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Conversations With Prostate Cancer Experts


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Dr. Ken Pienta: Chemo For Prostate Cancer

Dr. Kenneth J. Pienta, of the Johns Hopkins University School of Medicine, is an international expert in the development of novel chemotherapeutic agents for prostate cancer. He was the recipient of the first annual American Association for Cancer Research Team Science Award and is the author of more than 300 peer-reviewed articles. He frames this month’s conversations about chemotherapy for us.

Pienta_lab_Background

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In 2018, chemotherapy for prostate cancer continues to be one of the many options we have to lengthen the lives of patients suffering from metastatic prostate cancer. There are still multiple other therapies that we don’t consider chemotherapy. Second-generation anti-androgen therapies like Zytiga (abiraterone), Erleada (apalutamide), and Xtandi (enzalutamide) are all now standards of care in castrate-resistant prostate cancer. We also have Xofigo (radium-223) as an option for patients with bony metastases.

There are two chemotherapies that have been approved for prostate cancer: Taxotere (docetaxel) and Jevtana (cabazitaxel). Now, the real challenge for patients and providers is when to use those chemotherapies.

Multiple studies have demonstrated that, when you’re newly diagnosed with metastatic prostate cancer, it may be beneficial to receive a limited number of doses of Taxotere (docetaxel) at the start of hormone therapy. That’s especially true if you have multiple places where the cancer has spread. That’s not correct for all people, but for some patients, it is a good option. More and more physicians are prescribing Taxotere (docetaxel) with a luteinizing hormone-releasing hormone (LHRH) antagonist at the start of therapy.

However, that doesn’t mean you cannot use Taxotere (docetaxel) after other things have failed. If you failed second-line hormone therapy or have failed radium therapy, Taxotere (docetaxel) is still a good option that helps people live longer.

Jevtana (cabazitaxel) continues to be a good chemotherapy option if patients have failed Taxotere (docetaxel).

Thank goodness we’ve seen over the last several years an increase in the number of drugs available to treat metastatic prostate cancer in addition to chemotherapy. Chemotherapy has been around for quite a while now, but there is still a role for it.

Again, the challenge for all of us is: when do we slot them in for you? The chemotherapy we use for prostate cancer is really a single agent chemotherapy, either Taxotere (docetaxel) or Jevtana (cabazitaxel). This is not the multi-agent therapy we use for other cancers, so the idea of major side effects is a bit overblown. For example, nobody vomits from chemotherapy for prostate cancer. The drugs we use to prevent that are too good.

We also have gotten much smarter about limiting the number of doses we use. We don’t necessarily give chemotherapy until it doesn’t work anymore. Often, we just give several doses and then take a break. If you get more than a couple doses of chemotherapy, you will still lose your hair temporarily.

Chemotherapy can make you feel more tired when it lowers your blood count, and it can make you more susceptible to infections, but people are very rarely hospitalized now for an infection from chemotherapy. It’s virtually unheard of that somebody would die as a side effect of chemotherapy.

The major side effect of Jevtana (cabazitaxel) tends to be diarrhea, but again, as we’ve learned about the dosing of that drug, that has become more manageable.

Another side effect of both drugs can be peripheral neuropathy, which is tingling in the fingers and toes. But we watch for that too. If you start to develop that, we tend to stop the drug. These are very tolerable medicines.

The word chemotherapy always evokes images of horror, but chemotherapy in 2018 is a lot different than it was even five years ago. We just know how to give chemotherapy much better. When I started in the field 30 years ago, if you had metastatic castrate resistant prostate cancer, survival was 6 months. Now, with the advent of all these newer therapies, we’ve gotten much better. The landscape of how to treat prostate cancer has changed completely in the last five years. It will change completely again in the next five years. The challenge is in what order are we going to use all these powerfully good drugs rather than having only one drug to give or none at all.

For us as physicians, it’s an exciting time to take care of men with prostate cancer.

Join us to read this month’s conversations about chemotherapy for prostate cancer.


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The Genomic Revolution Comes To Prostate Cancer

Dr. Oliver Sartor, the Laborde Professor of Cancer Research in the Medicine and Urology Departments of the Tulane School of Medicine, is one of the leading researchers in advanced prostate cancer today. He is also the editor-in-chief of Clinical Genitourinary Cancer and the author of more than 300 scientific papers.

Dr. Sartor puts this month’s conversations about prostate cancer genomics into context for us.

