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Metastatic CSPC: Toxicity Management & Future Treatment

Insights From:Alicia Morgans, MD, MPH, Northwestern University Feinberg School of Medicine; Matthew R. Smith, MD, PhD, Massachusetts General Hospital Cancer Center
Published: Monday, Jan 13, 2020



Transcript: 

Alicia Morgans, MD, MPH:
When patients are choosing among agents for metastatic CSPC [castration-sensitive prostate cancer], I’m sure they have to think about toxicities; certainly, we do in my clinic. The toxicities are very different between chemotherapy and the AR [androgen receptor]–directed agents. Chemotherapy is more of an intense set of adverse events or patient-experienced events. In the 18 weeks during treatment, the AR-directed therapies are more of a long-term chronic exposure, but this is a much less intense experience in terms of adverse events.

The toxicities of chemotherapy are things like hair loss, nausea, the risk of neutropenia. The things that are associated with the AR-directed agents are much less severe, I would say, but go on for a longer duration of time. These are things like some fatigue associated with enzalutamide, the need to use prednisone for abiraterone, and hypothyroidism and rash associated with apalutamide. They’re all quite different, but certainly we can talk with our patients and choose among these agents. Importantly, some patients choose things like enzalutamide or apalutamide because of the lack of prednisone, which should be acknowledged.

My advice for approaching a patient regarding toxicities is to first choose between an AR-directed oral therapy or chemotherapy as your initial treatment for metastatic castration-sensitive prostate cancer. Once that decision is made, and that’s really a discussion about a daily pill versus an intense 18 weeks of chemotherapy, one can really dig into the adverse effects associated with the AR-directed therapies. I think about this as either being a prednisone-associated treatment, which is quite well tolerated but also requires a daily dose of prednisone, or the options that don’t require prednisone. So it’s abiraterone with prednisone, or apalutamide or enzalutamide without prednisone.

When I’m thinking about choosing from agents that don’t require prednisone, enzalutamide is an option for which we have much experience. We know that there is, for some patients, a certain level of fatigue that they experience, a potential risk of falls, and sometimes some cognitive slowing. Apalutamide, a newer drug, may be associated with a little less fatigue, and certainly this was what was reported in the TITAN data, though there have not been head-to-head data looking at enzalutamide versus apalutamide. We do know that some patients do develop hypothyroidism, and some patients actually can get a rash with this as well. It’s really thinking about all these different options, all of them actually being good options, but talking through what you would rather deal with, as a patient, in that clinical conversation.

Matthew R. Smith, MD, PhD: There have been really meaningful advances in the treatment of prostate cancer in recent years, with a variety of therapies that increase both progression-free survival and overall survival. But there remain significant unmet medical needs. Most patients who present with metastatic prostate cancer will go on to die of their disease. And while men are living longer and living better as a consequence of recently approved therapies, we really need to continue to improve our options for treating men and to allow them to live longer with the ultimate goal of actually curing at least some patients with metastatic prostate cancer.

Alicia Morgans, MD, MPH: There are multiple other drugs in development for metastatic castration-resistant disease that we do hope will move into metastatic castration-sensitive prostate cancer. The most exciting, at this point, is lutetium, which is a radiopharmaceutical targeting PSMA [prostate-specific membrane antigen] that delivers a radioactive payload that seems to be at least very effectively able to lower PSA [prostate-specific antigen]. There’s currently a phase III trial that is ongoing, but we’ll see if this can prolong overall survival. This is very exciting, and again, is something we’re moving into the metastatic castration-sensitive setting. Hopefully a trial will be launching next year related to that.

The other set of drugs that I think are furthest along and very exciting are the PARP inhibitors. Again, there are multiple PARP inhibitors available. These have been shown to improve radiographic progression-free survival in a recently reported trial. At least 1 of them has, and there are others that are coming along the way that look to have very promising results as well. These agents are coming, and I think we’re very excited. They seem to be for targeted populations, but we’ll see how we can use them either alone or in combination to really prolong lives of men with prostate cancer and hopefully make them feel better as well.

