Xtandi V. Zytiga: Cognitive Effects?

 

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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Surgery For Metastatic and High-Risk PCa

Edward Schaeffer, MD, PhD, Urology

Dr. Edward Schaeffer is the Chair of the departments of Urology a Northwestern University Feinberg School of Medicine and Northwestern Memorial Hospital.

In July, Prostatepedia spoke with him about the advances in urology. Subscribe to read the entire conversation.

What are the current thoughts on the role of surgery for recurrent oligometastatic disease? [Oligometastatic disease means you only have three to five metastatic lesions outside of the prostate gland.]

Dr. Edward Schaeffer: Many surgeons and patients are enthusiastic about aggressively treating oligometastatic prostate cancer. I’m also enthusiastic about the possibility that this approach could help patients. But I think it is very important for patients reading this interview to understand that these kinds of studies are totally experimental; we do not know yet if these approaches will benefit men. Although I’m personally enthusiastic about these kinds of approaches—and am the principal investigator on a study exploring this called the TED trial. (TED stands for Trimodal Elimination of Disease and uses surgery, radiation, and systemic [chemo-hormonal] therapy to eliminate all visible evidence of prostate cancer.) However, I really only recommend that the average patient seek treatment for their oligometastatic or recurrent prostate cancer in the setting of a clinical trial. This is really experimental. We don’t know if it helps and it may actually hurt people—this is why it needs to be done as a trial.

Is there any controversy over surgically treating the primary tumor when a man’s cancer has already spread outside the prostate gland?

Dr. Schaeffer: No, I don’t think there is any controversy in that. If you mean is there controversy in over-treating the prostate if a man has ogliometastatic disease, then yes, that is controversial. But in my mind, surgery benefits most men with large bulky high-grade cancers. Radiation is less effective in those cases.

In the last three to four years in my practice, I’ve seen more and more men with more advanced high-grade bulky cancers. I believe, although this hasn’t been shown in a randomized clinical trial, that the best way to manage these cancers is the way we manage many other cancers: a multimodal approach of surgery followed by radiation and potentially chemotherapy.

Why do you think more and more people are being diagnosed with bulky high-grade disease?

Dr. Schaeffer: Several reasons. One, the United States Preventive Services Task Force (USPSTF) changed their recommendations in 2008 for men over 75 and in 2012 for men under 75 for PSA screening. It’s well documented that there have been relaxations in PSA screening and that relaxations in PSA screening have resulted in fewer biopsies.

Think about the natural history of prostate cancer: if you had an aggressive localized cancer and left it alone for five to seven years, it would come back as a bulky aggressive cancer most probably involving the lymph nodes or beyond.

And that is exactly what we’ve seen. Dr. Jim Hu published that exact observation in JAMA Oncology in December 2016. Unfortunately, we’ve now proved that what we thought would happen did in fact happen. The screening recommendations are not to the benefit of the patient. Fortunately, the USPSTF recently revised their recommendations and now suggest that PSA screening is something that physicians should bring up and discuss with their patients. This is a big step in the right direction.

Advances in Urology

 

 

Dr. Edward Schaeffer is the Chair of the departments of Urology a Northwestern University Feinberg School of Medicine and Northwestern Memorial Hospital.

In July, Prostatepedia spoke with him about the advances in urology. Subscribe to read the entire conversation.

 

What are the current points of controversy in the world of prostate cancer surgery—both for men who have been newly diagnosed and for those facing recurrence?

Dr. Schaeffer: Surgery for prostate cancer remains the gold standard, the best way to c

ure the disease. It is also the oldest treatment. Prostate cancer surgery was first performed in 1904; it’s withstood the test of time.

The big hurdle for prostate cancer surgery has always been maintaining its outstanding cure rates while continuing to minimize postsurgical toxicity and side effects.

The operation has certainly evolved over the last 30 years. Dr. Patrick Walsh at Johns Hopkins University was my mentor. He perfected the open radical prostatectomy. Many Johns Hopkins alumni have now brought minimally invasive laparoscopic robotic prostatectomy online.

Today, for almost all cases, the laparoscopic robotic prostatectomy offers a state-of-the-art approach. Still, it is important for a man considering surgery for prostate cancer to find the most experienced surgeon he can. Ultimately, experience trumps approach.

You need to find a surgeon you like, because you’re going to have your surgeon for the rest of your life.

