostate cancer. C Offer pembrolizumab in patients with mismatch repair deficient or MSI-high metastatic castration-resistant prostate cancer. B https://web.pathway.md/diseases/recXj11agry4hkwmf 16/24 6/29/23, 11:31 PM Prostate cancer Pathway Management of castration-resistant prostate cancer, metastatic, radioligand therapy: As per SUO/AUA 2023 guidelines, offer lutetium-177-prostate-specific membrane antigen- 617 in patients with progressive metastatic castration-resistant prostate cancer previously received docetaxel and androgen pathway inhibitor with a positive prostate-specific membrane antigen positron emission tomography. B As per ESMO 2023 guidelines, offer lutetium-177-prostate-specific membrane antigen-617 in patients with metastatic castration-resistant prostate cancer expressing prostate-specific membrane antigen on positron emission tomography-prostate-specific membrane antigen and without prostate-specific membrane antigen non-expressing lesions, received a novel androgen receptor axis inhibitor (abiraterone, apalutamide, darolutamide, or enzalutamide) and docetaxel, and considered fit enough to receive this treatment. A As per ASCO 2022 guidelines, offer lutetium-177-prostate-specific membrane antigen-617 IV once every 6 weeks for 4-6 cycles as a treatment option in patients with prostate-specific membrane antigen positron emission tomography/CT-positive metastatic castration-resistant prostate cancer progressed on one prior line of androgen receptor pathway inhibitor and at least one line of prior chemotherapy. B Show 2 more As per CUOG/CUA 2022 guidelines: Offer radium-223 in patients with bone symptomatic metastatic castration-resistant prostate cancer progressed following taxane chemotherapy or unfit for chemotherapy, in the absence of visceral metastases. Do not combine radium-223 with abiraterone. Administer a bone-supportive agent (denosumab or zoledronic acid) always when using radium-223. A Offer lutetium-177-prostate-specific membrane antigen-617 for up to 6 cycles in patients with metastatic castration-resistant prostate cancer and prostate-specific membrane antigen-expressing metastatic lesions progressed on at least one previous taxane chemotherapy and an androgen receptor-axis-targeted therapy. A As per ISUP/SIOG/ESUR/ESTRO/EANM/EAU 2022 guidelines, offer lutetium-177-prostate- specific membrane antigen-617 in pre-treated patients with metastatic castration-resistant prostate cancer with 1 metastatic lesion, highly expressing prostate-specific membrane antigen (exceeding the uptake in the liver) on the diagnostic radiolabeled prostate-specific membrane antigen positron emission tomography/CT. A As per SUO/ASTRO/AUA 2021 guidelines, offer radium-223 in patients with metastatic castration-resistant prostate cancer with symptoms from bony metastases and without known visceral disease or lymphadenopathy > 3 cm. B As per ESMO 2020 guidelines, offer radium-223 in patients with bone-predominant, symptomatic metastatic castration-resistant prostate cancer without visceral metastases. B Do not use radium-223 in combination with abiraterone and prednisolone. B Management of castration-resistant prostate cancer, metastatic, prevention of skeletal- related events: As per CUOG/CUA 2022 guidelines, offer denosumab (120 mg SC) or zoledronic acid (4 mg IV) every 4 weeks to prevent disease-related skeletal-related events (including pathological fractures, spinal cord compression, surgery, or radiotherapy to bone) in patients with castration-resistant prostate cancer and bone metastases. A Show 3 more https://web.pathway.md/diseases/recXj11agry4hkwmf 17/24 6/29/23, 11:31 PM Prostate cancer Pathway As per ISUP/SIOG/ESUR/ESTRO/EANM/EAU 2022 guidelines, offer bone protective agents to prevent osseus complications in patients with metastatic castration-resistant prostate cancer and skeletal metastases. A Show 3 more As per SUO/ASTRO/AUA 2021 guidelines, discuss the risk of osteoporosis associated with androgen deprivation therapy and assess the risk of fragility fracture in patients with advanced prostate cancer. B Show 3 more As per ESMO 2020 guidelines, offer bisphosphonates or denosumab in patients with bone metastases from castration-resistant prostate cancer at risk for clinically significant skeletal- related events. B Management of castration-resistant prostate cancer (metastatic, surveillance): obtain imaging at least annually in patients with metastatic castration-resistant prostate cancer without PSA progression or new symptoms. E Management of biochemical recurrence: As per AUA 2023 guidelines, obtain periodic staging evaluations consisting of