Anis Hamid, MBBS
Christopher J. Sweeney, MBBS
ANTAGONISM OF THE ANDROGEN AXIS remains a cornerstone of systemic therapy for high-risk localized and metastatic prostate cancer, reflecting the central role of androgen-dependent biologic mechanisms in hormone-naive disease. Despite the use of standard androgen-deprivation therapy, men with metastatic hormone-sensitive prostate cancer almost inevitably experience disease progression. Underlying pathways of resistance to therapy continue to be defined.
What is clear, however, is deep androgen suppression with next-generation agents such as abiraterone acetate (Zytiga) and enzalutamide (Xtandi) is an effective strategy—both before and after docetaxel chemotherapy1-4—in the castration-resistant state. Employing abiraterone earlier in the natural history of metastatic disease echoes the rationale of other trials (CHAARTED5; STAMPEDE6) that have demonstrated significant survival benefits of docetaxel for men with newly diagnosed castration-sensitive prostate cancer at the time of androgen-deprivation therapy commencement.
Clinical Questions Remain
THE LATITUDE TRIAL, recently reported by Fizazi and colleagues,7 demonstrated a 38% decrease in the risk of death with the addition of abiraterone to androgen-deprivation therapy for men with high-risk, newly diagnosed castration-sensitive prostate cancer—a population indeed similar to those with “high-volume” disease in the CHAARTED trial. This tolerable regimen appears consistently effective across the study population subgroups. In establishing a new therapy standard, there remain important questions regarding the clinical applications of proven therapies for this type of prostate cancer as well as areas of focus for ongoing and future investigation.
Whether the benefit of abiraterone for men with castration-sensitive prostate cancer extends to those with lower-risk, low-volume metastatic disease or nonmetastatic disease was not assessed in the LATITUDE trial. However, the concurrently reported data from the STAMPEDE trial8 comparing androgen-deprivation therapy with androgen-deprivation therapy plus abiraterone for castration-sensitive prostate cancer have shed some light on this question.
“The challenges ahead lie in improving outcomes by intelligent therapy combinations and better patient selection informed by a greater understanding of the underlying disease biology.”— Anis Hamid, MBBS, and Christopher J. Sweeney, MBBS
In that study population, overall analysis of both metastatic (52%) and high-risk, nonmetastatic patients (48%, the majority of whom were planned for definitive radiotherapy) showed a clear survival benefit for androgen-deprivation therapy plus abiraterone—of a similar magnitude to that seen in the LATITUDE trial. In the nonmetastatic subgroup, there was a trend for benefit with the addition of abiraterone (hazard ratio [HR] = 0.75, 95% confidence interval = 0.48–1.18) that has not reached statistical significance, due to a low number of death events in both arms at current follow-up (44 vs 34 events). Reports of long-term outcomes will hopefully elucidate whether a clear clinical benefit with more statistical certainty exists. Notably, long-term efficacy data from the CHAARTED trial were presented at the 2016 European Society for Medical Oncology Congress9 and confirmed no significant survival benefit for the addition of docetaxel in patients with low-volume metastatic castration-sensitive prostate cancer (HR = 1.04, P = .86), despite an earlier analysis suggesting a trend toward improvement in overall survival.
Could the benefit of intensification of first-line therapy be limited to those patients with a greater burden of disease with an inherently poorer prognosis? It may well be that potent upfront suppression and/or elimination of clonally aggressive disease in high-risk patients is a key mechanism of the benefit of combination therapy over androgen-deprivation therapy alone. Conversely, in low-volume or nonmetastatic patients, sequential monotherapy may be able to salvage patients with a more indolent disease course. Refined analyses assessing the subgroups independently are needed to answer this question. The current trials do not have the data to answer these question, and it is an extrapolation to apply the results to the unique subgroups of low-volume metastatic disease and M0 patients at this time.
Choosing Between Therapies
ALTHOUGH THE FINDINGS of the LATITUDE and STAMPEDE trials confirm the benefit of combination therapy for high-risk patients, the relative superiority (or lack thereof) of docetaxel vs abiraterone (and vice versa) in this patient population is unclear. Pragmatically, in the absence of randomized trial data, the choice between therapies will necessarily balance access, affordability, tolerability, and overall treatment burden. An individualized approach to therapy selection remains ever important.
Abiraterone plus androgen-deprivation therapy is better tolerated than chemotherapy; however, the duration of treatment is a valid clinical consideration, as are the specific toxicities of abiraterone and prednisone. In addition, the merits of combination therapy with androgen-deprivation therapy plus abiraterone plus docetaxel are unknown, but they may be raised as a consideration for patients with high-volume disease, who are predicted to tolerate the potentially increased toxicities of such triplet therapy. Several studies combining androgen-deprivation therapy and novel hormonal therapies with stratification by use of docetaxel are ongoing and will hopefully provide important insights into the efficacy and tolerability of combining these agents. Mechanistically, combining multiple agents (hormonal and nonhormonal) targeting different pathways of tumor proliferation and survival may lead to more durable tumor suppression and improved survival outcomes.
INVESTIGATING TRANSLATABLE predictive biomarkers of benefit of combination hormonal therapy or chemohormonal therapy will hopefully improve clinical decision-making by moving toward a personalized approach to therapy. In recent years, the rich genomic mutational landscape, both germline and somatic, underpinning advanced castration-resistant prostate cancer has been studied. Correlative studies of metastatic castration-sensitive prostate cancer data sets are underway and will characterize this (likely heterogeneous) disease stage, as well as investigating whether a differential benefit and/or nonbenefit from therapy is driven by underlying genomic variants. Moreover, a greater understanding of androgen receptor-dependent and -independent mechanisms of therapy response and resistance may be a key to informing therapy selection at baseline. In the present and future, designing prospective trials incorporating biomarkers remains a challenge—but one that serves to achieve greater granularity in our endeavors to maximize patient benefit and limit the use of ineffective therapies.
The findings of the LATITUDE and STAMPEDE trials establish androgen-deprivation therapy plus abiraterone and prednisone as an effective treatment standard for castration-sensitive metastatic prostate cancer. The challenges ahead lie in improving outcomes by intelligent therapy combinations and better patient selection informed by a greater understanding of the underlying disease biology. ■
DISCLOSURE: Dr. Hamid reported no conflicts of interest. Dr. Sweeney has been a consultant with compensation for Astellas, Bayer, Genentech, Janssen, Pfizer, and Sanofi; he also has received research funding from Astellas, Janssen, Sotio, and Sanofi.
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6. 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 387:1163-1177, 2016.
7. Fizazi K, Tran N, Fein L, et al: Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med 377:352-360, 2017.
8. James ND, de Bono JS, Spears MR, et al: Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. June 3, 2017 (early release online).
9. Sweeney C, Chen Y-H, Liu G, et al: Long term efficacy and QOL data of chemohormonal therapy in low and high volume hormone naïve metastatic prostate cancer: E3805 CHAARTED trial. 2017 ESMO Annual Congress. Abstract 720.