You need someone who has enough experience to give you a good outcome. Patients ask, “Should I come to you?” I say, “I’m confident I can help you, but we need to have a great relationship as I’m going to take care of you for the next 30 years…”

Is there a learning curve for robotic prostate cancer surgery?

Dr. Schaeffer: There is a learning curve to prostate surgery, period. Prostate surgery is incredibly complex. In an average surgeon’s hands, it is a four-hour operation. The surgery requires an intense knowledge base. It’s difficult whether you choose an open approach or a laparoscopic robotic approach.

I believe there are some subtle things about a robotic approach that an experienced surgeon can translate into better outcomes for patients. Ultimately, an open operation is not that different from a laparoscopic approach. But, yes, there is a very steep learning curve to robotic prostatectomy.

My other general philosophy is that I don’t consider myself to be a technician—a robotic surgeon. Rather, I proudly consider myself to be a physician who takes care of men with prostate cancer. One of my skillsets is that I’m able to perform prostate cancer surgery well. I do both open and laparoscopic approaches in my practice, though I favor the robotic approach. Ultimately, though, I consider myself to be an expert in prostate cancer who offers patients a good understanding of which treatment approach may be right for them. That may be surgery or radiation or surveillance.

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Xofigo Combinations

Dr. 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 newer combinations with Xofigo.

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Dr. Petrylak: Xofigo (radium-223) can be very useful in patients. The prevailing wisdom in the past has been to only give isotopes late in the course of the disease because drugs like strontium and samarium had only palliative effects. There was also concern that strontium and samarium could cause prolonged myelosuppression (bone marrow suppression) in patients. Patients who are treated early in the course of their disease with strontium and samarium may have difficulty receiving subsequent chemotherapy.

Xofigo (radium-223) has an advantage over both strontium and samarium in that it is an alpha particle rather than a beta particle. The alpha particle will induce double-stranded DNA breaks as opposed to the beta particle’s single-stranded breaks. Double-stranded DNA breaks cause much more DNA damage in the tumor cells; it is much more difficult for the body to repair that damage.

The alpha particle’s other advantage is that it has a short nucleus, or radius of activity. It spares normal marrow and will hopefully cause less myelosuppression.

Xofigo (radium-223) has a survival benefit. It is approved for either pre- or post-chemotherapy.

There are a couple of interesting observations being made that will hopefully be confirmed in randomized trials. If you look at Xofigo’s (radium-223) expanded access protocol, there does appear to be better survival when you combine Xofigo (radium-223) with Zytiga (abiraterone). There is also better survival when you combine Xofigo (radium-223) with Xgeva (denosumab).

Combinations give you more bang for your buck. Randomized trials are now evaluating these combinations. I think there is great promise in these combinations. We all know that there is an interaction between hormones and radiation therapy. Giving the two together is very interesting.

The immune question is an important one. We have some data that we’re submitting for publication that shows that there is upregulation of PD-L1 on immune cells after patients receive Xofigo (radium-223). The question is: does that make the patients more sensitive to subsequent immune therapy?

There are clinical trials looking at combinations of Keytruda (pembrolizumab) plus Xofigo (radium-223), vaccine therapy plus Xofigo (radium-223), atezoluzimab plus Xofigo (radium-223) and Provenge (sipuleucel-T) plus Xofigo (radium-223) This is an important venue for trying to synergize between different treatments.

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Advances in Medical Oncology

Dr. 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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A New Prostate Cancer Vaccine?

Dr. Charles G. Drake of New York-Presbyterian/ Columbia University Medical Center spoke with Prostatepedia about new prostate cancer vaccines under investigation.

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Dr. Charles Drake: Hopefully before the end of the year, a trial called PROSPECT will read out. (Though it’s hard to tell nowadays when trials are going to read out because we already have a reasonable number of options: six FDA-approved drugs for men with metastatic castration-resistant disease.) PROSPECT is an international randomized Phase III trial of about 1,200 men that looks at Prostvac, an off-the-shelf PSA-targeted vaccine. The trial’s primary endpoint is overall survival.

Unlike the Provenge (sipuleucel-T) trials, which were sometimes a little complicated to interpret because we had crossover, patients on PROSPECT didn’t crossover. That means that patients on the placebo arm who progressed were not eligible for Prostvac, instead, they went on to standard treatments. The lack of crossover means we expect a fairly clean set of survival data to come out from this large PROSPECT trial. There are a lot of folks in the prostate cancer community looking forward to seeing whether or not PROSPECT will have a survival benefit.

