Guest Commentary: Resistance to androgen-targeting agents highlights unmet need in prostate cancer
In this guest commentary, Leonard J. Appleman, MD, PhD, of the division of hematology/oncology at the University of Pittsburgh Medical Center Hillman Cancer Center, discusses unanswered questions about the use of newer androgen-targeted agents following the presentation of the LATITUDE and STAMPEDE trials at the ASCO Annual Meeting.
There was a lot of important news about prostate cancer presented at the ASCO Annual Meeting. In particular, two abstracts highlighted an important theme: an unmet need in the treatment of the most aggressive prostate cancers that have metastasized and are resistant to some of our newer therapies. We heard a lot about the LATITUDE and STAMPEDE trials at the meeting, which demonstrated the incredible benefit of the androgen-targeting agents such as abiraterone. In those trials, even in patients with newly diagnosed, metastatic prostate cancer, we’ve known for several years now how helpful those agents have been in patients who have become refractory to initial androgen deprivation therapy.
The problem we face in the clinic is that all patients eventually develop resistance, even to this new generation of agents that are having such a huge impact. Fortunately, there is important clinical science being done to develop new treatments for these patients, including two trials that were presented at this year’s meeting.
In the ARMOR3-SV study, Mary-Ellen Taplin, MD, of Dana-Farber Cancer Institute and Harvard Medical School, and colleagues looked for circulating tumor cells that carried the androgen receptor-V7 (AR-V7) mRNA splice variant of the androgen receptor in patients with metastatic, castration-resistant prostate cancer. We believe this variant allows the prostate cancer cells to signal through the androgen receptor regardless of the presence of any anti-androgen agents at all, based on work from Emmanuel S. Antonarakis, MBBCh, and colleagues from Johns Hopkins University Medical School, as well as other groups. Dr. Taplin’s presentation emphasized the critical unmet need for new therapies for these patients, because, when the AR-V7 variant is present, it’s very hard to control the androgen receptor in these patients.
In the PLATO study, Gerhardt Attard, MD, PhD, clinician scientist at The Institute of Cancer Research and consultant medical oncologist at The Royal Marsden NHS Foundation Trust in London, and colleagues examined patients who had become resistant to enzalutamide, another androgen-targeted, second-generation drug. The researchers examined how men with metastatic, castration-resistant prostate cancer respond to treatment with continued enzalutamide plus abiraterone and prednisone or abiraterone and prednisone alone.
The groups did equally well, with a median PFS of 5.7 months among patients who received continued enzalutamide plus abiraterone and prednisone and 5.6 months for patients treated with abiraterone and prednisone alone. This work, which was done in a randomized, definitive way, reinforces and confirms our clinical experience and the reports from many single-institution studies demonstrating that, once patients’ cancers become resistant to one of those highly potent, second-generation drugs, it’s hard to get much benefit and long durability of benefit using another highly potent drug that targets the androgen pathway. In these situations, physicians must consider moving on to treatment with docetaxel, radium-223 or other agents that have shown a survival benefit in this setting but that may increase toxicity.
Both the ARMOR3-SV and PLATO studies have shown that, while we’re really excited about the new results with abiraterone from STAMPEDE and LATITUDE, we have a lot of work to do for patients whose cancers have become resistant to this new generation of androgen-targeted agents. This work needs to start with a better understanding of the molecular mechanisms of resistance as well as a lot of new drug development to target these mechanisms of resistance. I am hopeful that, in the next few years, we’ll start to see new research that addresses these questions and can help this group of patients.
Attard G, et al. Abstract 5004. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.
Taplin ME, et al. Abstract 5005. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.
Disclosures: Appleman reports that he receives research funding through his institution from Astellas, Cougar Biotechnology, Johnson and Johnson, Medivation, Inc. and Tokai Pharmaceuticals.