“We can divide genomics into two different categories. The first category is germline genomics, which is the DNA with which you’re born. It’s clear that about 12% of people with advanced prostate cancer will have alterations in their inherited DNA, in particular in genes involved with DNA repair. Most common of these alterations are BRCA2. There are a variety of others that are somewhat prevalent, including ATM, CHEK2, and BRCA1. There are others that are more rare.

The implications of these germline mutations are significant for the patient: in certain configurations they may predispose a cancer to be sensitive to certain therapies, such as PARP inhibitors or platinum-based chemotherapy or (rarely) immunotherapy. There is more complexity, but knowing the germline mutation helps the informed clinician make decisions. In my practice, we test all patients with advanced prostate cancer for these germline mutations. (A National Comprehensive Cancer Network guideline suggests the same approach.)

These germline mutations represent the DNA with which you’re born. That DNA is going to have repercussions if also mutated in your family members. Men who have some of these DNA repair mutations have an increased risk of prostate cancer. In addition, there is a small increased risk of pancreatic cancer and male breast cancer for those with some of the germline mutations. Around 30% of men with BRCA2 will be diagnosed with prostate cancer in their lifetime, but that cancer is more likely to be aggressive if diagnosed. With regards to females, it’s particularly important. Females with DNA repair defects are more likely to have breast and ovarian cancer. Female with DNA repair mutations, in particular BRCA1/

BRCA2, ought to consider having their breasts or ovaries removed at an appropriate time. Prophylactic surgery has been demonstrated to be potentially life-saving for those individuals. The risk of breast cancer may be as high as 70% and the risk of ovarian cancer may be as high as 40%.

Thus, for these germline mutations there are implications for treatment and implications for the patient’s family.

We should be doing prostate cancer screening earlier in men with these DNA repair defects for prostate cancer; we should be doing biopsies at a PSA of 3 or higher, and perhaps even lower, for younger men known to be at risk. Starting screening at age 45 has been suggested by some. In addition to germline genomics, we need to also talk about somatic genomics. Data indicates that about 60% of individuals who have a DNA repair germline mutation are likely to have another second genetic mutation occur within their tumor. In addition, many of the tumors can acquire an alteration in their tumor DNA even when the germline is normal.

Taken together, about 20 to 25% of men may have DNA repair mutations in their tumor’s DNA. That makes them particularly sensitive to certain therapies such as the PARP inhibitors, as I mentioned earlier, or platinum chemotherapy. When you have two DNA repair mutations in the same cell, the likelihood of response to these agents appears fairly high.

There are also other DNA defects of considerable interest, such as alterations of the mismatch repair genes MSH-2 and MSH-6. When these alterations do occur, there is a potentially increased probability of responding to immunotherapy such as the new PD-1 inhibitors.

Overall, the guiding light today in genetics in my practice is to look at both the germline DNA and the tumor DNA. I choose to look at the tumor DNA circulating free DNA (cfDNA) tests, in particular the Guardant Health assay. The ability of other assays to corroborate the Guardant Health findings is not yet clear. There is clear data to indicate that different assays give different results, but nevertheless, I think in the early exploratory phase we’re in now, it’s important to begin to test patients in order to better understand their genomics and hopefully guide us towards better therapies. This will happen part of the time but certainly not all of the time.

There is more to the story of prostate cancer genetics. We’ve looked at androgen receptor mutations that can have implications for a response to Androgen Receptor directed therapy, such as Xtandi (enzalutamide), Zytiga (abiraterone), and Erleada (apalutamide). We’re dissecting a number of permutations that occur. It’s a complex scenario, because very few men have only one mutation. Most have multiple mutations. And in most cases, these mutations are not targetable with current therapies. This is very important for people to know.

Everybody thinks if they get a genomics test that means they’ve got a treatment. It’s not the case. Many times we get the genomics results and find that there are no known treatments we can use for that man’s particular alteration. That said, there is a subset of men who will have informative genomics while many more people will have non-informative genomics.

There is a final issue I’d like to discuss. There is currently a bit of a debate amongst physicians over the utility of PARP inhibitors such as Lynparza (olaparib) as compared to platinum chemotherapy. But it is noteworthy that platinum-based chemotherapies are inexpensive compared to PARP inhibitors. This does not require a clinical trial. (Most men will access PARP inhibitors through a clinical trial, although sometimes insurance companies are willing to try.)