So then we’d have two vaccines for prostate cancer?

Dr. Drake: Provenge (sipuleucel-T) is an active drug with clear utility. The challenge with Provenge (sipuleucel-T) is that patients need to undergo leukapheresis to prepare this personalized vaccine. Prostvac is more like the vaccinia vaccine that was used for smallpox. It will be a bit easier to distribute widely.

Is inconvenience the only factor limiting Provenge (sipuleucel-T) use?

Dr. Drake: The prostate cancer field is like all other fields in that we tend to be trendy at times. When Provenge (sipuleucel-T) was first approved, there was a ton of enthusiasm about it and lots of people were using it. In fact, there was a bit of controversy over whether or not we could make enough of it.

With all the new drugs coming out, Provenge (sipuleucel-T) is probably used less than it once was. But this is something that has been FDA approved and has a clear survival benefit.

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Dr. Drake On Immunotherapy For Prostate Cancer

Dr. Charles G. Drake recently joined New York-Presbyterian/ Columbia University Medical Center as the Director of Genitourinary Oncology, Co-Director of the Cancer Immunotherapy Program, and Associate Director for Clinical Research at the Herbert Irving Comprehensive Cancer Center.

Prostatepedia spoke with him about current trends in immunotherapy for prostate cancer

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What are some of the more promising approaches to immunotherapy being investigated now?

Dr. Drake: I’m not 100% sure that everybody in the prostate cancer community is aware of this, but investigators at Merck did what is called a basket trial. They looked at patients with cancers that have a defect in what is called mismatch repair. Cancers that have a defective mismatch repair accumulate many mutations. Those mutations serve as antigens, or targets, for the immune system. It was first shown by Drs. Luis Diaz and Dung Le at Johns Hopkins that in colorectal cancer, where mismatch repair is common, checkpoint blockade with anti-PD-1 is very effective. It turns out that there are mismatch repair patients with every kind of cancer, including prostate cancer.

Based on this large basket trial, the anti-PD-1 antibody Keytruda (pembrolizumab) was recently approved for patients’ cancers that have mismatch repair defects. Across multiple tumor types, there have been really dramatic responses reported in the literature. This means that prostate cancer patients who have mismatch repair defects now have a second immunotherapy option. What percentage of prostate cancer patients have mismatch repair? It’s probably on the lower side, likely in the 3 to 5% range, but since prostate cancer is so common, that is actually a lot of patients.

I think that is fairly exciting and that perhaps the entire community is not completely aware that it is happening. True mismatch repair is rare in prostate cancer, but a significant fraction of patients have other mutations that lead to DNA damage repair defects. Those defects are different and are called DNA damage repair mutations. There have been some studies suggesting that this is actually pretty common in men with metastatic disease—as high as 10 to 20%. Those patients have been shown in a landmark paper by Dr. Johann de Bono published in the New England Journal of Medicine to respond to PARP inhibitors, which are reasonably well-tolerated oral drugs. There are now several ongoing trials testing this.

It is possible that these same patients might also respond to immunotherapy. I was part of a trial that Dr. Julie Graff published last summer that showed that out of the first 10 patients treated with Keytruda (pembrolizumab) who are progressing on Xtandi (enzalutamide), about three had a really beautiful response. Only one had true mismatch repair, but it could be that the other patients have mutations in DNA damage repair. That is important because that would extend the number of patients with prostate cancer who might be eligible for, or likely to respond to, anti-PD-1 or anti-PD-L1 agents.

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D’Amico On Surgery Versus Radiation

Dr. Anthony D’Amico is Professor of Radiation Oncology at Harvard Medical School and Chief of the Division of Genitourinary Radiation Oncology at Brigham and Women’s Hospital and Dana-Farber Cancer Institute in Boston, Massachusetts.

Dr. Anthony D’Amico is Professor of Radiation Oncology at Harvard Medical School and Chief of the Division of Genitourinary Radiation Oncology at Brigham and Women’s Hospital and Dana-Farber Cancer Institute in Boston, Massachusetts.

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

Are there any further thoughts on how radiation compares to surgery?

Dr. D’Amico: The ProtecT trial was published in the New England Journal of Medicine a couple of months ago. ProtecT is the first and only randomized study comparing surgery with radiation plus short-course hormones.

