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 )
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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.
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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).
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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 )
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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.
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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 )
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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.
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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 )
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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 )
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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 )
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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 )
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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.
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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 )
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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.
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Overview
Title
Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer
Authoring Organization
American Society of Clinical Oncology