cross-sectional imaging (CT, MRI) and technetium bone scan, and/or preferably prostate-specific membrane antigen positron emission tomography, in patients with PSA recurrence after the failure of local therapy at higher risk for the development of metastases (such as PSA doubling time < 12 months). B Show 2 more As per ASCO 2021 guidelines, consider offering intermittent therapy in patients with high-risk biochemically recurrent, locally advanced, non-metastatic prostate cancer after radical prostatectomy and/or radiotherapy. B As per AUA 2021 guidelines: Inform patients with PSA recurrence after exhaustion of local therapy regarding the risk of developing metastatic disease and follow such patients with serial PSA measurements and clinical evaluation. Consider obtaining radiographic assessments based on overall PSA and PSA kinetics. B Do not offer androgen deprivation therapy routinely in patients with biochemical recurrence. D . Consider offering intermittent androgen deprivation therapy in lieu of continuous androgen deprivation therapy, if androgen deprivation therapy is initiated in the absence of metastatic disease. D As per ASCO 2020 guidelines, decide on the imaging in patients with rising PSA after prostatectomy and negative conventional imaging (either initial PSA undetectable with a subsequent rise or PSA never nadirs to undetectable) based on the goal of therapy and the potential use of salvage local therapies, as both disease states indicate potentially undetected, residual local, locoregional, or micrometastatic disease and imaging options are not distinct or different between these scenarios. Do not obtain additional next-generation imaging in patients ineligible for or unwilling to receive salvage local or regional therapy. B Show 3 more As per ESMO 2020 guidelines, obtain positron emission tomography-CT in patients with biochemical relapse after radical radiotherapy and being eligible for local salvage or https://web.pathway.md/diseases/recXj11agry4hkwmf 18/24 6/29/23, 11:31 PM Prostate cancer Pathway metastasis-directed treatment. B Show 2 more 6. Specific circumstances Elderly patients: take into account individual life expectancy, health status, and comorbidities in the management of prostate cancer. A Show 5 more Patients with premalignant lesions: Consider obtaining additional risk evaluation, guided by PSA/DRE and multiparametric MRI findings, in patients with multifocal high-grade prostatic intraepithelial neoplasia. E Obtain additional testing in patients with atypical small acinar proliferation or atypical intraductal proliferation. E 7. Patient education General counseling: As per AUA 2022 guidelines: Counsel patients with prostate cancer that all treatment options carry risk. Incorporate the risks of treatment, in particular to the urinary, sexual, and bowel function, with the risk posed by cancer, patient life expectancy, comorbidities, preexisting medical conditions, and patient preferences in order to facilitate a shared decision-making approach to management. B Provide an individualized risk estimate of post-treatment prostate cancer recurrence in patients with prostate cancer. B 8. Preventative measures 5-alpha reductase inhibitors: consider discussing the benefits of 5-ARIs for 7 years for the prevention of prostate cancer and the potential risks (including the possibility of high-grade prostate cancer) to be able to make a better-informed decision in asymptomatic males with a PSA level 3.0 undergoing regular screening with PSA or anticipating to undergo annual PSA screening for early detection of prostate cancer, as well as in patients taking 5-ARIs for benign conditions such as LUTS. 9. Follow-up and surveillance Monitoring for progression, on active surveillance: As per ASTRO/AUA 2022 guidelines: Obtain serial PSA values and repeat prostate biopsy in patients with localized disease managed with active surveillance. E Obtain multiparametric MRI to augment risk stratification (but not to replace periodic surveillance biopsy) in patients selecting active surveillance. E https://web.pathway.md/diseases/recXj11agry4hkwmf 19/24 6/29/23, 11:31 PM Prostate cancer Pathway As per ISUP/SIOG/ESUR/ESTRO/EANM/EAU 2022 guidelines: Repeat biopsies at least once every 3 years for 10 years. B Do not progress to active treatment without a repeat biopsy in case of PSA progression or change in digital-rectal examination or MRI findings. D Monitoring for progression, after local treatment: As per ASTRO/AUA 2022 guidelines, obtain serial PSA and symptom assessment to monitor patients after treatment. B As per ISUP/SIOG/ESUR/ESTRO/EANM/EAU 2022 guidelines: Obtain