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Neuroendocrine Prostate Cancer

Agarwal

This month, Prostatepedia is talking about neuroendocrine prostate cancer, an aggressive form of the disease.

Dr. Neeraj Agarwal,e Director of the Genitourinary Oncology Program in the Oncology Division, the Co-Leader of the Urologic Oncology Multidisciplinary Program, and the Associate Director of Clinical Trials at the Huntsman Cancer Institute at the University of Utah, offers his insights into this month’s discussions.

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Until 2010, the only drug treatment we had for advanced prostate cancer was chemotherapy with Taxotere (docetaxel). Since then, we have seen the advent of many new drugs, including the drugs to target androgen signaling. Androgen signaling is a critical player in prostate cancer progression. Testosterone is needed for prostate cancer as a fuel; testosterone interacts with the androgen receptor, which is necessary for transcription within the prostate cancer cells.

These drugs induce a deeper blockage of androgen signaling. They include Zytiga (abiraterone) with prednisone, which diminishes the production of testosterone within the prostate cancer cells and adrenal glands, and Xtandi (enzalutamide), which is a next-generation androgen receptor blocker. We also have several new drugs that target androgen signaling in similar fashions such as apalutamide (ARN-509), and darolutamide (ODM-201).

However, over the past five years, we have observed that literally every patient experiences disease progression on these newer androgen signaling targeting drugs. When they progress, some unique features are seen. In approximately 25% of these patients, their PSA values do not necessarily go up in proportion to their disease burden, while their scans show disease progression. This phenomenon is what we now call androgen indifferent prostate cancer, or neuroendocrine prostate cancer.

Neuroendocrine or androgen indifferent prostate cancer existed in the past. A small number of patients—maybe 5%—have neuroendocrine disease from the day they come in for their first biopsy. But now, as these patients are living longer, courtesy of the new androgen signaling inhibitors, the prevalence of neuroendocrine prostate cancer has been increasing steadily. These patients do not really respond well to further manipulation of androgen signaling.

We don’t have standard guidelines in place to diagnose neuroendocrine or androgen-indifferent prostate cancer, so physicians are not always sure what to do when they see this unusual presentation of prostate cancer. Many renowned experts, such as Dr. Ana Aparicio or Dr. Himisha Beltran who are featured this month in Prostatepedia, are working on diagnosis, treatment, and establishing biomarkers for these patients.

From a clinician’s perspective, I can tell a patient has neuroendocrine or androgen-indifferent prostate cancer when I notice disease progression on the scans with disproportionally low PSA levels, and an increase in other tumor markers, such as LDH (lactate dehydrogenase) and alkaline phosphatase.

If you notice these features I recommend consulting with an expert who specializes in neuroendocrine type prostate cancer. Seek out an NCI-designated comprehensive cancer center where oncologists are specializing in prostate cancer, and are likely going to be more familiar with this form of prostate cancer.

I think it’s worth spending extra time, money, and effort up front for the correct diagnosis and a more appropriate treatment plan.

Subscribe to read Dr. Aparicio and Dr. Beltran’s comments on neuroendocrine prostate cancer.


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Xtandi V. Zytiga: Cognitive Effects?

Alicia Morgans, M.D., Hematology/Oncology

 photos by Susan Urmy

 

Dr. Alicia Morgans, a medical oncologist, specializes in treating advanced prostate cancer and is particularly interested in addressing treatment side effects.

In July, Prostatepedia spoke with her about her clinical trial that looks at the cognitive effects that Xtandi (enzalutamide) and Zytiga (abiraterone) can have.

 

 

Dr. Alicia Morgans: My research focuses on understanding the complications of cancer survivors and, specifically, understanding the complications of hormonal manipulation in men with prostate cancer. I’ve done work investigating osteoporosis and bone complications, cardiovascular complications, and metabolic complications like diabetes. The one area that I had not really explored, and that has been underexplored in the field, is the possibility that there may be cognitive changes associated with the hormonal therapies we use.

A patient who served as an inspiration for the study was a preacher who I met a few years ago, just a few weeks after his urologist started him on Xtandi (enzalutamide). His family was concerned because he developed a profound change in his motivation and planning skills, and he was unable to give sermons since starting the medication.

We were able to stop the medication, and a few weeks later, everyone said that he was back to normal. I just needed to understand why this might be the case. This led to the development of our study.

We are comparing the cognitive function of men starting Zytiga (abiraterone) or Xtandi (enzalutamide) over time to see if there is any difference between drugs that block the androgen receptor like Xtandi (enzalutamide) and drugs that just lower testosterone levels more completely like Zytiga (abiraterone).

Both of these drugs are used in the same patient population and are tremendously effective at controlling the cancer, so this comparison could be done safely.

I was fortunate to have some incredible collaborators with experience in traditional neurocognitive testing help develop the study protocol. In addition to comparing cognitive function between groups, the study validates a computer-based cognitive testing system (Cogstate) against traditional neurocognitive pen-and paper tests in the prostate cancer population. If the measures appear to provide similar assessments, I hope to integrate computer-based cognitive testing into many prospective therapeutic studies just as patient reported outcome measures of pain, fatigue, and depression have been.

Finally, I have to mention that we were very fortunate to pique the interest of the Prostate Cancer Foundation in this work, and they were incredibly generous in conferring an award to fund the study.

Their award allowed us to integrate an assessment of possible genetic predisposition to developing cognitive dysfunction. The award also provides funds to integrate advanced neuroimaging with a noninvasive MRI series into the protocol. This will enable us to look at structural and functional changes that may happen in the brain during treatment.

We are doing this trial now because it is definitely an area of clinical concern in my practice. I don’t think that previous work has been able to nail down which populations are at highest risk for cognitive dysfunction or develop a methodology that is both reliable and reproducible in larger scale settings. Our trial design may validate a computer-based methodology that can be expanded to other sites without requiring that trials include psychologists with neurocognitive expertise to administer cognitive tests. The computer-based method is less resource-intensive and more easily scalable.

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