As it turns out, neither the platinum-based chemotherapies nor the PARP inhibitors will be effective forever, so we do need strategies to manage patients after PARP inhibitors or platinum-based chemotherapies fail. Currently, that space is unexplored. We have to gather much more data before we can make conclusions about those with underlying DNA repair defects who have failed platinum-based chemotherapy or PARP inhibitors.

This is an area of active and important investigation that represents a conundrum for many patients today. I’ve got a patient right now going through this. We’re debating what to do next. I’ve tried to be as honest as I can when I say, “I don’t know what to do, but we’ve got to try something.”

We are in the middle of a revolution, but the parts and pieces are not yet clear. For some, understanding tumor genetics at the current level is helpful. For others, it is perplexing and expensive.

Join us to read this month’s conversations about prostate cancer genomics.

(Already a member? You can read all conversations in your copy of April’s Prostatepedia.)


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Dr. Charles Ryan: Why Oncology?

Dr. Charles J. Ryan is the Clinical Program Leader for Genitourinary Medical Oncology at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.

He primarily treats men with advanced prostate cancer. His research focuses on novel therapies for advanced prostate cancer.

Not a member? Join us to read Dr. Ryan’s conversation in our March issue on cancer recurrence.

Why did you become a doctor?

Dr. Ryan: I grew up in a medium-sized city called Appleton, Wisconsin. My father was the first medical oncologist and the first prescriber of chemotherapy in our town. He never did a fellowship because they didn’t exist when he finished his training.

I’m the youngest of four kids. By the time I was in junior high school, all of my siblings had gone away. My mother is a nurse, and she was working for hospice in our community. Sitting around the dinner table, it was just the three of us.

The dinner conversation was frequently about cancer, hospice, medicine, and things like that. That’s what shaped me at the time. I decided to become a physician in college, but I had given a lot of thought to oncology and medicine well before making the decision.

I guess medicine is the family business?

Dr. Ryan: Yes. It is sort of a family business. When I started my medical training, I felt a kinship with the medical oncologists I interacted with at the University of Wisconsin. I was randomly assigned to work in an oncology clinic and a prostate cancer clinic. I just felt like: these are my people. The timing was right for me to make a decision. It’s what I wanted to do with my life. I found the disease itself biologically compelling, and the emergence of new therapies and the community of physicians and researchers who worked on it were an interesting group of people. It was a natural decision.

Join us to read Dr. Ryan’s thoughts on Xtandi (enzalutamide) and Zytiga (abiraterone.)


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Living With Neuroendocrine Prostate Cancer

Stan P. has neuroendocrine prostate cancer. He spoke with Prostatepedia about his experiences with this aggressive form of prostate cancer.

How did you find out that you had prostate cancer?

Stan P: It was a PSA taken by my primary physician. It was taken kind of late. It came out to be 6.2, which is fairly high. After that, I started consulting around trying to find a doctor to treat me. That was back in 2006.

How did you find out that you had neuroendocrine prostate cancer? Was that when you were first diagnosed or was that after you’d been on some kind of treatment?

Stan P: I was taking Zytiga (abiraterone) for almost two years. The physician was also running blood tests. One of the substances in the blood test that stood out was this bone-specific alkaline phosphatase. It started to go up while at the same time my PSA was undetectable. It had reached undetectable status about a year after taking Zytiga (abiraterone).

The physician saw this one level going up, so he prescribed an F18 sodium bone scan along with a couple of other specialized blood tests. One of the blood tests was LDH, which I think detects cellular injury. Another was chromogranin A that detects neuroendocrine tumors. The third one was CEA, carcinoembryonic antigen, a marker for colon and thyroid cancer.

The one that stood out was the chromogranin A. It was high. At the same time, the F18 scan showed two neuroendochrine tumors. One was in the ileum (the end of the small intestine) and the other one was in the C5 vertebrae. With the undetectable PSA, these results from the scan, and some of the blood results, the physician suggested that it was probably neuroendocrine, which I didn’t even understand at the time.

He said something about adenocarcinoma being differentiated into this neuroendocrine tumor. From that point, his recommendation was to try some platinum-based chemo. I was not feeling any symptoms. I was not in any pain, and I was still doing my normal thing. He recommended that I undergo Xofigo (radium-223).

Were you still on the Zytiga (abiraterone) at this point or did he take you off the Zytiga?

Stan P: I was still on Zytiga (abiraterone) when all this happened. He took me off later because my kidneys started to show side effects from it—high creatinine. He took me off of that to see if it would lower the creatinine levels, and it did, so he kept me off it. I continued to take an androgen agonist (degarelix), which I’m still taking.

