Prolonging Overall Survival in Men with mCRPC with New Systemic Therapies - Commentary

In the past 10 years, the number of new treatment options for metastatic castration-resistant prostate cancer (mCRPC) has exploded. Prior to 2010, only one agent – docetaxel – had been shown to extend survival for mCRPC patients. Now, a decade later, we have many such agents beyond docetaxel, including abiraterone, enzalutamide, sipuleucel-T, radium-223, and cabazitaxel. In addition, two other agents have shown significant benefits in other disease settings prior to mCRPC – apalutamide and darolutamide. While all extend survival, in the mCRPC setting the added months of life, on average, range from ~2 to 5. Thus, if all the new agents are added together, it is well over a year of added life. However, can the survival months merely be added together? Alternatively, do you get the biggest bang with the first agents and subsequent agents add little? This is an important unanswered question.

To address this, Francini compared the survival of men with mCRPC seen at the Dana-Farber Cancer Institute between 2004 and 2007 to those seen between 2010 and 2013. The earlier cohort included 318 men while the latter cohort included 272 men. The study can be summed up with the old cliché of good news/bad news. The good news? In more recent years, the risk of death decreased by 41%. This was even better among men who initially presented with de-novo metastatic disease (54% reduced risk of death). The bad news? The overall survival benefit was 0.6 years – roughly 7 months. In short, the added months of survival from the various drugs cannot simply be added together. In this case, 1 plus 1 plus 1 did not equal 3.

Given these real-world data, it is clear that on average, patients do not reap all the benefits from all the drugs available. This may in part relate to cross-resistance. For example, we know that resistance to enzalutamide generally confers resistance to abiraterone and vice versa. However, it also likely speaks to the evolving biology of the tumor as it progresses. The biology of a tumor resistant to next-generation AR targeted drugs (i.e. abiraterone or enzalutamide) is not the same as a treatment-naïve tumor. Indeed, these tumors are likely much more aggressive and resistant to other treatments. Alternatively, if we better understand the biology of these treatment-resistant tumors, we may be able to design new and even more effective treatments. As such, to achieve the best possible outcomes we need to better understand the biology of both treatment-naïve tumors but also post-treatment tumors. In addition, we remain hopeful that combination therapies, which are not the norm in prostate cancer, will prove to be superior to single-agent treatment, analogous to other tumors. Moreover, with one lone exception (sipuleucel-T), we continue to await highly effective immunotherapy for prostate cancer. Finally, perhaps the greatest hope for truly altering the natural history of prostate cancer is to use the same agents earlier in the disease. Indeed, we have seen dramatic survival benefits for men with metastatic castrate-sensitive tumors when treated with the same drugs that have only modest survival benefits in the mCRPC setting. In summary, the paper by Francini highlights that though we have made progress, much work still exists.

Written by: Stephen J. Freeland, MD, Editor-in-Chief, Prostate Cancer and Prostatic Diseases, Cedars-Sinai Medical Center, Los Angeles, California

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