Treating Metastatic Castrate-sensitive Prostate Cancer: Beyond Androgen Deprivation Therapy
By: Adanma Ayanambakkam, MD, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City | Posted on: 09 Mar 2023
Androgen Deprivation Therapy
Despite a reduction in the overall incidence, the 2004-2018 SEER (Surveillance, Epidemiology, and End Results) data reveal a concerning trend of increase in the incidence of metastatic prostate cancer. It is crucial to understand the disease dynamics and the multitude of treatment options available to manage this issue effectively. Despite the advent of various novel hormonal and chemotherapy options, androgen deprivation therapy (ADT) still has an important role in the treatment of metastatic castrate-sensitive prostate cancer (mCSPC). Both surgical and medical castration are effective ADT methods with their own advantages. Attempts at decreasing toxicity (via intermittent ADT) have been unsuccessful, and continuous ADT is recommended for all patients with mCSPC. The newer gonadotropin-releasing hormone antagonists are an effective ADT method with unique advantages. They do not need a short duration of antiandrogen therapy to prevent a testosterone flare, have a rapid suppression of testosterone levels, and are associated with a decreased risk of cardiovascular disease. Despite the efficacy of ADT, a majority of mCSPC patients eventually develop ADT resistance. Addition of various novel hormonal therapy (NHT) options, like abiraterone, second-generation antiandrogens, and docetax, have been evaluated to improve outcomes in mCSPC.
Table 1. Randomized Controlled Trials Evaluating Doublet and Triplet Therapy in Metastatic Castrate-sensitive Prostate Cancer
|Intervention||Control||Trial||OS||HR (95% CI)|
|ADT + docetaxel||ADT||CHAARTED2||57.6 vs 47.2 mo||0.61 (0.47-0.80)|
|STAMPEDE3||59.1 vs 43 mo||0.81 (0.69-0.95)|
|GETUG-151||58.9 vs 54.2 mo||1.01 (0.75-1.36)|
|ADT + abiraterone||ADT||LATITUDE4||53.3 vs 36.5 mo||0.66 (0.56-0.78)|
|STAMPEDE5||79 vs 46 mo||0.60 (0.50-0.71)|
|ADT + enzalutamide||ADT||ARCHES7||71% vs 57% (4-y OS)||0.66 (0.53-0.81)|
|ENZAMET6||67% vs 57% (5-y OS)||0.70 (0.58-0.84)|
|ADT + apalutamide||ADT||TITAN8||65.2% vs 37.9% (4-y OS)||0.65 (0.53-0.79)|
|ADT + darolutamide + docetaxel||ADT + docetaxel||ARASENS9||62.7% vs 50.4% (4-y OS)||0.68 (0.57-0.80)|
|ADT + abiraterone + docetaxel||PEACE-110||NR vs 4.43 y||0.75 (0.59-0.95)|
|Abbreviations: ADT, androgen deprivation therapy; CI, confidence interval; HR, hazard ratio; NR, not reached; OS, overall survival.|
Table 2. Stratification of Metastatic Castrate-sensitive Prostate Cancer Randomized, Controlled Trial Outcomes Based on Metastatic Burden
|Intervention||Trial||High tumor burden||Low tumor burden|
|OS||HR||OS||HR (95% CI)|
|ADT + docetaxel||CHAARTEDa||51.2 vs 34.4 mo||0.63 (0.50-0.79)||63.5 mo vs NR||1.04 (0.70-1.55)|
|STAMPEDE (C arm)||39.9 vs 35 mo||0.81 (0.64-1.02)||93.2 vs 76.7 mo||0.76 (0.54-1.07)|
|ADT + abiraterone||LATITUDEb||49.7 vs 33.3 mo||0.62 (0.52-0.78)||93.2 vs 76.7 mo||0.76 (0.54-1.07)|
|STAMPEDE (G arm)||49% vs 28% (5-y OS)||0.54 (0.43-0.69)||72% vs 55% (5-y OS)||0.54 (0.40-0.74)|
|ADT + enzalutamide||ENZAMET||55% vs 49% (5-y OS)||0.79 (0.63-0.98)||80% vs 66% (5-y OS)||0.54 (0.39-0.74)|
|ADT + apalutamide||TITAN||NR vs 34 mo||0.57 (0.45-0.73)||NR vs NR||0.76 (0.54-1.07)|
|ADT + abiraterone + docetaxel||PEACE-1||4.1 vs 1.6 y||0.47 (0.30-0.72)||NR vs 2.7 y||0.58 (0.29-1.15)|
|Abbreviations: ADT, androgen deprivation therapy; CI, confidence interval; HR, hazard ratio; NR, not reached; OS, overall survival.
a CHAARTED high-volume definition: visceral metastases, and/or 4 bone metastases (at least 1 outside the vertebral bodies and pelvis).
b LATITUDE high-risk definition: presence of 2 of 3 high risk features (≥3 bone lesions, Gleason score ≥8, or visceral metastases).