at least a disease-specific history and PSA measurement for routine follow-up of asymptomatic patients. A Obtain imaging at recurrence if the result will affect treatment planning. A Monitoring for recurrence: As per EAU 2022 guidelines, obtain imaging at recurrence only if the result will affect treatment planning. A As per AUA 2021 guidelines, obtain a baseline measurement of PSA and serial measurements at 3-6-month intervals after initiation of androgen deprivation therapy in patients with metastatic hormone-sensitive prostate cancer. Consider obtaining periodic conventional imaging. B As per ASTRO 2019 guidelines, inform patients that the development of a PSA recurrence after surgery is associated with a higher risk of the development of metastatic prostate cancer or death from the disease. Obtain regular monitoring of PSA after radical prostatectomy to enable early administration of salvage therapies if appropriate. B Show 2 more Surveillance for osteoporosis: As per EAU 2022 guidelines, obtain initial dual emission X-ray absorptiometry to assess bone mineral density in patients starting on long-term androgen deprivation therapy. A Show 5 more As per AUA 2021 guidelines, discuss the risk of osteoporosis associated with androgen deprivation therapy and assess the risk of fragility fracture in patients with advanced prostate cancer. B Show 3 more As per ESMO 2020 guidelines, implement proper management to prevent cancer treatment- induced bone loss in patients starting on androgen deprivation therapy. Show 2 more Multidisciplinary rehabilitation: as per AUA 2022 guidelines, support patients with prostate cancer through continued symptom management and encourage engagement with professional or community-based resources. B Clinical findings Patient demographics Symptoms https://web.pathway.md/diseases/recXj11agry4hkwmf 20/24 6/29/23, 11:31 PM Prostate cancer Pathway African-american race Erectile dysfunction Fatigue Past medical history Hematospermia Hematuria Bone metastasis Lower urinary symptoms Hereditary breast and ovarian cancer syndrome Nocturia Urinary frequency Lynch syndrome Urinary hesitancy Obesity Urinary incontinence Rectal exam Urinary retention Urinary straining Enlarged prostate Urinary urgency Prostatic induration Weak urine stream Prostatic nodularity Weight loss Hematological findings Social history Anemia Tobacco use Genetic testing Lab findings Brca1 gene mutation serum PSA Brca2 gene mutation Imaging findings Spinal cord compression Studies 2021 STHLM3MR-2 In men aged 50 to 74 years with PSA levels 3 ng/mL, MRI-targeted biopsy was noninferior to standard biopsy with respect to the detection of a clinically significant cancer. Martin Eklund et al. N Engl J Med. 2021 Sep 2. 2009 ERSPC In men between the ages of 55 and 69 years, prostate cancer screening was superior to no screening with respect to death from prostate cancer. Schroder FH et al. N Engl J Med. 2009 Mar 26. Show 1 more References 1. N. Mottet, P. Cornford, R.C.N. van den Bergh et al. EAU EANM ESTRO ESUR ISUP SIOG Guidelines on Prostate Cancer. EAU. 2022 Mar. Open 2. Fred Saad, Armen Aprikian, Antonio Finelli et al. 2022 Canadian Urological Association CUA Canadian Uro Oncology Group CUOG guideline: Management of castration-resistant prostate cancer https://web.pathway.md/diseases/recXj11agry4hkwmf 21/24 6/29/23, 11:31 PM Prostate cancer Pathway CRPC . Can Urol Assoc J. 2022 Nov;16 11 E506 E515. Open 3. William T Lowrance, Rodney H Breau, Roger Chou et al. Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART I. J Urol. 2021 Jan;205 1 14 21. Open 4. Thomas M Pisansky, Ian M Thompson, Richard K Valicenti et al. 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Part II 2020 Update: Treatment of Relapsing and Metastatic Prostate Cancer. Eur Urol. 2021 Feb;79 2 263 282. Open 39. David J Hernandez, Matthew E Nielsen, Misop Han et al. Contemporary evaluation of the D'amico risk classification of prostate cancer. Urology. 2007 Nov;70 5 931 5. Open 40. Ni Chen and Qiao Zhou. The evolving Gleason grading system. Chin J Cancer Res. 2016 Feb; 28 1 58 64. Open 41. Matthew R. Cooperberg, MD, MPH et al. The UCSF Cancer of the Prostate Risk Assessment CAPRA Score: a straightforward and reliable preoperative predictor of disease recurrence after radical prostatectomy. J Urol. 2005 Jun; 173 6 1938 1942. Open 42. Matthew J Resnick, Christina Lacchetti, Jonathan Bergman et al. Prostate cancer survivorship care guideline: American Society of Clinical Oncology Clinical Practice Guideline endorsement. J Clin Oncol. 2015 Mar 20;33 9 1078 85. Open https://web.pathway.md/diseases/recXj11agry4hkwmf 24/24