expert roundtables

Metastatic Consequences of Advanced Prostate Cancer

by Peter R. Carroll, MD, MPH, E. David Crawford, MD, Leonard Gomella, MD, and Neal D. Shore, MD, FACS

Overview

Top experts in the field discuss the considerations of advanced prostate cancer, locoregional vs distant metastases, the number of sites, the biology, and the availability of new biomarkers when selecting appropriate therapy.

Q:

What are the metastatic consequences of advanced prostate cancer?

Peter R. Carroll, MD, MPH

Ken and Donna Derr – Chevron Distinguished Professor
Taube Family Distinguished Professor in Urology
Department of Urology
UCSF - Helen Diller Comprehensive Cancer Center
University of California, San Francisco
San Francisco, CA

I think the issue here is what disease state we are talking about. Metastatic disease could present before initial treatment in patients who are newly diagnosed vs those who failed standard therapy and relapsed with a rising prostate-specific antigen (PSA). I think the considerations here are going to depend on the disease state, locoregional vs distant metastases, the number of sites, and the biology – and this is where these molecular markers such as androgen-receptor splice variant 7 messenger RNA (AR-V7) come in to define the biology. Germ-line testing with hormonal-refractory disease has given us some insight into patients who may be candidates for poly ADP ribose polymerase (PARP) inhibitors. Advanced imaging, molecular profiling, disease state, symptoms – all of these things are considered when choosing treatment. As a result, we have had more precise recommendations based on much better evidence than in the past. So, we are treating much less in a vacuum now, and more with a better understanding of the extent of disease.

I would probably characterize the advances as relevant to subsets of patients, but people are racing into this field, and with a better understanding of biology, of course, you develop new targets. However, I think there will also be some wholesale changes. The way we manage low-risk disease is a wholesale change that could probably affect >40% of men currently diagnosed with prostate cancer in this country. On the other end of the spectrum, the data with docetaxel plus androgen-deprivation therapy (ADT) have been remarkable. I always say that we march toward the middle. In other words, we have seen these big changes in those with low-risk disease, and at the other end of the spectrum in those with metastatic disease. And now what I think you are seeing is medical oncologists and urologists marching toward the middle. You will see that we may be able to offer active surveillance to more men, based on molecular profiling. Alternatively, some of these systemic therapies will be offered earlier in the course of disease than we do currently.

“I always say that we march toward the middle. In other words, we have seen these big changes in those with low-risk disease, and at the other end of the spectrum in those with metastatic disease. And now what I think you are seeing is medical oncologists and urologists marching toward the middle.”

Peter R. Carroll, MD

Neal D. Shore, MD, FACS

Medical Director and CPI Carolina Urologic Research Center Managing Partner, Atlantic Urology Clinics
Myrtle Beach, SC

Most patients who develop metastatic disease, if they have been followed pretty closely during the transition from androgen sensitive to castration resistant, are going to be asymptomatic. If they have documentation of radiographic disease and they are asymptomatic and or have M1 castration-resistant prostate cancer (CRPC), I am happy to discuss with them the options of sipuleucel-T, and/or starting a novel oral hormonal therapy – either abiraterone acetate or enzalutamide. We’ve generated some phase 2 data demonstrating very nicely that one can combine sipuleucel-T with either abiraterone acetate or with enzalutamide. And usually because sipuleucel-T is given over such a short period of time – 4 to 6 weeks – that’s not really a challenge or a concern to start concomitant therapy. If the patient finishes the sipuleucel-T and is then started on a novel oral hormonal therapy, and then for example he has bone-predominant disease, and maybe with some small soft tissue disease, but no visceral disease – which is a very common presentation – I’ll start him on an oral therapy after we review the advantages and disadvantages of the 2 therapies. Patients can have a very long response of something between 12 and 24 months; however, sometimes it is much shorter. If the PSA starts to rise, and the patient is not necessarily showing any radiographic progression of disease and no change in symptomatology, I will keep that therapy and will rarely make a switch – unless I am looking at a clinical trial. If there are new lesions and/or any symptomatology change, then I will be very quick to switch to another therapy. I am not a proponent of switching from abiraterone to enzalutamide or enzalutamide to abiraterone, unless it’s part of a clinical study. In a real-world practice, I’d much rather consider getting in a window of opportunity to use radium-223 when appropriate – if indeed the patient is having some new symptomatology related to his bone disease, and there’s a good window of opportunity in my judgment that the patient can complete 5 to 6 cycles for the recommended course of radium-223.

“I am not a proponent of switching from abiraterone to enzalutamide or enzalutamide to abiraterone, unless it’s part of a clinical study. In a real-world practice, I’d much rather consider getting in a window of opportunity to use radium-223, when appropriate.”

Neal D. Shore, MD, FACS

I inform my patients that the use of all of these therapies is something that I want them to receive over time. I start with what I think are going to be the most tolerable therapies appropriate for the phenotype of their disease, based upon their symptoms and the rapidity of their disease progression radiographically and/or with serologic parameters such as PSA, hemoglobin, lactate dehydrogenase, and alkaline phosphatase. I have a conversation with them frequently that, at some point, they will certainly be offered and most likely will have very good benefit from taxane-based chemotherapy, which will include either docetaxel or cabazitaxel.

Q:

Dr Gomella, any thoughts on the layering of agents or what you start with when you have symptomatic metastases?

