Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer
Publication Date: April 3, 2023
Last Updated: September 7, 2023
Treatment
Initial Treatment
Recommendation 1.0
(Updated) Docetaxel, abiraterone, enzalutamide, apalutamide, or darolutamide each when administered with ADT, represent five separate standards of care (SOCs) for noncastrate metastatic prostate cancer. With the exception of the triplet therapies of docetaxel plus abiraterone plus ADT and docetaxel plus darolutamide plus ADT, the use of any of these agents in any other particular combination or in any particular series cannot yet be recommended. ( EB , , , S )
615
ANDROGEN DEPRIVATION THERAPY (ADT) PLUS DOCETAXEL
Recommendation 1.1
(Updated) For patients with metastatic noncastrate prostate cancer with high-volume disease (HVD) as defined per CHAARTED (four or more bone metastases, one or more of which is outside of the spine or pelvis, and/or the presence of any visceral disease) who are candidates for treatment with chemotherapy but are unwilling or unable to receive triplet therapy (e.g., due to insurance constraints), docetaxel plus ADT should be offered. ( EB , B , H , S )
Practical Information for Recommendation 1.1: Patients should be made aware that doublet therapy (docetaxel plus ADT) has proven inferior overall survival (OS) compared to triplet therapy, such as abiraterone and prednisone plus docetaxel plus ADT.
615
Recommendation 1.11
(New) For patients with de novo metastatic noncastrate prostate cancer with HVD as defined per CHAARTED who are being offered ADT plus docetaxel chemotherapy, triplet therapy (abiraterone and prednisone plus ADT and docetaxel) should be offered per PEACE-1. Abiraterone and prednisone plus ADT and docetaxel demonstrated significant OS and radiographic progression-free survival (rPFS) benefits compared to ADT and docetaxel alone for patients with HVD. ( EB , B , H , S )
Practical Information for Recommendation 1.11: OS data for patients with low-volume de novo metastatic noncastrate prostate cancer from PEACE-1 are still too immature to justify recommending abiraterone-based triplet therapy (abiraterone and prednisone plus ADT and docetaxel).
615
Recommendation 1.15
(New) For patients with de novo metastatic noncastrate prostate cancer who are being offered ADT plus docetaxel chemotherapy, triplet therapy (darolutamide plus ADT and docetaxel) should be offered per ARASENS. Compared to placebo plus ADT and docetaxel, darolutamide plus ADT and docetaxel demonstrated significant OS benefits, in addition to significantly longer times to castration-resistant prostate cancer, pain progression, first skeletal event, and initiation of subsequent systemic antineoplastic therapy. ( EB , B , H , S )
615
Recommendation 1.16
(New) The recommended regimen for patients with metastatic noncastrate prostate cancer treated with darolutamide, docetaxel and ADT is darolutamide (600 mg as two 300 mg tablets orally with food) twice daily (to a total daily dose of 1200 mg) with ADT. Docetaxel administration (75 mg/m2 ) should begin within 6 weeks of the first dose of darolutamide. Docetaxel should be administered intravenously every 3 weeks for up to six cycles. ( EB , B , H , S )
Practical Information for Recommendations 1.15 and 1.16: Discussions with patients should include the cost of darolutamide treatment compared with other options such as abiraterone.
615
Recommendation 1.2
(Updated) For patients with low-volume metastatic disease (LVD) as defined per CHAARTED who are candidates for chemotherapy, docetaxel plus ADT should NOT be offered due to lack of sufficient evidence. ( EB , B , H , S )
615
Recommendation 1.3
(Updated) For patients with metastatic noncastrate prostate cancer treated with docetaxel, the recommended regimen is 6 doses administered at 3-week intervals at 75 mg/m2 either alone (per CHAARTED) or with prednisolone (per STAMPEDE). ( EB , B , H , S )
Practical Information for Recommendation 1.3:
• The strongest evidence of benefit for docetaxel is for those patients who were diagnosed with de novo metastatic disease or HVD (defined per CHAARTED as four or more bone metastases, one or more of which is outside of the spine or pelvis, and/or the presence of any visceral disease). The criteria apply independent of the presence or absence of nodal disease.