Doublet Combination Therapy
Doublet therapy with docetaxel or NHT plus ADT has been proven to be superior to ADT monotherapy. While addition of docetaxel in GETUG-15 demonstrated no overall survival (OS) benefit (HR 1.01),1 CHAARTED demonstrated an OS benefit (13.6 months, HR 0.61).2 Preplanned subgroup analysis revealed that OS benefit with docetaxel (17 months, HR 0.63) was restricted only to patients with high-volume disease (defined as visceral metastases, and/or 4 bone metastases, 1 outside vertebral body or pelvis). STAMPEDE (arm C) refuted the prior data and demonstrated an OS benefit with the addition of docetaxel to ADT (16 months, HR 0.81) irrespective of the metastatic burden.3
LATITUDE demonstrated that abiraterone plus ADT resulted in an OS benefit (16 months, HR 0.66) in high-risk mCSPC.4 High-risk status was defined as the presence of 2 of the 3 features (≥3 bone lesions, Gleason score ≥8, or visceral metastases). Interestingly, STAMPEDE (arm G) demonstrated that doublet therapy with abiraterone was associated with an OS benefit (33 months, HR 0.60) irrespective of the tumor burden.5 Direct randomized comparative analysis of data from the 2 STAMPEDE trial arms indicates that abiraterone is a safe and effective alternative to docetaxel (irrespective of tumor burden). Unlike the first-generation antiandrogens, second-generation antiandrogens have an efficient role in mCSPC. Doublet therapy with enzalutamide resulted in an OS benefit in ENZAMET (HR 0.70)6 and ARCHES (HR 0.66).7 Apalutamide plus ADT was found to be effective in TITAN, with an OS benefit (HR 0.65).8
Triplet Combination Therapy
The incremental benefit of doublet combination therapy (ADT plus chemotherapy or NHT) over ADT has subsequently led to evaluation of triplet combination therapy (ADT plus chemotherapy plus NHT). Concurrent docetaxel and enzalutamide resulted in increased toxicity in ENZAMET,6 but post hoc analysis of ARCHES reveals that sequential enzalutamide after docetaxel was a safe approach, with further data needed to determine efficacy.7 ARASENS demonstrated a significantly longer OS with darolutamide plus ADT and docetaxel (HR 0.68) when compared to ADT and docetaxel.9 Outcome analysis based on tumor burden is still awaited. De novo mCSPC patients on PEACE-1 treated with abiraterone plus ADT and docetaxel demonstrated an OS benefit (HR 0.75) over ADT plus docetaxel.10 Preplanned subgroup analysis reveals that OS benefit was statistically significant in patients with high metastatic burden and immature data to demonstrate a similar benefit in patients with low-burden disease. Based on these data, darolutamide-based triplet therapy has been Food and Drug Administration approved, and both darolutamide- and abiraterone-based triplet therapies feature in the National Comprehensive Cancer Network guidelines (for high-burden mCSPC).
High- and Low-Burden mCSPC
Treatment based on the volume of metastatic disease in mCSPC remains controversial. Table 1 summarizes the important randomized clinical trials in mCSPC, and Table 2 summarizes stratified outcomes based on tumor burden. The high-volume CHAARTED definition and high-risk LATITUDE definition closely resemble a population that has been categorized as high burden. The lack of OS benefit in the CHAARTED and GETUG-15 trials could be attributed to the difference in sample size and proportion of de novo vs recurrent castrate-sensitive prostate cancer (which have varied outcomes). The consistent benefit irrespective of tumor burden in the STAMPEDE trials and other trials establishes the efficacy of doublet therapy in all mCSPC patients. Further clinical data from ARASENS and PEACE-1 will delineate the role of triplet therapy in low-burden mCSPC. While there is no proven role of radiotherapy to the prostate in all mCSPC patients, STAMPEDE demonstrated an 8% improvement in 3-year OS in oligometastatic mCSPC (<5 bone metastases).11 PEACE-1 demonstrated the safety of radiotherapy in the triplet combination as well, but further follow-up is required to determine their clinical significance.
Points to Consider
- Despite the increased sensitivity of prostate-specific membrane antigen positron emission tomography imaging, CT scans and bone scans remain the diagnostic modality of choice to assess disease burden and metastases.
- American Society of Clinical Oncology guidelines recommend against the routine use of bone-modifying agents in mCSPC. Their role is restricted to patients with osteoporosis or high fracture risk.
- Despite their efficacy, NHTs result in increased financial toxicity and a disproportionate impact in older age and Black patients, resulting in medication nonadherence.12
Treatment paradigms of mCSPC have moved beyond ADT monotherapy, and doublet and triplet combination therapies have established themselves as safer and more effective interventions across clinical and quality of life end points. The Figure depicts a proposed treatment algorithm for mCSPC. For all high-burden mCSPC, triplet combination therapy is recommended over doublet therapy (if tolerable). For low-burden mCSPC, triplet combination therapy can be considered in a young, fit individual, with doublet therapy and consideration of radiation to the prostate being an acceptable alternative. Shared decision-making with the patients, financial toxicity of NHTs, and potential clinical trial eligibility will be critical in choosing the right treatment.
- Gravis G, Fizazi K, Joly F, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14(2):149-158.
- Sweeney CJ, Chen Y-H, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737-746.
- James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387(10024):1163-1177.
- Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352-360.
- James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377(4):338-351.
- Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131.
- Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019;37(32):2974-2986.
- Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24.
- Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-1142.
- Fizazi K, Foulon S, Carles J, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet. 2022;399(10336):1695-1707.
- Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353-2366.
- Joyce DD, Sharma V, Jiang DH, et al. Out-of-pocket cost burden associated with contemporary management of advanced prostate cancer among commercially insured patients. J Urol. 2022;208(5):987-996.