Leonard Gomella, MD

Chairman, Department of Urology
Bernard W. Godwin, Jr. Professor of Prostate Cancer
Sidney Kimmel Medical College
Sidney Kimmel Cancer Center
Thomas Jefferson University
Philadelphia, PA

The only thing that literature has supported so far in this area, I think, is with regard to the patients who are likely to respond best to sipuleucel-T, those with minimally symptomatic or asymptomatic metastatic CRPC (mCRPC). Once you get beyond that, it becomes almost a “dealer’s choice” as to which agent to prescribe – although if the patient presents with very severe symptoms, a lot of our colleagues will go right to a chemotherapy regimen, such as docetaxel or radium-223. There is a spectrum of how patients present, however, and I think in the modern world, patients are not really coming in with disease that is as symptomatic as it might have been in the past. Because hopefully if men have been treated for local disease and then they progress to metastatic disease, and then to a castrate-resistant space, they’re being followed fairly closely. The evolution of their symptoms may not present as severely as it might have, say 15 or 20 years ago, with patients coming in with spinal cord compression or pathologic hip fractures. Beyond minimal disease with sipuleucel-T being one of those agents that you might want to think about first, everything else after that – unless the patient is really severely symptomatic – is really coming down to whether somebody wants to use abiraterone or enzalutamide or radium-223 or docetaxel or other agents. It’s really up to the individual clinician and their comfort level in conjunction with the patient and individual characteristics of the patient.

Q:

What about radiation? What number of bone metastases becomes limiting whereby it is impractical to do radiation?

Leonard Gomella, MD

Chairman, Department of Urology
Bernard W. Godwin, Jr. Professor of Prostate Cancer
Sidney Kimmel Medical College
Sidney Kimmel Cancer Center
Thomas Jefferson University
Philadelphia, PA

I don’t know how my colleagues feel about that. At our location, if stereotactic body radiation must be performed on more than 2 or 3 lesions, my colleagues get cautious and think more about systemic treatment like radium-223. This is due to the potential bone marrow toxicity of radiating more than 2 or 3 lesions, particularly if they are in the pelvis or in the vertebral body, and you are going to significantly impact the marrow.

E. David Crawford, MD

Professor of Urology
University of California, San Diego
Former, Distinguished Endowed Professor of Surgery, Urology, and Radiation Oncology
Head, Section of Urologic Oncology
University of Colorado Anschutz Medical Campus
Aurora, CO

Just adding to what Dr Gomella said, and others, several years ago when we had ADT, orchiectomy, estrogen, and luteinizing hormone-releasing hormone (LHRH) agonists, we did studies with combined androgen blockade, and when people failed, that was about it. In the Southwest Oncology Group, we pretty much studied every chemotherapy drug known to mankind, with not a lot of positive results until docetaxel was studied. Dan Petrylak, from our group, and others had done studies with docetaxel, showing that it improved the outcome in men who failed hormonal therapy – so that was a big step. And it wasn’t a giant step for mankind; it was a step forward with a few months of survival benefit that had not been seen before. So, all of a sudden, we had something to offer – docetaxel. And now, what’s happened is that docetaxel has sort of been pushed back to the end, because we have all these other agents that we have been talking about: abiraterone, enzalutamide, sipuleucel-T, radium-223, even cabazitaxel, and others. All have sort of displaced docetaxel. Many studies show that you can delay the time to chemotherapy, which is an important thing. Currently, we have been inundated with all these new biomarkers that help us. Now there’s ARV-7 and others that say, hey, you are not responding to enzalutamide or abiraterone, and chemotherapy works. So, we are getting more into the personalized medicine thing. But as Dr Gomella just said, when somebody presents with this metastatic castrate-resistant disease, it opens the door for all these drugs: how do you layer them? There are really good data about doing more than just one.

For sipuleucel-T, if you get that in early, we’ve shown that if your PSA is <20 ng/mL, then you have a 13-month survival benefit. You can add abiraterone to that, and then you can add enzalutamide to that, and you can start compounding these benefits. Radium-223 is unique: it’s an alpha particle, it’s large, it’s the only radiopharmaceutical to show an improvement in survival rate in mCRPC, and it’s not just for patients that are writhing in bone pain at the end of the line. The FDA approval is not simply to reduce pain, but it’s also for bone disease and improving outcomes – so that should be used earlier. There is a lot of excitement right now about these new drugs. How are we going to put them together, and how are we going to have an impact? We have already seen that. Survival rates for advanced and castrate-resistant disease are increasing significantly. I may be an optimist, but one day, with all these new drugs, maybe we will be able to convert prostate cancer to a chronic disease, like diabetes and heart disease – we don’t cure it, but we treat it. And I think that is something that could come to fruition in not too long a period of time.

“I may be an optimist, but one day, with all these new drugs, maybe we will be able to convert prostate cancer to a chronic disease, like diabetes and heart disease – we don’t cure it, but we treat it.”

E. David Crawford, MD

References

Liu LL, Xie N, Sun S, Plymate S, Mostaghel E, Dong X. Mechanisms of the androgen receptor splicing in prostate cancer cells. Oncogene. 2014;33(24):3140-3150.

Petrylak DP. Docetaxel for the treatment of hormone-refractory prostate cancer. Rev Urol. 2003; 5(Suppl 3):S14-S21.

Schellhammer PF, Chodak G, Whitmore JB, Sims R, Frohlich MW, Kantoff PW. Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial. Urology. 2013;81(6):1297-1302.

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