• Patients with metastatic disease who do not fit into these categories should NOT be offered docetaxel. The strength of the evidence to support an OS benefit is not compelling for patients who do not have de novo metastatic disease and/or who do not meet the HVD criteria. Long-term survival data from CHAARTED and a post hoc aggregated analysis of CHAARTED and GETUG-AFU-15 data only showed an OS benefit for patients with HVD and de novo metastases. There was no OS benefit for LVD, irrespective of whether the patients had metastases at diagnosis or after failure of prior local therapy. Clarke, et al re-examined OS by disease burden using STAMPEDE data with longer follow-up, but the analysis had inadequate statistical power (<80%) to detect an OS difference by disease burden if in fact one existed.
• As a chemotherapy agent, docetaxel is associated with somewhat greater toxicity than androgen-targeted therapies (novel hormone therapies), but the treatment course is relatively short (limited to 6 cycles), much less costly and generally covered by insurance, hence reducing the financial toxicity.
• The strongest evidence of benefit for docetaxel is for those patients who were diagnosed with de novo metastatic disease or HVD (defined per CHAARTED as four or more bone metastases, one or more of which is outside of the spine or pelvis, and/or the presence of any visceral disease). The criteria apply independent of the presence or absence of nodal disease.
• Patients with metastatic disease who do not fit into these categories should NOT be offered docetaxel. The strength of the evidence to support an OS benefit is not compelling for patients who do not have de novo metastatic disease and/or who do not meet the HVD criteria. Long-term survival data from CHAARTED and a post hoc aggregated analysis of CHAARTED and GETUG-AFU-15 data only showed an OS benefit for patients with HVD and de novo metastases. There was no OS benefit for LVD, irrespective of whether the patients had metastases at diagnosis or after failure of prior local therapy. Clarke, et al re-examined OS by disease burden using STAMPEDE data with longer follow-up, but the analysis had inadequate statistical power (<80%) to detect an OS difference by disease burden if in fact one existed.
• As a chemotherapy agent, docetaxel is associated with somewhat greater toxicity than androgen-targeted therapies (novel hormone therapies), but the treatment course is relatively short (limited to 6 cycles), much less costly and generally covered by insurance, hence reducing the financial toxicity.
615
ADT PLUS ABIRATERONE
Recommendation 1.4
For patients with high-risk de novo metastatic noncastrate prostate cancer, the addition of abiraterone to ADT should be offered per LATITUDE. ( EB , B , H , S )
615
Recommendation 1.5
For patients with low-risk de novo metastatic noncastrate prostate cancer, ADT plus abiraterone may be offered per STAMPEDE. ( EB , B , H , M )
615
Recommendation 1.6
The recommended regimen for patients with metastatic noncastrate prostate cancer is abiraterone 1,000 mg with either prednisolone or prednisone 5 mg once daily until progressive disease is documented. ( EB , B , H , S )
615
ADT PLUS ENZALUTAMIDE
Recommendation 1.7
(Updated) ADT plus enzalutamide should be offered to patients with metastatic noncastrate prostate cancer including both those with de novo metastatic disease and those who have received prior therapies, such as radical prostatectomy (RP) or radiotherapy (RT) for localized disease. Enzalutamide plus ADT has demonstrated short-term survival benefits (prostate-specific antigen [PSA] progression-free, clinical progression-free, and overall) when compared with ADT alone for patients with metastatic noncastrate prostate cancer as a group per ENZAMET. Enzalutamide also has long-term survival benefits overall, for those with low- or high-volume disease, and those with low- or high-volume disease and no docetaxel use. Per ARCHES, enzalutamide significantly improved time to first subsequent antineoplastic therapy in addition to survival benefits overall and among those with high volume disease, no prior docetaxel and previous use of ADT or orchiectomy. ( EB , B , H , S )
615
Recommendation 1.8
(Updated) The recommended regimen for patients with metastatic noncastrate prostate cancer is enzalutamide (160 mg per day) with ADT. ( EB , B , H , S )
Practical Information for Recommendation 1.8: Discussions with patients should include the cost of enzalutamide treatment compared with other options, such as abiraterone.
