SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 248,530 new cases of prostate cancer will be diagnosed in 2021 and 34,130 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second generation anti-androgen agents, which include ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide), ERLEADA® (Apalutamide) and NUBEQA® (Darolutamide). Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis.
This recent ASCO guideline, updates all preceding ASCO guidelines on initial hormonal management of noncastrate advanced, recurrent, or metastatic prostate cancer. This guideline was developed by a multidisciplinary expert panel and recommendations were made based on a systemic review of 4 clinical practice guidelines, 1 endorsement of a clinical practice guideline, 19 systematic reviews, 47 Phase III randomized controlled trials, 9 cohort studies, and 2 review papers.
CLINICAL QUESTION 1: What are the standard initial treatment options for metastatic noncastrate prostate cancer?
Recommendation 1: Docetaxel, Abiraterone, Enzalutamide, or Apalutamide, each when administered with Androgen Deprivation Therapy (ADT), represent four separate Standards of Care 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.
ADT Plus Docetaxel
Recommendation 1.1. For men with metastatic noncastrate prostate cancer with high-volume disease as defined per CHAARTED trial who are candidates for treatment with chemotherapy, the addition of Docetaxel to ADT should be offered.
Recommendation 1.2. For patients with low-volume metastatic disease as defined per CHAARTED trial who are candidates for chemotherapy, Docetaxel plus ADT should NOT be offered.
Recommendation 1.3. 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 trial) or with prednisolone.
ADT Plus Abiraterone
Recommendation 1.4. For men with high-risk de novo metastatic noncastrate prostate cancer, the addition of Abiraterone to ADT should be offered per LATITUDE trial.
Recommendation 1.5. For men with low-risk de novo metastatic noncastrate prostate cancer, ADT plus Abiraterone may be offered per STAMPEDE trial.
Recommendation 1.6. 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.
ADT Plus Enzalutamide
Recommendation 1.7. 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 (RP) or RadioTherapy (RT) for localized disease. Enzalutamide plus ADT has demonstrated short-term survival benefits (PSA progression-free, clinical progression-free, and overall) when compared with ADT alone for men with metastatic noncastrate prostate cancer as a group per ENZAMET trial.
Recommendation 1.8. The recommended regimen for men with metastatic noncastrate prostate cancer is enzalutamide 160 mg per day with ADT.
ADT Plus Apalutamide
Recommendation 1.9. 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 RP or RT for localized disease per TITAN trial.
Recommendation 1.95. The recommended regimen for men with metastatic noncastrate prostate cancer is Apalutamide 240 mg per day with ADT.
CLINICAL QUESTION 2: Are combination therapies such as combined androgen blockade (castration plus a nonsteroidal antiandrogen) better than castration alone, for men with noncastrate locally advanced nonmetastatic prostate cancer?
Recommendation 2.1. ADT plus Abiraterone and prednisolone should be considered for men with noncastrate locally advanced nonmetastatic prostate cancer, rather than castration monotherapy, because of the failure-free survival benefit per STAMPEDE trial. RT to the primary was mandated in STAMPEDE trial for patients with newly diagnosed node-negative, nonmetastatic disease and encouraged in patients with newly diagnosed node-positive, nonmetastatic disease. Failure-Free Survival (time to the earliest of biochemical failure, DP, or death) was significantly improved for patients with nonmetastatic 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 men with nonmetastatic disease.
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 men with locally advanced nonmetastatic prostate cancer, rather than castration monotherapy, based on recent meta-analyses.
CLINICAL QUESTION 3: Does early (immediate) Androgen Deprivation Therapy improve outcomes over deferred therapy for men with noncastrate locally advanced nonmetastatic disease?
Recommendation 3.1. Early (immediate) ADT may be offered to men who initially present with noncastrate locally advanced nonmetastatic 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 Overall Survival (OS) and Cancer-Specific Survival (CSS) among the larger population of men with locally advanced nonmetastatic disease.
CLINICAL QUESTION 4: Is Intermittent Androgen Deprivation Therapy better than continuous Androgen Deprivation Therapy for men with biochemically recurrent nonmetastatic disease?
Recommendation 4.1. Intermittent therapy may be offered to men with high-risk biochemically recurrent nonmetastatic prostate cancer after RP and/or RT based on evidence in meta-analyses of the noninferiority of Intermittent Androgen Deprivation Therapy (IADT) when compared with 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 more than 1 year and pathologic Gleason score less than 8. Low-risk biochemical recurrence after RT is defined as an interval to biochemical recurrence more than 18 months and clinical Gleason score less than 8. High-risk biochemical recurrence after RP is defined as a PSA doubling time less than 1 year or a pathologic Gleason score of 8-10. High-risk biochemical recurrence after RT is defined as an interval to biochemical recurrence less than 18 months or a clinical Gleason score of 8-10. Active surveillance may be offered to men with low-risk biochemically recurrent nonmetastatic prostate cancer.
Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer: ASCO Guideline Update. Virgo KS, Rumble RB, de Wit R, et al. J Clin Oncol 2021;39:1274-1305.