Conversations With Prostate Cancer Experts

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Prostate Cancer Recurrence

Dr. Alicia K. Morgans is a medical oncologist at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, Illinois. She specializes in treating advanced prostate cancer and is particularly interested in addressing treatment side effects.

She frames Prostatepedia’s March conversations about prostate cancer recurrence.

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One of the most common questions I’m asked as a doctor who treats prostate cancer is: what happens to me if my cancer comes back? This is always a difficult conversation, especially because people often ask it in the presence of their family members. A man’s wife or child is also really interested in knowing the answer to the question. The question is often driven by anxiety and fear in men who have already undergone what can be a life-altering treatment experience. They’re trying to look ahead and plan for their future. But there are many parts to any possible answer.

First: what do you go through to monitor before the cancer comes back? After treatment, we follow a man’s health, watch his PSA intermittently over time, and often do imaging studies.

If the cancer comes back, the first sign is often that a man’s PSA starts to rise. At this point, we typically use imaging studies to understand what the disease is doing. Even when the PSA is really low, our new imaging technologies can show us where the cancer is and help us determine how a man’s recurrence may be ultimately treated—whether that is with local or systemic treatment. Again, this is a really anxiety-laden situation. We’re fortunate to have these new exciting imaging technologies for patients and their clinicians, which Prostatepedia discusses at length in this edition.

We use these imaging technologies in men with biochemical or PSA-only recurrence to help us understand where the cancer is located. For some men, these new imaging techniques might show us that there is a cancer recurrence in the pelvis where radiation can be given to potentially cure them of recurrent prostate cancer. That is a huge win, progress for our patients, and of course, wonderful news for the men and their families.

For other men, it is possible that we will not necessarily find recurrence, even with new imaging techniques. In those cases, we often continue to wait and watch. Biochemical recurrence can be challenging psychologically because knowing that your PSA is rising can be stressful, and the data explaining the best approach to treatment is not complete.

For men who have a single area of prostate cancer that has come back, whether as a single bone lesion or a few locations, advances in therapy for oligometastatic disease have come fast and furious. In this issue, Dr. Piet Ost talks about oligometastatic prostate cancer and how we might use radiation or surgery to treat a small amount of recurrent prostate cancer. Several clinical trials are working hard to figure out if treating this low volume of prostate cancer in single areas will potentially cure men of recurrent cancer.

It’s really important that we have new treatments we can use for men with hormone-sensitive metastatic prostate cancer, too. Over the last few years, we’ve seen men with metastatic hormone-sensitive prostate cancer live well for many years with several options for treatment. New data describing chemo-hormonal therapy or androgen deprivation therapy (ADT) with Zytiga (abiraterone acetate) have been incorporated quickly into clinical practice and are being widely used to help men with metastatic hormone-sensitive prostate cancer live longer.

Unfortunately, sometimes a man’s prostate cancer comes back more broadly, as a rising PSA only, or with sites of metastatic disease. This can be challenging physically, because sometimes it’s coupled with fatigue or pain as well as emotional difficulty. The cancer that a man thought was gone has now come back. To address this, there are many scientists and physicians working to try to help men with prostate cancer live better by using therapeutic advances as well as psychosocial and pain support teams that can improve patient-reported as well as disease outcomes. By incorporating social work and psychiatrists, centers are able to support men and their families, helping patients cope with PSA anxiety, which is an issue that can be anxiety-provoking and potentially go on for years at a time.

In terms of therapies, we as a field are very excited about new data that offers new therapies to men with biochemical recurrence who develop castration resistance before they have radiographic evidence of metastatic disease. Two clinical trials presented last month in San Francisco at the annual ASCO Genitourinary Oncology Symposium suggest that using either Xtandi (enzalutamide) or Erleada (apalutamide)—both androgen receptor-directed therapies—can prolong metastasis-free survival for men with castration-resistant non-metastatic disease.

This is a valuable advancement because any day spent without metastasis is a day spent feeling stronger and with less pain. We are also excited because both of these oral drugs have relatively low toxicities. Both clinicians and patients win when we add a significant amount of metastases-free time with a few pills and minimal side effects.

As a clinician, I understand the anxiety that drives the question: what if my cancer comes back? But this is a time of incredible hope. Medical advances are helping men live longer and live better, even if their cancers do come back.

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Small cell? Or neuroendocrine cancer?

AparicioDr. Ana Aparicio is an Associate Professor in the Department of Genitourinary Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, Texas.

Prostatepedia spoke with her about rare but highly aggressive forms of prostate cancer.

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How did you become involved in such a specialized subset of prostate cancer research?

Dr. Aparicio: I was very frustrated by the fact that we treat homogeneously a disease that we perceive in the clinic to be heterogeneous. It drives me crazy that different people walk into the clinic with different diseases and yet we do the same thing to each and every one of them. This ends up meaning that many large Phase III trials are an enormous resource expense. It’s difficult to advance the field. I had remarkable responses for patients with Yervoy (ipilimumab) and yet the Phase III trial was negative. I felt like that was wrong. We should be smarter about what we’re doing. We need to understand the heterogeneity of prostate cancer and incorporate that understanding into clinical trials. Otherwise, it’s going to take us 200 years to make a difference in this disease.

