A predictive biomarker for prostate cancer drug resistance may lead to new drug development opportunities.
At ASCO 2014, one of the prostate cancer highlights was the oral presentation by Emmanuel Antonarakis MB BCh, Assistant Professor of Oncology at Johns Hopkins.
He presented elegant research, albeit in a small group of patients, about how constitutively active splice variants (AR-V’s) may represent one potential mechanism of resistance to androgen receptor (AR) signalling inhibitors such as enzalutamide (Astellas/Medivation) and androgen synthesis inhibitors such as abiraterone (JNJ).
I spoke to Dr Charles Ryan, Professor of Medicine and Urology at the University of California San Francisco (UCSF) about the significance of the data to clinical practice, and the new drug development opportunities that may follow-on from it.
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San Francisco – In the ASCO GU prostate cancer session yesterday morning one of the most interesting presentations was by Andrew J Armstrong, Associate Professor of Medicine and Surgery at the Duke Cancer Institute.
I previously referenced Dr Armstrong’s excellent education presentation at ASCO 2012 in my piece on Xconomy about the emerging challenges of prostate cancer drug development.
He’s a speaker that I particularly enjoy listening to, so my attention was immediately drawn to his presentation at ASCO GU on, “Beyond Enzalutamide and Abiraterone: What’s Next in Androgen Therapy.”
Looking at this title, at first glance the question that comes to mind is do we really need new treatments that target the Androgen Receptor (AR), after all we’ve heard this week about the PREVAIL trial with enzalutamide?
Based on Dr Armstrong’s presentation the answer is a resounding yes!
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At the 2012 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Oliver Sartor, Professor of Cancer Research and Medical Director of the Tulane Cancer Center in New Orleans told attendees in the educational session on castration-resistant prostate cancer (CRPC) that he was tired of being asked the question of what is the optimal sequence for new advanced prostate cancer drugs?
There is “No data,” Sartor told the ASCO 2012 audience. As a result he recommended the use of less toxic therapies first and that patients be involved in the decision making. Not quite the guidance the audience perhaps hoped for.
Sartor is, however, correct that we don’t yet have the data – the clinical trials have yet to be done that will answer the question of what is the optimal sequencing of prostate cancer drugs?
The approval of abiraterone acetate (Zytiga®) for the treatment of men with advanced prostate cancer, post chemotherapy, and the expected approval of enzalutamide (formerly MDV3100) and radium-223 (Alpharadin) have focused attention on sequencing and combination options.
A poster at ASCO 2012 showed that cross resistance may occur between abiraterone and enzalutamide, suggesting that if resistance to one develops it may lower the efficacy to the other if given subsequently. More data and research is needed to validate this finding and understand how resistance develops.
Reciprocal feedback between the PI3-Kinase and androgen receptor (AR) signaling pathways means that blocking the androgen receptor may stimulate the PI3K pathway and vice versa, leading to the tumor trying to ensure its survival. This is particularly important in prostate cancers that have the PTEN tumor suppressor gene, the result is that the targeting of both PI3K and the AR to avoid crosstalk may be required.
The scientific rationale for combining enzalutamide with a PI3-kinase inhibitor was discussed on Pharma Strategy Blog in Sally Church’s video from the 2011 American Urological Association annual meeting. Clinical trials are being planned to investigate the use of PI3-kinase inhibitors in prostate cancer.
I have written more from ASCO 2012 about the emerging challenges in prostate cancer drug development in a guest post published on Xconomy. Many thanks to Luke Timmerman, National Biotech Editor, for the opportunity to contribute.
Hopefully, there will be more insights available at ESMO 2012 later this year and at ASCO next year on prostate cancer drug resistance, optimal sequencing and the benefits that combinations therapies may offer.