Precision Medicine in mCRPC

Insights From: Emmanuel S. Antonarakis, MBBCh, Johns Hopkins Medicine; Andrew J. Armstrong, MD, MSc, Duke Cancer Center; Howard I. Scher, MD, Memorial Sloan Kettering Cancer Center


Andrew J. Armstrong, MSc: In liquid biopsies, a lot of information can be obtained, just like a metastatic biopsy. The AR-V7 test is one piece of that information derived from the AR variance, either protein or RNA expression. But there’s a wealth of additional genomic information in the blood through these cell-free DNA assays, circulating tumor plasma assays, and circulating tumor cell assays. Some of the most compelling data in prostate cancer are the DNA repair defects. And about 10% to 20% of men have germline or somatic mutations in BRCA1, ATM, BRCA2, and other homologous repair enzymes.

These patients tend to have remarkable responses to platinum-based chemotherapy or PARP inhibitors. And there are about 4 or 5 PARP inhibitors really positioning themselves for approval in this space. A liquid biopsy would be a noninvasive way of getting a patient on a clinical trial right now and for deciding eventually in the clinic whether a patient can benefit from these, assuming that they get approved.

The other novel approach to treating men with prostate cancer is through immunotherapy, and right now, we don’t have a great biomarker for predicting who responds to immunotherapy. And a liquid biopsy approach really has some potential promise there, where the number of mutations and the genomic complexity of a tumor sample—whether a circulating tumor cell expresses immune checkpoints—are all avenues of ongoing research to see if we can predict which prostate patient responds to immunotherapy.

A number of other biomarkers can be ascertained in the liquid biopsy through cell-free DNA sequencing. If I have 100 patients with prostate cancer, every one of those patients’ profiles is genomically different. So, understanding their individual mutations, which oncogenes are turned on, and which tumor suppressors are turned off, that’s going to be unique and that will foster precision medicine approaches for these patients.

Bone-targeted agents, right now in the clinic, are radium, denosumab, and zoledronic acid. The vast majority of patients tend to benefit from these in terms of preventing skeletal events, fracture, and pain and improving survival, particularly with radium-223. There is a need to really stratify patients based on response. Some of the bone markers in the circulation can help with that. For example, alkaline phosphatase is a bone marker that tends to be associated when elevated with a greater benefit with radium.

Right now, these bone-targeted therapies are used widely without a predictive biomarker and there are ongoing efforts to really quantify using a liquid biopsy, whether a bone marker or a bone pattern of spread is going to be predictive of these bone-targeted therapies. This is an area of active research.

I can imagine 5 or 10 years from now, a patient walks in the door with hormone-resistant disease and instead of a biopsy, they get a liquid biopsy. It’s a blood draw. It’s a noninvasive test. They’ve already had their prostate biopsy; they know what that’s like and they don’t want another biopsy where a needle is stuck into their bone or liver or lungs. Those are invasive tests, and they’re very hard to do repeatedly over time, as opposed to a blood draw where this can be easily done and you can monitor the evolution of the cancer during the selective pressure of your treatment at multiple different time points. Cancer changes both in space and time and within patients and between patients. And so, the liquid biopsy approach is really changing how we treat all sorts of different cancer types, particularly prostate cancer.

Transcript Edited for Clarity
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