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Conversations With Prostate Cancer Experts


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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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Aggressive Forms of Prostate Cancer

Dr. Snuffy Myers talks about Prostatepedia’s August issue on aggressive forms of prostate cancer.

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In August, we’re talking about what used to be thought of as a rare form of metastatic prostate cancer but now appears to be quite common. In this month’s guest commentary, Dr. Neeraj Agarwal summarizes the problem of neuroendocrine cancer and frames the conversations that follow. You will notice a broad consensus among our experts that metastatic prostate cancer is a heterogeneous disease. Unfortunately, the large randomized Phase III trials that established our current treatment guidelines behave as if all metastatic prostate cancers are alike. As this is clearly not the case, treatment guidelines need to be interpreted with prostate cancer’s heterogeneity in mind. This is especially true if your PSA is low for the amount of cancer that you have; if you have lytic bone metastases; or if your cancer is predominately in your liver, lung, or other organs rather than in your bone. If your cancer fits this picture, the conversations that follow may help you better understand your treatment options.

These atypical prostate cancer presentations are poorly served by standard treatments and yet we haven’t really defined yet what the proper treatment might be.

Drs. Ana Aparicio, Himisha Beltran, and Daniel George have thought creatively about how we might better treat men with these atypical prostate cancer presentations.

It is already clear that patients with this aggressive presentation vary in their response to existing drugs as well as to agents currently in development. A key step will be to find molecular markers that predict which treatments are likely to be most effective for each patient. This type of research, while still early in the process, is progressing rapidly.

We now have laboratory models for neuroendocrine and anaplastic prostate cancers. It is possible to rapidly test agents in these models; that process has identified promising agents.

I think estradiol is one of these promising agents. One of my patients illustrates this nicely. A young man had at initial diagnosis a Gleason 10 prostate cancer with a 14-day doubling time. His cancer became PSA negative while he was on Lupron (leuprolide) and Casodex (bicalutamide). He developed a large lytic metastasis in his pelvis. I asked a radiation oncologist to radiate his pelvic lytic lesion and then started him on estradiol. He entered a complete remission that lasted eight years. After eight years, he developed an oligometastatic recurrence that I again asked a radiation oncologist to treat with radiation. He entered a remission. He finally developed metastatic cancer of the pancreas and is now receiving chemotherapy.

Over the years, I have seen estradiol result in multi-year cancer control in other patients with a similar presentation. I never understood how hormonal therapy like estradiol could work in a group of patients notorious for being unresponsive to hormonal treatment. But we now know that estradiol can act through the estrogen receptor beta to block the action of a protein called snail (SNAI) that is important in neuroendocrine transformation and metastatic spread.

My point is that a diagnosis of aggressive prostate cancer doesn’t mean you’ve only got a few months left. Years-long disease control can happen. It is in your best interest to seek out an expert in this form of prostate cancer—even if you have to travel great distances to see him or her.


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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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Advances in Medical Oncology

PetrylakDr. Daniel P. Petrylak, Professor of Medicine and Urology at Yale School of Medicine, has been a pioneer in the research and development of new drugs and treatments to fight prostate, bladder, kidney, and testicular cancers.

Prostatepedia spoke with him about advances in medical oncology for prostate cancer.

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What are the current points of controversy and/or trends in the field of medical oncology for prostate cancer?

The first controversy is over localized disease. There are really two forms of prostate cancer. There is the nonaggressive form that is not going to be lethal and that you’ll die with and not from. Then, unfortunately, there is the lethal form of the disease that kills about 30,000 men a year in the United States. The controversy is how do you treat these patients? How do you decide who to treat and who not to treat?

For advanced metastatic disease, there are controversies over the right treatments, the right sequences of treatments, when to use other hormones, and when to use other chemotherapies. There are a lot of questions that need to be answered.

Unfortunately, prostate cancer has always been behind other tumors. If you look back to the 1990s, there was about five times less funding for prostate cancer than breast cancer. We were behind in funding compared to other tumors, but have made significant strides in increasing money available for research.

We’re catching up in the area of personalized medicine. We didn’t really have markers a couple of years ago. But now we’re beginning to see markers—whether that be with BRCA mutations, BRCA-like mutations, or AR-V7—employed in the treatment of advanced metastatic disease to help select therapies. These approaches are in the advanced stages of development and have yet to be approved by the FDA. Those are the major controversies.

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