Andrew J. Armstrong, MD
PARP inhibitors and immunotherapy agents continue to be investigated in the field of metastatic castration-resistant prostate cancer (mCRPC), and a focus must now be put on optimally selecting patients for these treatments, according to Andrew J. Armstrong, MD.
Multiple phase III trials are ongoing, such as PROfound, which is investigating olaparib (Lynparza) versus physician’s choice of abiraterone acetate (Zytiga) or enzalutamide (Xtandi; NCT02987543). Additionally, immunotherapy agents in combination with standard-of-care agents and PARP inhibitors are also emerging as a possibility in this setting.
Much work is being done with biomarkers to help select patients for such therapies. For example, assays that assess circulating tumor cells, such as the Epic Sciences AR-V7 Test, have shown promise.
Armstrong, a medical oncologist and associate professor of medicine at Duke Cancer Institute, spoke on precision medicine in mCRPC during the 2017 OncLive
State of the Science SummitTM
on Genitourinary Cancers. In an interview during the event, Armstrong discussed emerging treatments and techniques for precision medicine in mCRPC.
OncLive: Please provide an overview of your presentation.
I spoke about men with metastatic disease who have progressed on hormone therapy. Most of the approved drugs in prostate cancer are for these men. These include immunotherapy with sipuleucel-T (Provenge), hormonal therapy with abiraterone acetate, enzalutamide, chemotherapies, and radium-223 dichloride (Xofigo). I am focusing on what we call precision medicine, which is the ability to use biomarkers to help select patients for optimal therapy.
For abiraterone and enzalutamide, there is a wealth of knowledge nowadays about how men develop resistance to those drugs, and how we can possibly predict whether a patient will respond. One of the lead candidates for that is a blood test called the AR-V7 assay. This can [be used in] men before treatment or to make a decision following progression on abiraterone, whether to receive enzalutamide, or, if they are progressing on enzalutamide, whether to receive abiraterone. There is cross resistance between these drugs, and one of the big limitations is that these drugs do not work as well after one another as they do upfront. This test can help select for patients who may be more appropriate for alternative therapies who would be predicted not to respond.
Right now, there are 2 lead candidates for the AR-V7 tests. There is one made by Genomic Health called the Epic Sciences AR-V7 Test, and that is being studied in external validation trials. Right now, we are leading that study. The second test from Johns Hopkins Medicine that is a more RNA-based assay. Both use circulating tumor cells; they have different characteristics in terms of their sensitivity and both are undergoing prospective validation. Neither of these are FDA approved—they are considered research assays at this point. They are not recommended in the NCCN guidelines, but they are one of the hot areas of research right now to help predict the future, as far as drug selection and therapies.
I also talked about other types of therapies that are upcoming. These include immunotherapies, and drugs that work on patients with more hereditary or DNA-repair–deficient prostate cancers.
One of the most important findings of the past year was the identification of a form of hereditary prostate cancer that is in about 10% to 15% of men with mCRPC, depending on the populations that are looked at. These mutations are in homologous repair enzymes; these are DNA repair enzymes. When they are mutated, more mutations happen and this creates a very aggressive form of prostate cancer.
Fortunately, for these men who are predisposed to prostate cancer—particularly aggressive forms of the disease—there are therapies that are particularly effective. They include old drugs, such as platinum-based chemotherapy, but also new drugs, such as PARP inhibitors. We spoke about the evidence supporting their use and biomarkers that are being developed to predict that. These include germline testing and somatic tumor profiling, such as the FoundationOne assay. I spoke about when the appropriate time is to consider molecular profiling for these men, in order to optimally identify a patient for clinical trials for these approaches.
The second approach is immunotherapy. Immunotherapy was labeled the breakthrough of the year in all of oncology in 2015 and 2016. Prostate cancer has yet to reap the benefits of those breakthroughs. We have sipuleucel-T, which is a particularly effective therapy for prostate cancer; however, some of the emerging therapies include immune checkpoint blockade. Immune checkpoint blockade in prostate cancer is effective in a small fraction of men, and developing biomarkers that can identify who will respond is a big area of research.