Posted 6/29/2013 12:37 PM (GMT -6)
Sorry about that...I think it's more of a study on the sequence...not the combination of the two:
Cross-Resistance With Novel Androgen Blockers in Prostate Cancer
Zosia ChusteckaJun 28, 2013
There might be some cross-resistance between the 2 new androgen-blocking drugs for prostate cancer, despite their different mechanisms of action. It appears that abiraterone (Zytiga) is less active when it is given after enzalutamide (Xtandi), according to 2 new studies.
In addition, there are some data to suggest that docetaxel (Taxotere), which is a cornerstone of the treatment of castration-resistant prostate cancer (CRPC), might be less effective when given after abiraterone.
The "equation may be very complicated," write Amir Goldkorn, MD, and David Ian Quinn, MBBS, PhD, FRACP, from the University of Southern California Norris Comprehensive Cancer Center in Los Angeles, and Ana Aparicio, MD, from the Department of Genitourinary Oncology at the University of Texas M.D. Anderson Cancer Center in Houston, in an editorial published in the July issue of the Annals of Oncology.
Clinicians involved in making treatment decisions in this clinical setting could be left "pondering the opportunity cost of starting with one agent and keeping the others until later," they note.
Different Mechanism of Action
The 2 agents are both hormonal agents but have different mechanisms of action; abiraterone inhibits androgen synthesis, whereas enzalutamide blocks androgen receptors.
Both of these drugs were tested in clinical trials of CRPC patients who had already received docetaxel (the COUGAR 301 trial of abiraterone and the AFFIRM trial of enzalutamide). Those data led to the approval of the agents for use in CRPC patients who had received docetaxel. The US Food and Drug Administration (FDA) approved abiraterone for this indication in April 2011 and approved enzalutamide in August 2012.
Both drugs were then investigated in CRPC patients who had not previously been treated with docetaxel (the COUGAR 302 trial of abiraterone and the PREVAIL trial of enzalutamide). Data from COUGAR 302 led to FDA approval in December 2012 of abiraterone for CRCP patients not previously treated with docetaxel. The enzalutamide trial is still ongoing.
In all of these clinical trials with the 2 drugs, an enrolment criterion was that the patients had not been previously treated with the other novel agent.
So the issue of whether one mechanism of inhibiting the androgen receptor axis followed by the other has an effect on the response to the second agent has not been addressed, until now, the editorialists note.
New Data on Sequential Use
The publication of 2 studies in the July issue of the Annals of Oncology provides such an opportunity. In both, patients with CRPC were treated with docetaxel and enzalutamide, and then went onto receive treatment with abiraterone.
In the French study, Yohann Loriot, MD, from the Department of Cancer Medicine at the Institute Gustave Roussy in Villejuif, France, and colleagues report on 38 such patients.
Of the 38 patients, a reduction in prostate-specific antigen (PSA) level of at least 50% was achieved by 3 patients, and a reduction of at least 30% was achieved by 7. Of the 12 patients who could be radiologically assessed, only 1 achieved a confirmed partial response.
The researchers conclude that abiraterone has a modest effect in patients with CRPC who have been previously treated with docetaxel and enzalutamide.
In the Canadian study, Krista Noonan, MD, and colleagues from the Department of Medical Oncology at the BC Cancer Agency in Vancouver, British Columbia, Canada, and colleagues report data on 30 patients.
Of the 30 patients, a reduction in PSA level of more than 30% was achieved by 3 patients, 2 of whom had PSA progression as a best response.
"In this study of patients progressing after enzalutamide, treatment with abiraterone was associated with a modest response rate and brief duration of effect," they conclude.
These 2 studies "lead us to presuppose that abiraterone will be less active after enzalutamide, but not in every patient," write the editorialists.
There were some recorded responses to abiraterone in patients with early resistance to enzalutamide. But overall, the PSA responses in the patients who received abiraterone after enzalutamide are lower than those seen in studies in which patients receive abiraterone after placebo.
"The modest response to abiraterone in patients previously treated with enzalutamide may be mediated by mechanisms of cross resistance," the editorialists note. They add that this "emergence of cross-resistance underscores the need for determining the optimal sequencing of novel agents."
The question of how these drugs will fare when given in the opposite sequence — abiraterone followed by enzalutamide — is being addressed now, as data accumulate from the enzalutamide expanded-access program. Because abiraterone was approved first and because it is approved for use before docetaxel, up to 80% of the patients now entering enzalutamide expanded-access programs will have been previously treated with abiraterone, the editorialists note.
More data are needed, as are predictive biomarkers to help with the selection of patients who will benefit from a second-line therapy, they conclude.
Ann Oncol. 2013;24:1717-1720, 1802-1807, 1807-1812. Editorial, Canadian Abstract, French Abstract