Editing CUA: Castrate-resistant Prostate Cancer (2021)

'''See Original Guideline'''

'''See 2020 AUA Advanced Prostate Cancer Guideline Notes'''

'''See CRPC Chapter Notes'''

===== *****All of the content below is included in the more comprehensive CRPC Chapter Notes***** =====

===== '''Management''' =====

* '''UrologySchool.com Summary'''
** '''General principles'''
*** '''Whenever possible, clinical trials should remain the first choice in patients with CRPC.'''
*** '''ADT should be continued'''
** '''Non-metastatic CRPC'''
*** '''PSADT <10 months and life expectancy > 5 years: apalutamide, enzalutamide, or darolutamide'''
** '''Metastatic CRPC'''
*** '''Asymptomatic or minimially symptomatic:'''
**** '''First-line: abiraterone or enzalutamide'''
**** '''Second-line: docetaxel'''
*** '''Moderate or severe symptoms:'''
**** '''First-line: docetaxel or radium-223'''
***** '''Radium-223 if pain due to bone metastases and do not have visceral metastases'''
**** '''Abiraterone or enzalutamide in patients that cannot tolerate docetaxel'''
*** '''Progression after docetaxel:'''
**** '''Cabazitaxel'''
**** '''Radium-223'''
**** '''If not received prior to docetaxel:'''
***** '''Abiraterone acetate'''
***** '''Enzalutamide'''
*** '''Olaparib in mCRPC patients with homologous recombination repair (HRR) mutation who have progressed on a previous androgen receptor-axis-targeted therapy (ARAT) i.e., abiraterone, enzalutamide, apalutamide, darolutamide, without or without previous docetaxel'''
*** '''CRPC with bone metastasis'''
**** '''Daily calcium and vitamin D supplementation'''
**** '''Denosumab (120 mg subcutaneous) or zoledronic acid (4 mg intravenous) every four weeks'''

* '''Androgen-deprivation therapy (ADT)'''
** '''Should be continued for the remainder of a patient’s life'''
*** Because the androgen receptor remains active in most patients who have developed castration-resistant disease, it is recommended that ADT should be continued for the remainder of a patient’s life
** '''In patients who develop CRPC, the addition or change of first-generation androgen receptor antagonists (flutamide, bicalutamide, or nilutamide) may be considered'''
*** Changing the anti-androgen or using corticosteroids with or without ketoconazole have been noted to cause transient PSA reductions in ≈30% of patients but have not been shown to improve any of the clinically meaningful outcome measures
*** In patients treated with luteinizing hormone-releasing hormone (LHRH) analogue monotherapy or those who have had an orchidectomy, the addition of androgen receptor antagonists, such as bicalutamide, '''can offer modest PSA responses that are short-lived in 30–35% of patients.'''
** '''For patients who have undergone total androgen blockade (TAB), the androgen receptor antagonist should be discontinued to test for an anti-androgen withdrawal response'''

