Initial Treatment

• Docetaxel, abiraterone, enzalutamide, or apalutamide, each when administered with ADT, represent four separate standards of care (SOCs) for noncastrate metastatic prostate cancer. The use of any of these agents in any particular combination or in any particular series cannot yet be recommended (Strong Recommendation; EB-B-N/A).

Androgen Deprivation Therapy (ADT) Plus Docetaxel

• For men with metastatic noncastrate prostate cancer with high-volume disease (HVD) as defined per CHAARTED who are candidates fortreatment with chemotherapy, the addition of docetaxel to ADT should be offered (Strong recommendation [for patients with HVD]; EB-B-H).

• For patients with low-volume metastatic disease (LVD) as defined per CHAARTED who are candidates for chemotherapy, docetaxel plus ADT should NOT be offered (Strong recommendation [for patients with LVD]; EB-B-H).

• The recommended regimen of docetaxel for men with metastatic noncastrate prostate cancer is six doses administered at 3 week intervals at 75 mg/m² either alone (per CHAARTED) or with prednisolone (per STAMPEDE) (Strong Recommendation; EB-B-H).

• The strongest evidence of benefit for docetaxel is for those men 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.
• Men with metastatic disease who do not fit into these categories should not be offered docetaxel. The strength of the evidence to support an overall survival (OS) benefit is not compelling for men 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 men 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., reexamined OS by disease burden using STAMPEDE data with longer follow-up, but the study was inadequately powered (< 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 such as abiraterone, but the treatment course is relatively short, and the costs associated with treatment are generally covered by insurance, hence reducing the financial burden to the patient.

ADT Plus Abiraterone

• For men with high-risk de novo metastatic noncastrate prostate cancer, the addition of abiraterone to ADT should be offered per LATITUDE (Strong recommendation [for patients with high-risk disease as defined per LATITUDE]; EB-B-H).

• For men with low-risk de novo metastatic noncastrate prostate cancer, ADT plus abiraterone may be offered per STAMPEDE (Moderate recommendation; EB-B-H [for patients with low-risk disease per STAMPEDE]).

• The recommended regimen for men with metastatic noncastrate prostate cancer is abiraterone 1,000 mg with either prednisolone or prednisone 5 mg once daily until progressive disease is documented (Strong recommendation; EB-B-H).

ADT Plus Enzalutamide

• ADT plus enzalutamide should be offered to men with metastatic noncastrate prostate cancer including both those with de novo metastatic disease and those who have received prior therapies, such as radical prostatectomy or radiotherapy for localized disease. Enzalutamide plus ADT has demonstrated short-term survival benefits (PSA progression-free, clinical progression-free, and overall) when compared to ADT alone for men with metastatic noncastrate prostate cancer as a group per ENZAMET (Strong recommendation; EB-B-H).

• The recommended regimen for men with metastatic noncastrate prostate cancer is enzalutamide (160 mg per day) with ADT (Strong recommendation; EB-B-H).

• Among the subgroup of men with metastatic noncastrate prostate cancer previously treated with docetaxel, it is currently unclear whether similar survival benefits accrue long term when compared to treatment with first-generation antiandrogens plus ADT since the final trial results for ENZAMET and ARCHES are not yet available, though it is anticipated that the long-term results will confirm the early findings. Early results (14.4 months median follow-up) from the ARCHES trial show that the risk of radiographic disease progression or death was significantly reduced with ADT plus enzalutamide versus ADT plus placebo overall as well as for pre-specified subgroups, such as prior docetaxel versus no prior docetaxel and high-volume disease versus low-volume disease. In the ENZAMET trial at 34 months, none of the planned planned subgroup analyses for heterogeneity, as among those receiving early docetaxel, were significant after adjusting for multiple comparisons. Enzalutamide was FDA approved for use in the metastatic noncastrate prostate cancer setting on December 16, 2019. Discussions with patients should include the lack of data regarding long-term benefits and the cost of enzalutamide treatment compared to other options such as abiraterone.