615
ADT PLUS APALUTAMIDE
Recommendation 1.9
ADT plus apalutamide should also be offered to patients with metastatic noncastrate prostate cancer, including those with de novo metastatic disease or those who have received prior therapy, such as RP or RT for localized disease per TITAN. ( EB , B , H , S )
615
Recommendation 1.95
(Updated) The recommended regimen for patients with metastatic noncastrate prostate cancer is apalutamide (240 mg per day) with ADT. ( EB , B , H , S )
Practical Information for Recommendations 1.9 and 1.95:
• Patients with metastatic noncastrate prostate cancer previously treated with docetaxel appear to have improved rPFS, but evidence of clinical benefit is not yet conclusive. At 22.7 months, ADT plus apalutamide was associated with significantly longer rPFS and OS compared with ADT plus placebo. A rPFS significant benefit of ADT plus apalutamide was found for most subgroups, including disease volume, Gleason score, and metastasis stage (M0/M1) at initial diagnosis, but was not statistically significant for patients with previous docetaxel use. Long-term results may strengthen the early findings. Median OS among patients previously treated with docetaxel was not reached. Longer follow-up is needed. Apalutamide was FDA-approved for use in the metastatic noncastrate prostate cancer population on September 17, 2019. Discussions with patients should include immature OS results for patients previously treated with docetaxel and the cost of apalutamide treatment.
• Discussions with patients should include the cost of apalutamide treatment compared with other options, such as abiraterone.
• Patients with metastatic noncastrate prostate cancer previously treated with docetaxel appear to have improved rPFS, but evidence of clinical benefit is not yet conclusive. At 22.7 months, ADT plus apalutamide was associated with significantly longer rPFS and OS compared with ADT plus placebo. A rPFS significant benefit of ADT plus apalutamide was found for most subgroups, including disease volume, Gleason score, and metastasis stage (M0/M1) at initial diagnosis, but was not statistically significant for patients with previous docetaxel use. Long-term results may strengthen the early findings. Median OS among patients previously treated with docetaxel was not reached. Longer follow-up is needed. Apalutamide was FDA-approved for use in the metastatic noncastrate prostate cancer population on September 17, 2019. Discussions with patients should include immature OS results for patients previously treated with docetaxel and the cost of apalutamide treatment.
• Discussions with patients should include the cost of apalutamide treatment compared with other options, such as abiraterone.
615
Combination Therapies
Recommendation 2.1
ADT plus abiraterone and prednisolone should be considered for patients with noncastrate locally advanced non-metastatic prostate cancer, rather than castration monotherapy, because of the failure-free survival benefit per STAMPEDE. RT to the primary was mandated in STAMPEDE for patients with newly diagnosed node-negative, non-metastatic disease and encouraged in patients with newly diagnosed node-positive, non-metastatic disease. Failure-free survival (time to the earliest of biochemical failure, DP, or death) was significantly improved for patients with non-metastatic disease treated with ADT plus abiraterone and prednisolone compared with those treated with ADT alone, although ADT plus abiraterone was administered for 2 or less years to patients with non-metastatic disease. ( EB , B , H , S )
615
Recommendation 2.2
In resource-constrained settings where drugs such as abiraterone may not be available, combined androgen blockade using ADT plus a first-generation antiandrogen, such as flutamide, nilutamide, or bicalutamide, may be offered to patients with locally advanced non-metastatic prostate cancer, rather than castration monotherapy based on recent meta-analyses. ( EB , B , H , M )
Practical Information for Recommendation 2.2: For patients with high-risk non-metastatic prostate cancer progressing after RP or RT or both, it is currently unclear whether enzalutamide (160 mg) plus leuprolide, improves metastasis-free survival compared to enzalutamide monotherapy or placebo. Although recruitment is complete for the ongoing phase III EMBARK trial, which is designed to answer this question, results are not yet available. Thus, no recommendation can be made at this time.
615
Early Androgen Deprivation
Recommendation 3.1
Early (immediate) ADT may be offered to patients who initially present with noncastrate locally advanced non-metastatic disease who have not undergone previous local treatment and are unwilling or unable to undergo RT based on evidence in one meta-analysis of a modest but statistically significant benefit in terms of both OS and cancer-specific survival among the larger population of patients with locally advanced non-metastatic disease. ( EB , B , I , M )
Practical Information for Recommendation 3.1:
• Discussions with patients regarding early ADT should include the risk of short- and long-term side effects. Deferred ADT is often preferred by patients who desire to avoid, or at least delay, potential ADT side effects. Consideration should be given to restricting deferred ADT to those patients who are asymptomatic.
• No recommendation can be provided at this time for patients with PSA relapse after local treatment. Although existing studies suggest a potential OS benefit, additional research is needed as such studies were underpowered.
• Discussions with patients regarding early ADT should include the risk of short- and long-term side effects. Deferred ADT is often preferred by patients who desire to avoid, or at least delay, potential ADT side effects. Consideration should be given to restricting deferred ADT to those patients who are asymptomatic.
