ASCO 2017: Targeting the AR: Biomarkers and Novel Therapeutic Approaches

Chicago, IL ( Dr. Terence Friedlander focused on targeting the androgen receptor (AR), with an emphasis on biomarkers and novel therapeutic approaches. In the setting of metastatic prostate cancer (PCa), androgen deprivation therapy (ADT) remains the standard of care. Cancers that progress despite castration levels of testosterone (testosterone < 20) are considered castration-resistant (CRPC). While the standard treatment since approximately 2004 has been docetaxel chemotherapy, there was growing evidence that re-activation of the androgen axis played a significant role in the development of ADT resistance. With the development of enzalutamide and abiraterone, there has been an influx of new medications that target the AR axis with excellent efficacy.

However, at the end of the day, there remains an approximately 30-40% primary non-response rate to AR targeted therapy. Also, all patients eventually progress on AR targeted therapy – it is not a cure, but merely a temporizing measure.

First, he addresses the role for circulating biomarkers in this context? In his mind, there are four roles:
1) Establish prognosis
2) Predict response
3) Near term (surrogate) endpoint for clinical trials
4) Discovery of new targets

He first discussed Abstract 5015 by HI Scher et al. As background, prior research has found that high baseline circulating tumor cell (CTC) counts correlate with poor prognosis. The CellSearch assay, approved by the FDA to monitor mCRPC, dichotomizes the results into 5+ cells/7.5 mL or <= 4 cells/7.5 mL. While only approximately 50% of men with mCRPC have >5 cells/7.5 mL at baseline, limiting its utility, it can still serve as a surrogate endpoint. In their abstract, Scher et al reanalyzed the COU-AA-301 data (in which abiraterone’s efficacy in post-chemotherapy setting was established). They found that 53% of the 1195 patients had >= 5 CTCs/7.5 mL, and 14% of them converted to <5 CTCs/7.5 mL after therapy. Of note, they did censor any patients for whom CTC data could not be obtained. They found that OS was improved in CTC responders (median OS 17.0 months vs. 7.5 months). Similar findings noted when using cutoff of 1. RECIST responses also correlated to CTC counts. As such, he suggests that this measure may serve as an important early surrogate endpoint for clinical trials, and that a CTC >= 1 vs. <1 may be an equivalently good cutoff.

He then went on discuss Abstract 5016 by Grande et al. which went on to ask whether the detection of AR in cell-free DNA (cfDNA) is associated with enzalutamide resistance. They are conducting this in the context of the PREMIERE study, which is a biomarker assessment (CTCs, ARV7). This utilized 98 patients from 16 hospitals. Of these, 11 patients (or about 12% of patients) were found to have an AR gain. These patients also tended to be older, have a much higher PSA, and higher rate CTC detection. On the waterfall pot, it would appear that patients with this AR gain were more likely to have enzalutamide resistance. Based on this study, we learned that detection of circulating AR cfDNA is associated with worse outcomes, and also supports other studies that show that other biomarkers are all biomarkers of poor outcomes. Few caveats though – cfDNA was only detected in 12% of samples, making it less generalizable. Also, would a composite marker of cfDNA with other biomarkers be better?

Lastly, he goes on to talk about abstract 5017 by Tepley et al. In this study, the authors assess if there is modification of the traditional androgen blockage by periodically causing suprathepeutic levels of AR. They hypothesized that supratherapeutic testosterone levels may inhibit CRPC growth by stabilizing the AR, preventing DNA relicensing, and inducing double-strand breaks. In this phase II study, mostly in good-risk enzalutamide-resistant mCRPC patients (N=30), they assessed PSA response and subsequent enza re-challenge. Patients were treated on bipolar androgen therapy (BAT), in which they were continuously treated with ADT, but intermittently treated with testosterone monthly, during which time they would scan every 3 cycles. This would continue until progression. Enzalutamide would then be used as a re-challenge. Of note, most patients were ECOG 0 and median PSA 39.8. They found that 30% of patients had >50% PSA reduction of 50% and some had durable responses. During retreatment with enzulutamide, almost all the patients had some signal of clinical improvement. While median numbers of BAT tolerated was 6, 13% of patients discontinued due to serious adverse events (NSTEMI and pulmonary emboli). But, QOL scores improved, likely due to testosterone supplementation.

At the end of the day, these are very healthy patients. BAT seems to provide benefit, but we need to better understand the side effect profile of supratherapeutic testosterone. Prospective validation is needed.

Presented By: Terence W. Friedlander, MD, University of California, San Francisco Medical Center, San Francisco, CA

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

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