Dr. Berchuck Discusses Androgen Indifferent Prostate Cancer

Jacob Berchuck, MD, Genitourinary Medical Oncologist, Dana-Farber Cancer Institute, Instructor in Medicine, Harvard Medical School, discusses a recent study, Clinical considerations for the management of androgen indifferent prostate cancer. This is part one in a two-part interview.

GU Oncology Now: What are the key takeaways from the study?

Dr. Berchuck: We recently published a review article on the clinical considerations of management of androgen in different prostate cancer, such as neuroendocrine prostate cancer. The majority of our drugs for advanced prostate cancer work by blocking androgen receptor signaling, but with increased use of these drugs, we’ve seen a increasing number of men develop androgen indifferent prostate cancer, as a resistance mechanism to these therapies. We have the best estimates for neuroendocrine prostate cancer, which seems to arise in about one in six, to one in 10 men with metastatic castration resistant prostate cancer. Detecting these androgen indifferent prostate cancer variants has important clinical implications.

First is that they’re often associated with poor outcomes, shorter overall survival, and worse response to antigen receptor signaling inhibitors, such as Abiraterone or Enzalutamide. Second is that they seem to respond to non-traditional prostate cancer therapies. The standard of care treatment for neuroendocrine prostate cancer, for example, is Etoposide plus platinum chemotherapy, which is extrapolated from the small cell lung cancer literature, and is not a chemotherapy regimen we would typically use in prostate cancer.

And finally, as our understanding of these prostate cancer variance is expanded, there are several ongoing clinical trials investigating targeted therapy and immunotherapy approaches in these patients. And so I think maximizing survival for men with advanced prostate cancer is going to require a precision medicine approach, which will include defining consensus criteria for these prostate cancer subtypes, developing novel biomarkers and molecular imaging techniques for early and accurate detection of these prostate cancer subtypes, and developing and testing subtype specific therapies to maximize survival for men diagnosed with these androgen indifferent prostate cancer subtypes.

Could you provide insight on phenotypic precision medicine, and how it may facilitate decision-making when treating patients with prostate cancer?

We now have several diagnostic modalities to identify subgroups of men with advanced prostate cancer who are likely to benefit from targeted therapies. These include germline sequencing, tumor genomic profiling, cell-free DNA analysis, and molecular imaging. And after years of using these tools to study and understand drivers of prostate cancer, we now have several targeted therapy for men in biomarker selected populations of advanced prostate cancer, who will benefit from these targeted therapies.

The first class of drugs to be approved as targeted therapy in advanced prostate cancer was PARP inhibitor, specifically Olaparib and Rucaparib for men with DNA damage repair deficient prostate cancer. The PROfound study for prostate, or for Olaparib in advanced prostate cancer, demonstrated benefit for men with several DNA damage repair gene alterations, since then, we’ve fine tuned our understanding of this, and emerging literature suggests that certain genes, BRCA1, BRCA2, PALB2, seem to indicate the largest benefit, or the most likely to benefit from treatment with PARP inhibitor. Whereas other genes like ATM and others, seem less likely to predict benefit to treatment with PARP inhibitors.

The newest treatment, which we’ll talk a little bit more about later on is Lutetium PSMA, which just demonstrated benefit in the VISION trial for men with PSMA PET positive advanced prostate cancer.

I think we have a long way to go, and there’s a lot of exciting work being done to develop biomarkers for selecting patients, selecting treatment in patients with advanced prostate cancer. A study by led by Anis Hamid and Chris Sweeney that was recently published in the annals of oncology, demonstrated that transcriptome, or RNA-Seq profiling, of metastatic hormone sensitive prostate cancer tumors from the CHAARTED study, identified molecular signatures that were predictive, or most predictive, of benefit to the addition of early docetaxel to androgen deprivation therapy.

In contrast, a separate molecular signature was identified, a cohort of men who did not seem to benefit from the addition of early docetaxel. And so I think studies like this provide a really important proof of principle that we can use these molecular tools to identify specific populations of patients with advanced prostate cancer who are most likely to benefit from one therapy or another. And I think there’s a particularly big need in metastatic hormone sensitive prostate cancer, where we have several highly effective therapies, but are really lacking in biomarkers to identify which patients are most likely to benefit from which treatment.