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Should oncologists recommend hormone therapy plus abiraterone for patients with nonmetastatic prostate cancer?
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Yes.
This question is highly clinically relevant, given that the STAMPEDE trial included men with M1 hormone-sensitive prostate cancer, M0N1 hormone-sensitive prostate cancer and M0N0 very high-risk localized disease. In fact, 915 men with nonmetastatic hormone-sensitive prostate cancer were included in this trial. These patients received abiraterone with curative-intent external beam radiotherapy for 2 years, rather than continuously until progression.
Although there is no debate about the merits of abiraterone for men with M1 hormone-sensitive prostate cancer based on the STAMPEDE and LATITUDE trials, the STAMPEDE trial was not powered for subgroup analysis of OS in these nonmetastatic patient populations. In STAMPEDE, 509 men had M0N0 disease and 369 had M0N1 disease — which are sizable numbers — but there are very few mortality events in the nonmetastatic subset, with only 78 deaths. This limits power at this time for definitive analysis of OS.
Based on the data published this year, it appears the HR for OS is similar among men with M0 disease (0.75) as it is among men with M1 disease (0.61), with no statistical evidence of heterogeneity. Men with node-positive disease had a similar HR for survival as node-negative patients (0.61 vs. 0.69), but a breakdown of OS outcomes in each treatment group by M0N0 and M0N1 subsets was not provided and is likely highly underpowered. However, failure-free survival (FFS) — a PSA recurrence-based endpoint — markedly improved among nonmetastatic patients (HR = 0.21), with evidence of a clear improvement in FFS apparent at 85% to 90% 4 years following randomization with abiraterone and ADT, vs. 60% with ADT alone. It is compelling to think that recurrence may be prevented with the use of more potent androgen receptor inhibition in such high-risk or very high-risk men when combined with radiation. Strong preclinical data support androgen receptor in regulating DNA repair and radio-resistance.
Thus, OS data remain immature in the nonmetastatic subset of men in STAMPEDE, and larger dedicated prospective controlled trials of abiraterone and other androgen receptor inhibitors are needed in these men with curative-intent radiation. Such trials are ongoing and should continue. However, the benefits of abiraterone and ADT for 2 years on FFS over time remain compelling and may predict that these studies will improve long-term disease control for these patients. Given the favorable and known toxicity profile of abiraterone, a 2-year course of ADT and abiraterone upfront for some patients with M0N0 or M0N1 disease may prevent the need for indefinite systemic therapy down the road. Thus, after informed discussions, many patients and providers may elect to pursue this course of action if insurers will provide coverage for this approach.
Andrew J. Armstrong, MD, ScM, FACP, is associate professor of medicine and surgery and associate director for clinical research in genitourinary oncology at Duke Cancer Institute. He can be reached at andrew.armstrong@duke.edu. Disclosure: Armstrong reports he is a consultant for and received research funding from Astellas, Bayer, Janssen Pharmaceuticals, Medivation/Pfizer and Sanofi.
No.
The evidence for routine abiraterone use in nonmetastatic disease is incomplete. The LATITUDE study focused on metastatic disease and the STAMPEDE study included a broad section of patients, including those with nonmetastatic disease. Although the observed effect on survival was consistent across all groups as estimated by the HR, the majority of the survival benefit reported reflects the outcomes among patients with metastatic disease. Only 78 patients with nonmetastatic disease had died. That means the CIs — a measure of our certainty that the survival estimates are indeed correct — are wide. The strength of the evidence in that group is quite low and additional data are necessary.
There also are reasons to be concerned about prescribing abiraterone earlier. We do not yet have a full understanding of the side effects and clinical implications of very long-term exposure to these agents. Patients with nonmetastatic disease are frequently asymptomatic and have a relatively long life expectancy; therefore, the safety profile of treatment is an important consideration. Lowering testosterone to extremely low levels for a very long period might result in long-term toxicities that we don’t fully recognize. It took us decades to recognize the long-term adverse consequences of conventional hormonal therapy, such as osteoporosis, potential to accelerate the risk for diabetes and the possibility that it may increase the risk for heart complications. Those issues began to be discussed several decades after routine use of hormonal therapy and gave us pause about the use of hormonal therapy in patients for whom benefits are not well documented.
Abiraterone is a relatively new agent; it is a more potent form of hormonal therapy, and we ought to understand the totality of its long-term benefits and risks before we adopt it routinely for patients who are at relatively low risk for dying of their disease. We should take a closer look at whether one can achieve a similar outcome with later use of abiraterone. We know it extends survival in castration-resistant metastatic disease. We also know it can improve survival in hormone-naive metastatic disease. The STAMPEDE study did not require routine use of abiraterone after disease progression.
Finally, it is worth noting that nonmetastatic is not one disease condition. It includes patients with newly diagnosed localized disease or locoregional disease that has spread to regional lymph nodes. It might include patients with a rising PSA alone as evidence of disease. Each of those subsets of patients faces a unique prognosis and clinical challenges. I would advocate for studies in each of these quite distinct patient populations to fully define the benefits and risks of earlier abiraterone use. The addition of abiraterone to standard hormonal therapy has shown impressive results in newly diagnosed metastatic disease and is a promising strategy that is being studied in earlier disease states. We should concentrate on completing these studies and demand stronger evidence before endorsing the routine use of abiraterone in nonmetastatic disease.
Tomasz M. Beer, MD, FACP, is professor of hematology/medical oncology and deputy director of Oregon Health & Science University Knight Cancer Institute. He can be reached at beert@ohsu.edu. Disclosure: Beer reports he is a consultant for Janssen Pharmaceuticals.