* '''Non-metastatic CRPC'''
** '''First-generation androgen receptor antagonists should be discontinued in patients already receiving these agents'''
** '''If PSADT'''
*** '''≥ 10 months: observation or secondary hormonal treatments'''
*** '''< 10 months (high-risk nmCRPC) AND estimated life expectancy > 5 years'''
**** '''First-line options (2):'''
****# '''Apalutamide'''
****# '''Enzalutamide'''
****# '''Darolutamide'''
***** All options should be with continuous ADT
***** Until 2018, there was no standard of care and no approved regimen for the nmCRPC state.
**** '''Second-line options in high-risk nmCRPC who are felt to be unsuitable or refuse approved therapies:'''
****# '''Observation'''
****# '''Use of first-generation androgen receptor antagonists may be attempted [if patient not previously on first-generation androgen receptor antagonist]'''
*** PSADT < 10 months has been associated with worse outcomes and has been used in recent clinical trials as the definition for high-risk nmCRPC.
*** '''3 trials: See CRPC Chapter Notes PSA'''
**** '''PROSPER 2018 (enzalutamide)'''
**** '''SPARTAN 2018 (apalutamide)'''
**** '''ARAMIS 2019 (darolutamide)'''
*** '''All 3 trials reported similar results in significantly improving metastases-free and overall survival.'''
** '''Detection of metastases and imaging in untreated patients'''
*** '''Recommended screening for patients who progress on ADT without evidence of distant metastases:'''
**** '''Modalities:'''
***** '''Bone scans''' for bone metastases
***** '''Imaging of the chest/abdomen/pelvis''' to monitor for lymph node and visceral metastases/progression
****** Imaging techniques most commonly used include abdominal/pelvic CT and chest X-ray.
****** The role of positron-emission tomography (PET) such as PSMA-PET are still unclear and the benefits unknown
**** '''Frequency of imaging'''
***** '''PSADT <10 months or PSA >20: every 3–6 months'''
****** At high risk for developing metastases earlier
***** '''PSADT > 10 months: every 6–12 months'''
**** If metastases are detected, patients should be treated based on metastatic CRPC recommendations.

* '''Metastatic CRPC (mCRPC)'''
** General principles
*** Multidisciplinary care is optimal to maximize survival and quality of life.
*** Because any treatment for advanced disease remains non-curative, patients with advanced prostate cancer should be encouraged to participate in clinical trials.
**** Whenever possible, clinical trials should remain the first choice in patients with CRPC.
** '''Chemotherapy naïve mCRPC'''
*** '''Asymptomatic or minimally symptomatic'''
**** '''First-line (2):'''
****# '''Abiraterone acetate 1000 mg/day plus prednisone 5 mg PO BID OR'''
****# '''Enzalutamide 160 mg/day'''
****** '''Patients who have had little or no response to hormonal agents OR who progress with minimal change in PSA OR with significant visceral metastases should be considered for early chemotherapeutic options'''
***** Minimally symptomatic defined as pain that is relieved by acetaminophen or a non-steroidal anti-inflammatory
**** '''Second-line: Docetaxel (75 mg/m2 every 3 weeks plus prednisone 5 mg PO BID)'''
***** The timing of docetaxel therapy in men with evidence of metastases but without symptoms should be individualized based on patients’ clinical status and preferences
***** '''Rising PSA only during docetaxel chemotherapy should not be used as the sole criteria for progression; assessment of response should incorporate clinical and radiographic criteria'''
*** '''Moderate or severe symptoms'''
**** '''Docetaxel''' (75 mg/m2 every 3 weeks plus prednisone 5 mg PO BID) '''is recommended'''
**** '''Radium-223 every 4 weeks for six cycles is recommended in patients with pain due to bone metastases and who do not have visceral metastases'''
***** '''Radium-223 significantly improved overall survival and reduced symptomatic skeletal related events in patients with symptomatic mCRPC who had previously received docetaxel chemotherapy or were deemed unfit for docetaxel'''
***** '''A bone-supportive agent (denosumab or zoledronic acid) should always be used when using radium-223'''
***** '''Radium-223 should not be combined with abiraterone'''
****** ERA 223 was a RCT that compared the combination of radium-223 with abiraterone/prednisone vs. abiraterone/prednisone alone and in the first-line mCRPC setting demonstrated no advantage and an increased risk of fractures§
**** '''Abiraterone''' (1000 mg/day plus prednisone 5 mg twice daily) '''or enzalutamide''' (160mg/day) '''may be considered as first-line therapy in patients who cannot receive or refuse docetaxel'''
***** NOTE: The studies in the chemo-naive setting did not include patients with moderate or severe symptoms; however, abiraterone and enzalutamide may be potential therapeutic options in patients who are deemed chemotherapy-ineligible or refuse chemotherapy
**** '''Alternative therapies that have not demonstrated improvement in OS but can provide disease control, palliation, and improve quality of life include:'''
***** '''Weekly docetaxel plus prednisone'''
***** '''Mitoxantrone plus prednisone'''
** '''mCRPC who progress after docetaxel-based chemotherapy'''
*** '''Options with survival benefit (5):'''
**** '''Cabazitaxel''' (25 mg/m2) plus prednisone (5 mg/day) '''TROPIC trial'''
**** '''Radium-223 every four weeks for six cycles ALSYMPCA trial'''
**** '''If not received prior to docetaxel:'''
***** '''Abiraterone acetate''' (1000 mg per day) '''plus prednisone''' (5 mg twice daily) '''COU-AA-301 trial'''
***** '''Enzalutamide''' (160 mg/day) '''AFFIRM trial'''
*** '''Options with unknown survival benefit'''
**** '''Docetaxel plus prednisone re-exposure in patients who have had a previous favourable response to docetaxel may be reasonable'''
**** '''Mitoxantrone may be considered a therapeutic option in symptomatic patients with mCRPC in the first- or second-line setting. Mitoxantrone has not shown any survival advantage but may provide symptomatic relief'''
** '''Olaparib'''
*** Dosing: 300 mg twice daily
*** '''Indications:'''
**** '''mCPRC and homologous recombination repair (HRR) mutation who have progressed on a previous androgen receptor-axis-targeted therapy (ARAT) i.e., abiraterone, enzalutamide, apalutamide, darolutamide, with or without previous docetaxel'''