ADT Plus Apalutamide

• ADT plus apalutamide should also be offered to men with metastatic noncastrate prostate cancer, including those with de novo metastatic disease or those who have received prior therapy, such as radical prostatectomy or radiotherapy for localized disease per TITAN (Strong recommendation; EB-B-H).

• The recommended regimen for men with metastatic noncastrate prostate cancer is apalutamide (240 mg per day) with ADT (Strong recommendation; EB-B-H).

• Men with metastatic noncastrate prostate cancer previously treated with docetaxel appear to benefit with respect to radiographic progression-free survival, but the answer is not yet conclusive. At 22.7 months, ADT plus apalutamide was associated with significantly longer radiographic progression-free survival (rPFS) and OS compared to ADT plus placebo. The effect of ADT plus apalutamide on rPFS was consistently favorable and statistically significant for most subgroups, including disease volume, Gleason score and metastasis stage (M0/M1) at initial diagnosis, but not previous docetaxel use (favored ADT plus apalutamide but was not statistically significant). It is anticipated that the long-term results will confirm the early findings. Median OS among men previously treated with docetaxel could not yet be estimated. Longer follow-up is needed. Apalutamide was FDA approved for use in the metastatic noncastrate prostate cancer population as of September 17, 2019. Discussions with patients should include the lack of long-term benefit data for men previously treated with docetaxel and the cost of apalutamide treatment.

Combination Therapies

• ADT plus abiraterone and prednisolone should be considered for men with noncastrate locally advanced non-metastatic prostate cancer, rather than castration monotherapy, due to the failure-free survival benefit per STAMPEDE. Radiotherapy 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, disease progression, or death), was significantly improved for patients with non-metastatic disease treated with ADT plus abiraterone and prednisolone compared to those treated with ADT alone, even though ADT plus abiraterone was administered for two or less years to men with non-metastatic disease (Strong recommendation;  EB-B-H).

• 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 men with locally advanced non-metastatic prostate cancer, rather than castration monotherapy based on recent meta-analyses. (Moderate recommendation;  EB-B-H).

• For men with high-risk non-metastatic prostate cancer progressing after radical prostatectomy or radiotherapy or both, it is currently unclear whether enzalutamide (160 mg) plus leuprolide improves metastasis-free survival compared to enzalutamide monotherapy or placebo. Though 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.

Early Androgen Deprivation

• Early (immediate) ADT may be offered to men who initially present with noncastrate locally advanced non-metastatic disease who have not undergone previous local treatment and are unwilling or unable to undergo radiotherapy based on evidence in one meta-analysis of a modest but statistically significant benefit in terms of both overall survival and cancer-specific survival among the larger population of men with locally advanced non-metastatic disease. (Moderate recommendation; EB-B-I).

• 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 men with PSA relapse after local treatment. Although existing studies suggest a potential overall survival benefit, additional research is needed since such studies were underpowered.

Intermittent Androgen Deprivation

• Intermittent therapy may be offered to men 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 overall survival. This is further supported by evidence from four meta-analyses testing superiority. Low-risk biochemical recurrence after radical prostatectomy is defined as a PSA doubling time > 1 year and pathologic Gleason score < 8. Low-risk biochemical recurrence after radiotherapy is defined as an interval to biochemical recurrence > 18 months and clinical Gleason score < 8. High-risk biochemical recurrence after radical prostatectomy is defined as a PSA doubling time < 1 year or a pathologic Gleason score of 8–10. High-risk biochemical recurrence after radiotherapy is defined as an interval to biochemical recurrence < 18 months or a clinical Gleason score of 8–10. Active surveillance may be offered to men with low-risk biochemically recurrent non-metastatic prostate cancer (Strong recommendation; EB-B-H).

• Although men with noncastrate de novo metastatic prostate cancer were included in the studies reviewed for this clinical question, alternative standard of care therapies with proven survival benefits now exist, as outlined in Recommendation 1 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 men with LVD or those who develop M1 disease after prior local therapy, and further research is needed. No specific additional recommendation with respect to the use of IADT in the noncastrate 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.

Figure 1. Patients with Noncastrate Recurrent, Advanced, or Metastatic Prostate Cancer