I think of it in the following way. I take all of the prostate cancers and peel away the most aggressive ones. I then look to see how that relates to the rest of the disease. If we peel back in that way, we will start to understand the disease.

So then the work you’re doing can potentially change not only how we treat patients, but also how we design clinical trials?

Dr. Aparicio: Yes.

What is neuroendocrine prostate cancer?

Dr. Aparicio: Neuroendocrine prostate cancer is a histological definition of a prostate cancer variant. The prostate is composed of glandular tissue. When a pathologist looks at your garden-variety prostate cancer under the microscope, she sees it is composed of groups of glands. That is why it’s called adenocarcinoma: adeno meaning of or relating to the glands, carcinoma referring to the cancer arising from epithelial tissue. It’s cancer and not normal prostate tissue, but you can still recognize the glandular structures. Prostate adenocarcinomas respond very well to hormonal therapies.

On the other hand, small-cell prostate cancers basically look like sheets of cancer cells under the microscope. There is no glandular formation of any sort. These are small, round cells that have small amounts of cytoplasm (the gel-like material surrounding the nucleus) so their nuclei look very prominent. Small-cell cancers often express neuroendocrine markers, which are a type of protein expressed by a number of different tissue types and in a number of different cancers. Neuroendocrine markers are in no way specific to small-cell prostate cancers, but because the small-cell prostate cancers express them frequently, the other name that is given for small-cell prostate cancers is ‘poorly differentiated neuroendocrine prostate carcinoma.’ Many garden-variety prostate adenocarcinomas (those composed of groups of glands) also express these neuroendocrine markers. Again, the word neuroendocrine is not specific to small-cell cancers. Small cell refers to sheets of cells that are small with little amounts of cytoplasm.

The presence of small-cell cancer morphology on a surgical specimen or a biopsy is often associated with atypical clinical features for prostate cancer and a poor response to hormone therapies.

Garden-variety prostate adenocarcinomas most often spread to the bone and make round sclerotic (hardening) or osteoblastic bone metastases that show on a CT scan like a white patch.

In contrast, small-cell prostate carcinomas are often associated with what we call lytic (relating to disintegration) bone metastases, which show on a CT scan like a dark, punched-out hole. And that’s when the carcinomas go to the bone because they often don’t even show up in the bone. Men with small-cell cancer morphology can have exclusive visceral metastases, meaning their cancer has only gone to the liver, lymph nodes, or lung. They might also have bulky tumor masses, including bulky and symptomatic primary prostate tumors or bulky liver or lymph node masses. While they don’t respond well to hormonal therapies, small-cell prostate cancers often respond to chemotherapy.

A problem we ran into was that we would often find these atypical clinical features that I just described, but under the microscope where we expected to find small-cell prostate carcinoma morphology to justify chemotherapy, we didn’t. What happens when we see those atypical clinical features, but the biopsy doesn’t show small-cell morphology? Our experience shows that those people don’t do well with hormone therapies. In other words, when we do a biopsy and we find small-cell carcinoma morphology, we know that those cancers need to have chemotherapy sooner rather than later, as opposed to treatment with hormonal therapy. They need early chemotherapy as well; so we coined the term aggressive variant prostate cancers, which are tumors that share clinical features with small-cell cancers but may have different morphologies under the microscope. When we do a biopsy, they might look like adenocarcinoma, but they behave like small-cell cancer.

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Diagnosing Neuroendocrine Prostate Cancer

Prostatepedia spoke with Dr. Himisha Beltran, an Assistant Professor of Medicine at Weill Cornell Medical College in New York City, about diagnosing neuroendocrine prostate cancer.

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How is small-cell or neuroendocrine prostate cancer diagnosed? Biopsy? Imaging?

Dr. Himisha Beltran: Small-cell or neuroendocrine prostate cancer is diagnosed by tumor biopsy. The pathologist typically makes the diagnosis by looking at the morphologic features of the cancer under a microscope and may perform additional testing to look at expression of neuroendocrine markers or classical prostate markers to support the diagnosis.

One of the reasons why neuroendocrine prostate cancer was thought to be so rare was that doing metastatic biopsies on patients already diagnosed with prostate cancer was just not done in the clinic. It is only recently that we are recommending biopsies to look for neuroendocrine prostate cancer in select patients with aggressive clinical features and low PSA levels. Biopsies are also being considered to look for other emerging molecular targets. There are now several prostate cancer clinical trials targeting different mutations and alterations.

An obvious next step is to try to diagnose neuroendocrine prostate cancer noninvasively. Imaging is a noninvasive way to detect different cancers, but there hasn’t been any sort of imaging tool yet that can really identify these patients. We’re starting to see clues that there may be some molecular markers that are expressed that might help future research in this area. Another noninvasive approach we have been investigating is the use of liquid biopsies that include circulating tumor cells as well as circulating tumor DNA to see if there are clues that can help us identify these patients without a biopsy. This is still in research development.






Read the rest of Dr. Beltran’s comments on neuroendocrine prostate cancer.

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Neuroendocrine Prostate Cancer


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.

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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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