• No recommendation can be provided at this time for patients with PSA relapse after local treatment. Although existing studies suggest a potential OS benefit, additional research is needed as such studies were underpowered.
615
Intermittent Androgen Deprivation
Recommendation 4.1
Intermittent therapy may be offered to patients with high-risk biochemically recurrent non-metastatic prostate cancer after RP and/or RT based on evidence in meta-analyses of the non-inferiority of intermittent androgen deprivation therapy (IADT) when compared to continuous androgen deprivation therapy (CADT) with respect to OS. This is further supported by evidence from four meta-analyses testing superiority. Low-risk biochemical recurrence after RP is defined as a PSA doubling time >1 year and pathologic Gleason score <8. Low-risk biochemical recurrence after RT is defined as an interval to biochemical recurrence >18 months and clinical Gleason score <8. High-risk biochemical recurrence after RP is defined as a PSA doubling time <1 year or a pathologic Gleason score of 8–10. High-risk biochemical recurrence after RT is defined as an interval to biochemical recurrence <18 months or a clinical Gleason score of 8–10. Active surveillance may be offered to patients with low-risk biochemically recurrent non-metastatic prostate cancer. ( EB , B , H , S )
Practical Information for Recommendation 4.1:
• Although patients with non-castrate de novo metastatic prostate cancer were included in the studies reviewed for this clinical question, alternative SOC therapies with proven survival benefits now exist, as outlined in Recommendation 1.0 to include ADT plus docetaxel, ADT plus abiraterone, ADT plus enzalutamide or ADT plus apalutamide. Similar support for these existing standards of care does not universally exist for patients with LVD and further research is needed. No specific additional recommendation with respect to the use of IADT in the non-castrate metastatic prostate cancer population was possible at this time because IADT has not been studied in combination with additional cytotoxic or hormonal agents in this population.
• Patients considering IADT should be made aware of the potential benefits of IADT associated with the off-treatment intervals, such as reduced treatment side effects, quality-of-life benefits and lower cost. As patients on IADT require close follow-up, they must be motivated to adhere to frequent doctor visits for monitoring, even during off-treatment periods.
• Although patients with non-castrate de novo metastatic prostate cancer were included in the studies reviewed for this clinical question, alternative SOC therapies with proven survival benefits now exist, as outlined in Recommendation 1.0 to include ADT plus docetaxel, ADT plus abiraterone, ADT plus enzalutamide or ADT plus apalutamide. Similar support for these existing standards of care does not universally exist for patients with LVD and further research is needed. No specific additional recommendation with respect to the use of IADT in the non-castrate metastatic prostate cancer population was possible at this time because IADT has not been studied in combination with additional cytotoxic or hormonal agents in this population.
• Patients considering IADT should be made aware of the potential benefits of IADT associated with the off-treatment intervals, such as reduced treatment side effects, quality-of-life benefits and lower cost. As patients on IADT require close follow-up, they must be motivated to adhere to frequent doctor visits for monitoring, even during off-treatment periods.
615
Recommendation Grading
Overview
Title
Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer
Authoring Organization
American Society of Clinical Oncology
Publication Month/Year
April 3, 2023
Last Updated Month/Year
October 1, 2024
Supplemental Implementation Tools
Document Type
Guideline
External Publication Status
Published
Country of Publication
US
Target Patient Population
Patients with prostate cancer
Inclusion Criteria
Male, Adult, Older adult
Health Care Settings
Ambulatory, Home health, Hospital
Intended Users
Nurse, nurse practitioner, physician, physician assistant, social worker
Scope
Management
Diseases/Conditions (MeSH)
D011467 - Prostate
Keywords
recurrent, Metastatic Prostate Cancer, Clinical guidelines, Noncastrate Advanced, Immediate ADT, Intermittent ADT
Source Citation
Virgo KS, et al. Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer: ASCO Guideline Focused Update. J Clin Oncol. 2023 April 3. doi: 10.1200/JCO.23.00155.
Virgo KS, et al. Initial Management of Non-Castrate Advanced, Recurrent or Metastatic Prostate Cancer: ASCO Guideline Update. J Clin Oncol. 2021 January 26. doi: 10.1200/JCO.23.03256.
Supplemental Methodology Resources
Methodology
Number of Source Documents
121
Literature Search Start Date
January 1, 2007
Literature Search End Date
July 1, 2018