The androgen receptor pathway … this morning in San Francisco


So today’s early morning session of the GU Oncology meeting was highly focused on the evolution of newer therapies affecting the androgen receptor pathways in the treatment of advanced and progressive forms of prostate cancer.

Dr Peter Nelson of the Fred Hutchinson Cancer Research Center in Seattle, WA, provided us with a thorough overview of the role of the androgen receptor pathways and their relevance to the evolution of differing forms of late stage disease, which can be affected by many specific factors, often driven by the genomics and epigenetics of the specific subforms of prostate cancer evident in a specific individual.

Speaking on behalf of Dr. Geoff Rosenfeld, who was unable to attend the meeting at the last minute, Dr Christopher Evans of the Davis Comprehensive Cancer Center at the University of California Davis in Sacramento, then talked about potential places where new forms of intervention (based on so-called “long, non-coding” forms of ribonucleic acids”) may, perhaps, be used to “manage” the ways in which prostate cancer is treated once traditional forms of androgen deprivation therapy (ADT) have failed … but we have some way to go before we have clear data on the effectiveness of these types of treatment, and they would need to be very highly targeted to very highly defined groups of patients.

Dr. Howard Sandler reviewed the historic data on combinations of radiation therapy with ADT (and of surgery + ADT) and then discussed evolutions in the potential to combine radiation and/or surgical treatment with some of the newer agents (e.g., abiraterone acetate and enzalutamide). He made the point that, historically, combining ADT with surgery had been relatively unsuccessful, whereas it had clearly had value in the treatment of men with high-risk, locally advanced forms of prostate cancer. But he made the additional point the evolving data suggest that new combinations of drugs like abiraterone and enzalutamide with surgicy and radiotherapy might be very helpful when used early for carefully selected patients initially diagnosed with high-risk, localized prostate cancer. The problem is going to be to prove this type of efficacy in large trials, and most ongoing trials (as well as trials that have already reported) are very small, Phase II studies.

Dr. Andrew Armstrong of Duke University, in a talk titled “Beyond enzalutamide and abiraterone,” then gave us an overview of evolutions in the development of newer drugs for the treatment of late stage prostate cancer by inducing new effects on the androgen pathways. There is a whole spectrum of such products in the very early stages of development. It can only be hoped that some of these agents will prove to have levels of effectiveness at least as high as abiraterone acetate and enzalutamide … but results leading to new drug approvals may be a few years away yet.

“Last but by no means least” (to quote one of the session co-chairpersons), Dr. Tomasz Beer presented the full results of the PREVAIL trial, which we have already mentioned several times before. There were few really new data in his presentation, but there are a couple of additional key points that are worthy of mention:

  • Enzalutamide was clearly just as effective in the prevention of progression of visceral (“soft tissue”) metastases as in preventing the progression of bone metastases.
  • Although we have no directly comparable data for similar patients treated with either abiraterone acetate + prednisone or enzalutamide alone, Dr Beer clearly felt that selection of the most appropriate form of first-line treatment for chemotherapy-naive patients newly diagnosed with metastatic, castration-resistant prostate cancer (mCRPC) needed to be made on the basis of individual patient characteristics and that it would be inappropriate to insist on initial treatment with either abiraterone acetate + prednisone prior to enzalutamide or the opposite (enzalutamide prior to abiraterone acetate + prednisone) s any form of “step therapy”.

This latter matter is something that the drugs’ manufacturers will need to sort out with the payer community. It is quite clear that, for some patients, one form of therapy should be preferred initially to the other (e.g., in men with visceral disease, who should clearly get enzalutamide first, whereas men with a history of seizures are probably more appropriately treated with abiraterone acetate + prednisone). It could be a serious problem for some patients if price alone were to drive these decisions.

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