What was your initial reaction when you heard all this? Did you immediately start researching about neuroendocrine prostate cancer? How did you respond?

Stan P: I had no idea what a neuroendocrine tumor was. I didn’t even know what a PSA was. I got this medical explanation, and then when I started delving into it on the Internet, I found out that only 1% of the prostate cancer patients get this or have this condition. Then I knew it was serious.

There really are no cures. I consulted with two other prostate specialists. One was the chief of hematology and the other was the chief of prostate cancer research at a teaching hospital. One doctor said that he treats this through standard-of-care treatment, which means platinum-based chemo. The other doctor told me to go back on the Zytiga (abiraterone), which really didn’t make any sense. My understanding is that this neuroendocrine tumor does not have any androgen receptors. But the real issue is there aren’t many doctors around who spend a lot of time with this type of cancer.

What is your current doctor’s plan going forward?

Stan P: I just went through six months of Xofigo (radium-223) and completed that at the end of March. The recommendation has been to wait for three months and get a scan then. In the meantime, I take Firmagon (degarelix). During the six months on Xofigo (radium-223), I had a couple of scans. One was a technetium-99 bone scan, which was performed after two treatments with Xofigo (radium-223).

The strange thing was they only found one neuroendocrine cancer in the ileum. They did not find the one at the C5 vertebrae. Maybe the F18 was oversensitive to the scan. I don’t know.

At the same time, I entered a clinical trial for C11 Acetate PET/CT scan. They were giving me these C11 Acetate PET/CT scans every month, and I decided I should stop doing that because it was affecting my blood counts too much. I had two C11 Acetate PET/CT scans, and both were uneventful. They didn’t find anything, which I kind of expected because my PSA is undetectable. They did not detect any of the neuroendocrine tumors either.

Since ending the Xofigo (radium-223), I have not had any scans. I’m waiting another month, and then I’ll get another scan to see the effect of that. During the time I was undergoing Xofigo (radium-223), the blood tests were becoming much more positive. The bone-specific alkaline phosphatase went down to normal levels. That indicated that maybe the tumor was not growing anymore. The plan right now is to just stay on Firmagon (degarelix) and get another scan in another month. Treatment will be scheduled then.

Do you have any advice for other men who have been told that they have neuroendocrine prostate cancer?

Stan P: First, make sure you actually have a neuroendocrine tumor. Then consult with a doctor who specializes in neuroendocrine prostate cancer. I found a nationwide list on the site carcinoid.org. And just keep the faith. I have a positive outlook that something’s going to come to help me either put off the growth of this tumor or to cure it. I keep looking, and that’s about all I can do. Just keep the faith.

What about any advice for doctors treating patients like you?

Stan P: I would recommend that the doctors educate themselves on the ongoing clinical trials for this disease. Even if they don’t know about any while the patient is visiting them, they should at least tell the patient that they will do research themselves. I’m sure doctors have a better way of finding these things out than the layman.


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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.

Join us to read the rest of the conversation.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


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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

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Dr. Himisha Beltran, an Assistant Professor of Medicine at Weill Cornell Medical College in New York City, is keenly interested in developing research programs to study neuroendocrine prostate cancer.

We spoke with her about this aggressive form of prostate cancer.

Your research deals with a small subset of patients and is considered a specialized area of research. How did you become interested in neuroendocrine prostate cancer as opposed to another aspect of the disease?

Dr. Himisha Beltran: I take care of prostate cancer patients at all different stages of their disease. We know that not all patients with prostate cancer are the same and they may respond variably to the therapies that we use. My research has focused on understanding mechanisms of treatment resistance and identifying subsets of patients that may benefit from nonstandard approaches.

Neuroendocrine prostate cancer is one subtype within the spectrum of advanced prostate cancer that tends to look and act differently compared to your typical prostate cancer. They tend to be less responsive to standard therapies and often do not make PSA.

That is really what led me to neuroendocrine prostate cancers. I was struck by how some patients had tumors that looked very different under a microscope and acted very different clinically than others looked and acted. By understanding a small subgroup of patients, we can also better understand the entire group. That is really what precision medicine is about: identifying subgroups of patients that either have clinical, molecular, or other features that will help guide treatment. While my research is focused on a small subgroup of men, I think the impact potentially affects many more.

