ASCO 2017: Making Androgen Receptor Targeted Therapy Great Again

Chicago, IL (UroToday.com) Dr. Tanya Dorff provided an excellent summary of the preceding 3 abstracts, highlighting the key points and limitations of each of the studies. Regardless of the positive or negative results of each study, each had something we could learn from. Dr. Dorff was able to bring the three together in well-constructed summary presentation.

The three talks all related to treatment of the androgen receptor (AR) and androgen axis in the management of advanced or metastatic prostate cancer (PCa).

Dr. Dorff started off her talk by highlighting the main take-away points from each of the 3 studies.
1) LBA 5003 – STAMPEDE update by James et al – Up-front abiraterone improves overall survival in metastatic prostate cancer.
2) Abstract 5004 – PLATO final by Attard et al – continuining enzalutamide beyond progression wile beginning abiraterone does not improve progression-free survival (PFS)
3) Abstract 5005 – ARMOR3-SV by Taplin et al – current ARV-7 assay doesn’t predict lack of enzalutamide response.

Dr. Dorff then went into a discussion of the concepts and take-home points from each abstract.

Following the introduction of docetaxel and taxane chemotherapy, the introduction of enzalutamide and abiraterone, both of which target the androgen axis at different levels, has revolutionized the management of this disease state. However, over the past few years, there has been an emphasis on moving these therapies earlier and earlier in the natural history of prostate cancer. The hypothesis is that broader, more intense up-front may be address castration-resistant or androgen-insensitive clones that wouldn’t have responded to ADT alone. As we know, docetaxel chemotherapy was established to provide benefit when given up-front in hormone-sensitive prostate cancer, particularly in high-volume metastatic disease.1 Prior to even publishing that trial, the trial to assess abiraterone in a similar role had been initiated and was enrolling. Dr. Dorff notes that a neoadjuvant abiraterone trial had demonstrated some partial and complete responses at the time of radical prostatectomy, which supported the rationale.2

Dr. Dorff next presented the results of the STAMPEDE study assessing abiraterone, but compared the results side-by-side against prior STAMPEDE results assessing docetaxel. While at first glance it may appear that abiraterone was superior (HR 0.63 vs. HR 0.75), there are some important differences between the cohorts. In both groups, the benefit was not evident in subset analysis of the M0 patients. There were much less patients with visceral metastases in the docetaxel study and a slightly different distribution of M0/M1 patients which may account for the differences. Ultimately, all we can say is that both docetaxel and abiraterone appear to be effective, but further studies are needed to determine one is better than the other or if sequencing or coadministration is superior to monotherapy.

Unanswered questions include: comparative cost in exchange for clinical benefit, long-term impact of profound testosterone suppression & glucocorticoid use. Patients on AA+P will be using it for much longer in this setting than in CRPC. Docetaxel continues to be a much cheaper drug, and once 6 cycles are completed, it is no longer administered; abiraterone is taken for at least 2 years.

Next, Dr. Dorff addressed the issue of drug sequencing. In the traditional model for management of advanced prostate cancer, except for ADT, when a medication fails, it is stopped and a new medication is initiated. However, as patients who failed abiraterone or enzalutamide usually failed slowly, it suggested that failure was due to minor clone that grew slowly. As such, maintaining combined suppression would result in better response or delay progression. Unfortunately, this seems to have been proven to be false in this study – but only this particular combination has been effectively proven. We cannot rule out that similar combinations with docetaxel, Radium-223, or other novel agents may not generate benefit.

Lastly, she addressed the ARMOR3-SV results. Her main point, as was the case in Dr. Taplin’s presentation, is that despite being failed clinical study due to patient selection, there was much we could learn about biomarkers in prostate cancer and re-evaluate what we know about ARV-7 role in prostate cancer resistance. Based on Antonarakis et al data,3 we know that ARV-7 expression is associated with Enza and Abi resistance. However, what this study highlighted is that our technology may not be good enough to identify those patients accurately – 42% of patients treated with enzalutamide on this study still had good response, despite being ARV-7 positive. There is much more to be learned about identifying ARV-7s, either by improving the technology or what we consider positive (presence or absence, quantity, temporal transient nature?).

That concluded her nice summary of the three talks, with particularly time and emphasis placed on the late-breaking STAMPEDE results.

Presented By: Tanya Dorff, MD, Keck School of Medicine of University of Southern California, Los Angeles, CA

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Princess Margaret Cancer Centre
Twitter: @tchandra_uromd

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA

REFERENCES:
1. Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, Wong YN, Hahn N, Kohli M, Cooney MM, Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia JA, DiPaola RS. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med. 2015 Aug 20;373(8):737-46. doi: 10.1056/NEJMoa1503747. Epub 2015 Aug 5.
2. Taplin ME, et al. Intense androgen-deprivation therapy with abiraterone acetate plus leuprolide acetate in patients with localized high-risk prostate cancer: results of a randomized phase II neoadjuvant study. J Clin Oncol. 2014 Nov 20;32(33):3705-15. doi: 10.1200/JCO.2013.53.4578. Epub 2014 Oct 13.
3. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, Lotan TL, Zheng Q, De Marzo AM, Isaacs JT, Isaacs WB, Nadal R, Paller CJ, Denmeade SR, Carducci MA, Eisenberger MA, Luo J. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014 Sep 11;371(11):1028-38. doi: 10.1056/NEJMoa1315815. Epub 2014 Sep 3.
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