* '''See Figure 1 from Original Guideline'''
* The optimal sequence of available options remains unknown. In general, it is felt that changing therapeutic mechanism of action with each line of therapy is likely to lead to better and longer lasting response
* '''CRPC with bone metastases [includes the pre- or post-chemotherapy settings]'''
** '''Denosumab (120 mg subcutaneous) or zoledronic acid (4 mg intravenous) every 4 weeks, along with daily calcium and vitamin D supplementation, is recommended to prevent disease-related skeletal related events, including pathological fractures, spinal cord compression, surgery, or radiation therapy to bone'''
*** '''Zoledronic acid should not be used in men with baseline creatinine clearance <30 mL/min'''
*** '''The optimal duration of zoledronic acid and denosumab in CRPC and bone metastases is undefined.'''
**** '''The risk of osteonecrosis of the jaw appears to be related to time on bone-targeted therapy, caution should be taken in using these agents > 2 years'''
*** Denosumab and zoledronic acid are not approved and not indicated for SRE prevention in the treatment of metastatic castration-sensitive prostate cancer or for bone metastases prevention
* '''Other supportive agents'''
** '''Systemic corticosteroid therapy with low-dose prednisone or dexamethasone may also offer improvements in PSA values and/or palliative outcomes in up to 30% of patients in both symptomatic and asymptomatic men.'''
*** '''Steroids may also exert an anti-neoplastic effect on prostate cancer'''

* '''Palliative radiation'''
** '''Should be considered in patients with pain'''
** '''Malignant spinal cord compression is an oncological emergency that requires immediate diagnosis, if suspected, with an MRI. Options for treatment are radiation with (3):'''
**# '''Steroids'''
**# '''Debulking surgery'''
**# '''Vertebrectomy with stabilization'''

===== '''Questions''' =====

# What are the prognostic factors in CRPC?
# What paraneoplastic syndromes are associated with CRPC?
# Which patients with non-metastatic CRPC should be offered treatment in addition to ADT? What are the treatment options?
# Describe the recommended treatment of mCRPC
# What treatment options have OS benefit in those that failed docetaxel?

===== References =====

* Saad, Fred, et al."2021 Canadian Urological Association (CUA)-Canadian Uro Oncology Group (CUOG) guideline: Management of castration-resistant prostate cancer (CRPC)." ''Canadian Urological Association Journal'' 15.2 (2021): E81.