Questions Loom Over Androgen-Targeting Strategies in Metastatic Prostate Cancer

Robert Dreicer, MD, MS

Targeting androgen receptor (AR) signaling with recently approved agents has improved outcomes for men with metastatic castration-resistant prostate cancer (mCRPC) but significant questions linger about how to tackle resistance to the therapies, whether there is cross-resistance in sequential paradigms, and what predictive biomarkers can be identified.

Those were the key points that Robert Dreicer, MD, MS, associate director for Clinical Research and deputy director of the University of Virginia Cancer Center, stressed during a presentation at the New York GU™: 9th Annual Interdisciplinary Prostate Cancer Congress® and other Genitourinary Malignancies. Physicians’ Education Resource (PER) hosted the conference March 19 in New York City.

“We find ourselves in this time frame of having good, effective antiandrogen agents, but we are trying to refine how best to use them,” said Dreicer.

The modern era of AR targeting began about 5 years ago with the FDA’s approval of abiraterone acetate (Zytiga) in combination with prednisone for patients with mCRPC who have previously received docetaxel. In 2012, abiraterone’s indication was expanded to the prechemotherapy setting, and enzalutamide (Xtandi) gained approval as a second-line therapy.

Dreicer said both agents are well tolerated, demonstrate antitumor activity, bring about PSA declines, promote symptomatic improvement, and provide survival benefits. “What’s not to like?” he asked.

Resistance

Yet Dreicer said that over time patterns of response and resistance have emerged. He said clinicians have observed that not every patient responds to abiraterone or enzalutamide: about one-third of patients will have no response; about one-third will have a modest, medium response for 2 to 3 months; and one-third will have significant benefit. Compounding these therapeutic questions is the onset of resistance to AR-targeting agents.Resistance to abiraterone results from a number of factors including upregulation of CYP17 and other androgen-converting enzymes, upregulation of AR (amplification/overexpression), glucocorticoid-activated AR mutations (when abiraterone is administered with prednisone/dexamethasone), progesterone-activated AR mutations (because abiraterone causes an increase in progesterone levels), and AR splice variants.

Particular interest focuses on the AR splice variant-7 (AR-V7) evaluated by Antonarakis and colleagues.1 AR-V7 is a truncated form of the AR that does not have the ligand-binding domain. Detection of AR-V7 in circulating tumor cells (CTCs) can be used to predict resistance to AR-targeting agents, such as abiraterone or enzalutamide. AR-V7—positive patients treated with either drug had lower PSA response rates and shorter progression-free and overall survival rates than men with negative AR-V7 status.¹

A recently launched study, ARMOR 3-SV², is exploring the AR-V7 splice variant in men with progressive metastatic disease who have received prior androgen deprivation therapy. The men will be randomized to receive either galeterone (2550 mg once daily), a selective small molecule that disrupts AR signaling, or enzalutamide (160 mg once daily).

Galeterone, formerly known as TOK-001, is distinct from other mCRPC therapies in that it combines inhibition of CYP17 lyase, which hampers androgen synthesis, while blocking androgen binding and employing the novel mechanism of increasing AR protein degradation.

Cross-resistance

Dreicer also discussed other mechanisms that suggest resistance to the AR, including the glucocorticoid receptor (GR). Arora et al,³ investigated increased expression of the GR that has potential to explain the development of resistance to enzalutamide in a patient subset. “GR substituted for the AR to activate a similar but distinguishable set of target genes and was necessary for maintenance of the resistant phenotype,” they reported.³The challenge of cross-resistance can develop if the agents are used sequentially, with mounting clinical implications, Dreicer noted.

Noonan et al⁴ reported on outcomes among 30 patients who progressed after being treated with enzalutamide in the phase III AFFIRM study. Patients were subsequently managed with abiraterone/prednisone. Of 27 evaluable patients, the median prior enzalutamide treatment duration was 41 weeks. Subsequent abiraterone/prednisone treatment duration was 13 weeks.

The researchers reported that no objective radiographic responses were observed, and the median time to progression with abiraterone was 15.4 weeks, with a median overall survival of 50.1 weeks. Investigators concluded that abiraterone in this treatment setting resulted in “a modest response rate and brief duration of effect.”

Loriot Y et al⁵ reported on 38 patients who had evidence of progressive disease after treatment with docetaxel and enzalutamide and were subsequently treated with abiraterone/prednisone. Only 3 patients (8%) attained a ≥50% PSA response, with a median PFS of only 2.7 months.

Abiraterone and enzalutamide’s effect following therapy with other agents has also been explored, particularly their effectiveness after taxane administration and the efficacy of taxanes after AR-targeting therapy.

Nadal et al found that patients who had not been treated with docetaxel before enzalutamide therapy had more robust PSA responses compared with those who had received docetaxel (43.2% vs 25.4%, respectively), a longer median time to PSA progression (7.2 months vs 2.6 months, respectively), and a longer median progression-free survival (not reached vs 3.3 months, respectively).⁶ In a retrospective analysis of outcomes among 119 patients, men who received abiraterone before docetaxel (n = 24) had a higher risk of progression than those who had only received docetaxel (n = 95).⁷

Predictive Biomarkers

“There are innumerable, increasingly day-to-day demonstrations of resistance to abiraterone and enzalutamide,” said Dreicer. “It is becoming evident that when you move from one drug to another, the response rate that you might have anticipated in the de novo setting is not evident.”Current management of the patient with mCRPC is based on response to initial androgen-deprivation therapy, the presence or absence of disease-related symptoms, the presence of visceral metastases, and duration of response to initial agent used in subsequent AR-directed therapy.

But at this point in 2016, “we don’t have data to tell us which drug to use, to avoid, or even if we should use non-AR-targeted therapies, such as radium-223 or taxanes,” said Dreicer. “We are approaching a biomarker-driven environment, but I don’t think we’re quite there yet.”

Clinical decisions will be based on the interpretation of symptoms, he said, and that could include noting “in new patients, a drop in PSA levels suggesting a patient who may be less AR responsive.” He also noted that studies involving prechemotherapy data for both abiraterone and enzalutamide, which are important outcomes, don’t provide information about exactly when a patient should be treated. “How you make these clinical decisions should be informed by these symptoms,” he said.

Dreicer was hopeful, however, about the eventual emergence of predictive biomarkers, in combination with prospective data from randomized trials, which would better enable optimal management of patients with mCRPC.

References

1. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371(11):1021-1038.
2. NIH Clinical Trails registry. ClinicalTrials.gov Identifier: NCT02438007.
3. Arora VK, Schenkein E, Murali R, et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell. 2013;155(6):1309-1322.
4. Noonan KL, North S, Bitting RL, et al. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol. 2013;24(7):1802-1807.
5. Loriot Y, Bianchini D, Ileana E, et al. Antitumor activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100). Ann Oncol. 2013;24(7):1807-1812.
6. Nadal R, Zhang Z, Rahman H, et al. Clinical activity of enzalutamide in docetaxel-naïve and docetaxel-pretreated patients with metastatic castration-resistant prostate cancer. Prostate. 2014;74(15):1560-1568.
7. Schweizer MT, Zhou XC, Wang H, et al. The influence of prior abiraterone treatment on the clinical activity of docetaxel in men with metastatic castration-resistant prostate cancer. Eur Urol. 2014;66(44):646-652.

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