Let’s back up a bit and define neuroendocrine prostate cancer.

Dr. Beltran: Most prostate cancers consist of adenocarcinoma cells, which are derived from normal prostate tissue. They have more glandular prostate features. They express many prostate markers. When we say a cancer is neuroendocrine, we mean that the tumor looks less like a typical adenocarcinoma and has features that look more like neuroendocrine cells, which have a distinctive morphology under a microscope. Neuroendocrine cells tend to be smaller and may not express classical prostate markers such as the androgen receptor, which is the target of many of our drugs like Zytiga (abiraterone) and Xtandi (enzalutamide). These cancers also acquire other distinct molecular features.

What we’ve learned in recent years is that neuroendocrine prostate cancer rarely arises de novo; they most commonly develop in later stages of prostate cancer progression from a preexisting prostate adenocarcinoma as a way for the cancer cells to evade therapy. The tumors try to change their identity to develop new ways to grow. There is a spectrum as tumors progress from androgen-driven prostate adenocarcinoma toward an androgen independent neuroendocrine prostate cancer. Within this spectrum, the cancers may develop mixed or overlapping features, expressing some prostate markers but also acquiring new resistance markers.

Is there any way to predict who is going to develop treatment resistance?

Dr. Beltran: By studying the clinical and molecular features of patients, how cancers evolve with time, and how these features affect the biology of the cancer, we now have better insights into mechanisms of response and resistance to specific therapies. This growing knowledge sets the stage for biomarker development.

We are interested in identifying patients before they develop neuroendocrine prostate cancer. We are investigating the genomics and other molecular features of tumor biopsies and applying this to noninvasive approaches such as liquid biopsies— looking at cancer cells or DNA from cancers that may be detected in the blood. If we can identify patients, we can also select patients most likely to benefit from a neuroendocrine type of regimen.

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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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Prostate Cancer Treatment Advances

Pp_July_2017_V2_N12_ThumbIn July, Prostatepedia is talking about advances in urology, radiation therapy, oncology and immunotherapy for prostate cancer.

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Dr. Oliver Sartor, one of the leading researchers in advanced prostate cancer today, has the following to say about this month’s conversations.

Three of the biggest areas in prostate cancer right now are: 1) the use of the checkpoint inhibitor PD-1 to treat men with mismatch DNA repair defects, 2) the use of either PARP inhibitors or platinums to treat mismatch DNA repair defects, and 3) better imaging techniques.

Within the next year or two, we’ll be able to define a subset of patients who will benefit from the PD-1 inhibitors that Dr. Charles Drake discusses in his conversation on immunology. I anticipate that PD-1 inhibitors may be meaningful for around 10% of men.

The FDA recently approved Keytruda (pembrolizumab) for those with mismatch DNA repair mutations, which applies to a subset of prostate cancer patients. This story will be meaningful to watch as testing for these mutations becomes more prevalent.

As Dr. Daniel Petrylak alludes to, there are now a variety of rapidly moving clinical trials looking at the combination of three DNA repair defects—BRCA1, BRCA2, and ATM. Data to support the use of PARP inhibitors in men with this combination of repair defects is rapidly evolving. This practice remains unproven in prostate cancer, though, despite promising preliminary data published by Dr. Joaquin de Mateo in the New England Journal of Medicine in 2016. [See Prostatepedia June 2016 for a conversation with Dr. Mateo about his work.]

But I do want to make sure that Prostatepedia readers are aware that if you have metastatic prostate cancer and a DNA repair defect—like BRCA1, BRCA2, and ATM—there is some reasonable preliminary data to support using carboplatin. We have a manuscript at press right now that shows that if you have an inherited BRCA2 mutation, there is better activity if a carboplatin plus a taxane are administered as opposed to just giving you a taxane alone. Thus carboplatin appears to be an option for men with certain DNA repair alterations.

Advances in imaging are also discussed in several of the conversations that follow. PSMA imaging is moving quickly. Axumin (fluciclovine F18) is the new imaging technique on the block with FDA approval. I think that in using these newer imaging techniques we will be able to define oligometastatic disease groups more and more efficiently. The consequences will be less therapy that just sets patients up to fail and, hopefully, more therapy that, if targeted to those lesions, will have a meaningful effect.

Stay tuned: the prostate cancer field is evolving really fast right now. I believe some men with advanced disease will potentially have molecularly targeted therapies available to them within the next several years.

Subscribe to read our July conversations on advances in treatment.