SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 164,690 new cases of prostate cancer will be diagnosed in 2018 and 29,430 men will die of the disease. Prostate cancer patients with newly diagnosed radiographic evidence of metastatic disease, either as part of a de novo diagnosis of prostate cancer, or as a manifestation of disease progression from an earlier clinical disease state, are considered to have “clinical metastatic: non-castrate” disease, by Prostate Cancer Working Group, provided that they have testosterone levels in the non-castrate level (more than 50 ng/dL). These patients may or may not have received limited courses of Androgen Deprivation Therapy (ADT) for their earlier clinical states.
The standard therapy for newly diagnosed metastatic non-castrate prostate cancer has been ADT alone. Upon progression, these patients are described as having metastatic Castration Resistant Prostate Cancer (mCRPC). These patients are continued on ADT and are offered additional treatments.
The ASCO multidisciplinary Expert Panel developed this guideline, following a systematic review of all phase III randomized controlled trials and meta-analyses, published from 2015 through October 2017. These studies included men with metastatic non-castrate prostate cancer (testosterone levels more than 50 ng/dL), being considered for treatment with Docetaxel (TAXOTERE®) or Abiraterone (ZYTIGA®), in addition to ADT. The Clinical Practice Guidelines are provided by the American Society of Clinical Oncology, (ASCO) to assist providers in clinical decision making.
This clinical practice guideline addresses the addition of Abiraterone or Docetaxel to Androgen-Deprivation Therapy (ADT) for metastatic prostate cancer, that has not been treated (or has been minimally treated) with testosterone-lowering agents.
Guideline Question: Is there an Overall Survival (OS) advantage associated with the addition of Docetaxel or Abiraterone to Androgen-Deprivation Therapy (ADT) in men with metastatic non-castrate prostate cancer? Other outcomes of interest include Progression-Free Survival (PFS), Failure-Free Survival (FFS), PSA response, Overall Response Rate, and Quality of Life (QOL).
Target Population: Men with metastatic non-castrate prostate cancer being considered for treatment with ADT.
Key Recommendations and Qualifying Statements:
ADT Plus Docetaxel
1) Docetaxel in addition to to ADT should be offered for men with metastatic non-castrate prostate cancer with High-Volume Disease (HVD), who are candidates for treatment with chemotherapy, as the strongest evidence of benefit for Docetaxel is for those men who were diagnosed with de novo metastatic disease or HVD, per CHAARTED study.
2) CHAARTED trial is a randomized phase III trial in which patients with newly diagnosed metastatic prostate cancer, were randomly assigned to receive either Androgen Deprivation Therapy alone or ADT plus Docetaxel. The addition of Docetaxel to ADT significantly prolonged Overall Survival in men with High-Volume Disease.
3) In the CHAARTED study, High-Volume Disease was defined 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 were agnostic to the presence or absence of nodal disease.
4) For patients with Low-Volume Disease (LVD) and who are candidates for chemotherapy, Docetaxel plus ADT may be offered per CHAARTED study. However, the strength of the evidence to support an OS benefit is less compelling for men who do not have de novo metastatic disease and/or who do not meet the HVD criteria. A subset analysis of CHAARTED did not demonstrate a survival benefit for Low-Volume Disease, and the GETUG-15 trial was negative.
5) The appropriate regimen of Docetaxel is 75 mg/m2 every 3 weeks for 6 cycles either alone or with prednisolone.
ADT Plus Abiraterone
1) For men with high-risk, de novo metastatic non-castrate prostate cancer, Abiraterone in addition to ADT should be offered per LATITUDE study.
2) LATITUDE is a randomized, double-blind, placebo-controlled, phase III trial, which evaluated the clinical benefit of adding Abiraterone along with Prednisone to Androgen Deprivation Therapy (ADT), as compared with ADT and placebo, in patients with newly diagnosed, metastatic non-castrate prostate cancer. The addition of Abiraterone to ADT significantly increased Overall Survival and radiographic Progression Free Survival, in this patient group.
3) LATITUDE trial defined high-risk factors associated with a poor prognosis and included at least two of the following three high-risk factors: a Gleason score 8 or greater, 3 or more bone lesions, and presence of measurable visceral disease.
4) For men with lower-risk de novo metastatic non-castrate prostate cancer, Abiraterone may be offered per STAMPEDE study. STAMPEDE trial did not include a high risk definition.
5) LATITUDE and STAMPEDE are mutually supportive for treating high-risk disease with ADT and Abiraterone, with only STAMPEDE furnishing evidence that includes men with lower-risk disease.
6) The appropriate regimen is Abiraterone 1000 mg with either prednisolone or prednisone 5 mg orally once daily, until treatment(s) for mCRPC are initiated.
Docetaxel and Abiraterone
Docetaxel and Abiraterone should be considered as two separate standard treatments for metastatic non-castrate prostate cancer. These two standards have not been compared head to head, and their benefits seem to be quite similar. It is not known which patient subgroups might do better with one standard as opposed to the other and therefore practical factors should be taken into consideration. The use of both standards in combination or in series has not been assessed and therefore cannot be recommended.
In summary, the addition of either Docetaxel or Abiraterone to ADT in men with newly diagnosed metastatic prostate cancer offers a survival benefit, as compared with the use of ADT alone. In the absence of randomized data comparing the addition of Docetaxel versus Abiraterone to ADT in men with metastatic non-castrate disease, additional variables including patient comorbidities, toxicity, QOL considerations, drug availability, and cost will ultimately need to be taken into consideration.
Optimizing Anticancer Therapy in Metastatic Non-Castrate Prostate Cancer: American Society of Clinical Oncology Clinical Practice Guideline. Morris MJ, Rumble RB, Basch E, et al. J Clin Oncol 2018;36:1521-1539.
