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Guest Commentary: STAMPEDE trial provides exciting results, questions in prostate cancer treatment
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In this guest commentary, Terence Friedlander, MD, discusses the benefits associated with the addition of abiraterone acetate to standard treatment in patients with high-risk advanced prostate cancer and the challenges facing the community, following a presentation of the STAMPEDE trial delivered at the ASCO Annual Meeting by Nicholas James, BSc, MBBS, PhD, from Queen Elizabeth Hospital in Birmingham, United Kingdom. Friedlander is an assistant clinical professor at the division of hematology/oncology at UCSF’s Helen Diller Family Comprehensive Cancer Center.
The reason why the STAMPEDE trial is so exciting is because abiraterone acetate (Zytiga, Janssen) plus prednisone is an oral therapy taken daily that doesn’t involve chemotherapy. While the treatment does have some side effects, they are manageable and do not involve the sort of more serious potential side effects seen with chemotherapy.
In terms of the benefit of adding abiraterone and prednisone to standard androgen deprivation therapy, if we think about even adding one year of life to a single man's survival, that translates into thousands and thousands of cumulative life years saved or improved. So the efficacy of this is exciting. It's also exciting because it starts to shed some more light on the biology of metastatic prostate cancer. For a long time, we have had weaker anti-androgens that didn't clearly add that much benefit when given together with androgen deprivation drugs like bicalutamide and flutamide, which are much older generations. Because abiraterone depletes multiple androgens in the circulation and in the tumor microenvironment, what STAMPEDE showed was that depriving the cancer of any androgen stimulus really does make a difference clinically, and not just in a lab. It might help drive further the next study, which seeks to answer the question: Can we further block hormone therapy in these patients? Will that have further benefit? Maybe, maybe not - maybe we're reaching a limit. That's not so clear. The trial also shows that by treating men with abiraterone and prednisone at the time they are first diagnosed with metastatic disease, even though they can live for years after initial disease progression and after switching to different medications like chemotherapy, we can still really move the bar and provide benefit to patients. That's the most important message coming out of this study.
The STAMPEDE study included more than just men with frankly metastatic disease, in that it also included almost 1000 men with non-metastatic prostate cancer, including some men who had a rising PSA after definitive therapy to the prostate. It appears from the data that there was a survival benefit to using abiraterone plus androgen deprivation therapy in the non-metastatic population; however, the overall number of deaths in this subgroup of patients was rather small, so it is not so clear that this study has changed the standard of care for these non-metastatic patients. With more time we may be able to see more events which may give more statistical confidence in the outcomes. I think figuring out whether to offer abiraterone to men with non-metastatic prostate cancer will be a major point of discussion in the years to come, and eagerly await the follow up data and subset analyses from STAMPEDE to help answer this question.
I think another major challenge now, for the community, is how to think about how to use chemotherapy, docetaxel in particular, in this population of men with hormone sensitive metastatic disease. Both the CHAARTED trial, as well as the docetaxel arm of the STAMPEDE study, both reported at prior ASCO meetings, explored the benefit of adding docetaxel to ADT for men with hormone-sensitive metastatic prostate cancer. Both studies showed a survival benefit and strongly reinforced each other’s findings. Now, in light of the recent abiraterone data, I think a major question is: Does docetaxel still have a role? What would happen if we gave docetaxel followed by abiraterone, or concurrent with abiraterone? Would we get a further benefit? I would like to think the answer is yes, but I'm not going to put my nickel down until we have real prospective data on this. The good news is that there are a number of ongoing studies that are exploring this question, so we will likely have our initial answer in the coming 3 to 5 years. These studies are focusing on the benefit of either abiraterone, or novel high-potency AR-targeting drugs like enzalutamide (Xtandi; Astellas, Medivation), darolutamide, or apalutamide in combination with hormone therapy in this space. Those studies will allow people to receive docetaxel, and some are stratifying by docetaxel use as part of the randomization of the trial design so that there is balance in the docetaxel use between the arms. One study, I believe it's the darolutamide study, is requiring patients to receive docetaxel. There's no study that I'm aware of however that is directly randomizing men to receive ADT + chemotherapy vs. ADT + next-generation AR vs. the combination - which I think is the major question now facing the field, because if there is indeed synergy to using androgen deprivation therapy, next-generation AR targeting therapy, and chemotherapy together in men with newly diagnosed metastatic disease that would be exciting because it would add more years to these men's lives.
Reference:
James N, et al. Abstract LBA5003. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.
Disclosures: Friedlander reports receiving research funding from Janssen and serving on a speaker’s bureau for Astellas.