What I found very exciting about their results is that for 10 years we don’t see a difference in metastatic prostate cancer between the two major modalities of either radiation or surgery. It’s the first evidence that men with Gleason 6 or 7 prostate cancer truly have a choice between radiation therapy with short-course hormones or surgery. ProtecT is a randomized, 1,500-patient study. This is level-one evidence. ProtecT also shows that the quality of life men experience following these two treatments is very different. Two recent papers also show that even with advances in robotic prostatectomy and in radiation, the side effect profiles of those treatments have not really changed relative to one another. The absolute rates of toxicity have decreased, but you still have more urinary incontinence and erectile dysfunction with surgery and more bowel issues with radiation.

How do we rank surgery versus radiation, knowing as we do that cancer control is truly equivalent? Patients can choose their treatment based on the side effect profile alone and not worry that they may die of prostate cancer if they make the wrong choice.

So the choice of surgery versus radiation comes down to personal preference?

Dr. D’Amico: Correct. Just like in breast cancer: lumpectomy and radiation versus mastectomy? Women have a choice. Men with a Gleason 6 or 7 prostate cancer have a choice.

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D’Amico On Advances in Radiation Therapy

Dr. Anthony D’Amico is Professor of Radiation Oncology at Harvard Medical School and Chief of the Division of Genitourinary Radiation Oncology at Brigham and Women’s Hospital and Dana-Farber Cancer Institute in Boston, Massachusetts.

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

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Why did you become a doctor?

Dr. Anothony D’Amico: I was studying physics at Massachusetts Institute of Technology (MIT) when I was assigned jury duty. Believe it or not, one of the other jurors was a woman who later became my wife and whose mom happened to be the head of infectious disease nursing at a Boston hospital. I got exposed to medicine from her perspective. Then, when I was in graduate school, I lost a woman who was a second mom to me during my childhood to breast cancer. After that, I decided to cross-register at Harvard Medical School, which I could do as an MIT student. I took introductory medical school classes—anatomy and physiology. I had an amazing experience and discovered that the medical students sitting next to me in the classroom were much more like me in terms of their desire and ability to want to help others than the graduate students sitting next to me at MIT in my physics courses.

I completed my PhD at MIT in radiological physics and decided to go to medical school. It was an eight-year commitment. At that point, it meant starting all over again, but it definitely was the right decision. I have never regretted that decision nor looked back. I’m extremely grateful. The lesson I learned is that just because you’re good at something doesn’t necessarily mean it’s what you should do. I was really amazing at physics and I’m great at medicine now, but I wasn’t great at medicine when I started.

It’s funny the path life takes you on.

Dr. D’Amico: There are no accidents. Everything happens for a reason.

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

Dr. D’Amico: First of all, one of the most significant advances in our technical approach to radiation is image-guided radiation therapy (IGRT), which builds on intensity-modulated radiation therapy (IMRT).

Two decades ago, we had nothing to guide radiation treatment other than a regular x-ray, which only showed the bone. X-rays couldn’t see anything else: not the organs, not organ motion, not respiratory motion, nor any other factor that might go into making radiation therapy more precise.

From x-ray, we went to CT-based planning that allowed us to see some structure, but still didn’t fully account for motion.

Today, we have image-guided radiation therapy. We put markers in the organ—three gold seeds into the prostate or liver—and then take a picture each day, which shows us exactly where the target is. Using IMRT, we can create a radiation treatment that can treat a cancer the size of a dime with millimeter precision.

And we can account for motion. We can take pictures sequentially over seconds so that we can see how far the treatment area moves in one direction or the other when the patient is breathing. We can then sculpt the volume to account for respiratory and/or organ motion so we don’t miss the target.

Right now, we’re on the cusp of going from CT-based IMRT to MRI-based IMRT. MRI is a more sophisticated way of imaging structures that CT scans can’t see. For example, the very bottom of the prostate, where the nerve bundles that control erectile function reside, is not very well visualized on CT scan, but it is very well visualized on MRI.

We’re just now building machines that incorporate PET/CT that use functional imaging into radiation treatment planning and delivery. This means that we will be able to actually monitor the progress of a treatment as it is being delivered over the course of several weeks. We can see whether the cancer is now dead in a certain area or not, which means we can, in turn, modify treatment volume to make it smaller as we go along and only treat areas with still-viable cancer.

This is where we are right now in 2017. During the next five years, I expect that we’ll be able to use functional imaging to guide and sculpt your treatment while it is actually happening in real time.

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