Matthew R. Smith, MD, PhD: The landscape for prostate cancer treatment continues to evolve in sometimes unpredictable ways. Some of the better understanding of the biology of prostate cancer in recent years has led us really in 2 directions. First, there’s an understanding that there is a small subset of patients who benefit from checkpoint inhibition. Those are patients with mismatch repair defects. Then there’s a somewhat larger minority of patients who have DNA repair defects. Preliminary evidence suggests that they benefit from use of PARP inhibitors. Really, that age of precision oncology has now come to prostate cancer, and 1 of the important parts of that in managing patients with advanced disease, particularly as they progress through some of our standard therapies, is to look for tumor mutations that would predict response or benefit to either a checkpoint inhibitor or a PARP inhibitor.

The progress that’s been made in prostate cancer in the last few years really would have been hard to predict a decade ago. We now have this abundance of new drugs that prove to treat the disease, and extension of the label of those drugs to settings that really weren’t previously appreciated. I anticipate that progress will continue and that we’ll have not only new drugs but a better understanding of the use of our currently available therapies.

Alicia Morgans, MD, MPH: My advice for medical oncologists and urologists who are treating metastatic castration-sensitive prostate cancer is that the landscape is becoming very, very crowded. What I would very strongly advise is that we have candid conversations with our patients about the adverse-effect profiles and the way we administer these drugs, the co-pays that patients have to pay, the time that they may need to stay out of work, and the things that matter to them in their daily lives that are different with all these drugs. This can really make a difference to them as they’re making this choice.

The other piece of advice that I would give—and I think many of us are already doing this—is that we, as a community treating men with prostate cancer, need to work together. Urologists and medical oncologists need to partner, because there are issues that might be best dealt with by a medical oncologist, as well as issues that might be best dealt with by a urologist, and sometimes by a radiation oncologist in this patient population. We owe it to them to give them the specialists they need to really work together, put our heads together, and get the best outcomes for our patients.


Transcript Edited for Clarity
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Transcript: 

Alicia Morgans, MD, MPH:
When patients are choosing among agents for metastatic CSPC [castration-sensitive prostate cancer], I’m sure they have to think about toxicities; certainly, we do in my clinic. The toxicities are very different between chemotherapy and the AR [androgen receptor]–directed agents. Chemotherapy is more of an intense set of adverse events or patient-experienced events. In the 18 weeks during treatment, the AR-directed therapies are more of a long-term chronic exposure, but this is a much less intense experience in terms of adverse events.

The toxicities of chemotherapy are things like hair loss, nausea, the risk of neutropenia. The things that are associated with the AR-directed agents are much less severe, I would say, but go on for a longer duration of time. These are things like some fatigue associated with enzalutamide, the need to use prednisone for abiraterone, and hypothyroidism and rash associated with apalutamide. They’re all quite different, but certainly we can talk with our patients and choose among these agents. Importantly, some patients choose things like enzalutamide or apalutamide because of the lack of prednisone, which should be acknowledged.

My advice for approaching a patient regarding toxicities is to first choose between an AR-directed oral therapy or chemotherapy as your initial treatment for metastatic castration-sensitive prostate cancer. Once that decision is made, and that’s really a discussion about a daily pill versus an intense 18 weeks of chemotherapy, one can really dig into the adverse effects associated with the AR-directed therapies. I think about this as either being a prednisone-associated treatment, which is quite well tolerated but also requires a daily dose of prednisone, or the options that don’t require prednisone. So it’s abiraterone with prednisone, or apalutamide or enzalutamide without prednisone.

When I’m thinking about choosing from agents that don’t require prednisone, enzalutamide is an option for which we have much experience. We know that there is, for some patients, a certain level of fatigue that they experience, a potential risk of falls, and sometimes some cognitive slowing. Apalutamide, a newer drug, may be associated with a little less fatigue, and certainly this was what was reported in the TITAN data, though there have not been head-to-head data looking at enzalutamide versus apalutamide. We do know that some patients do develop hypothyroidism, and some patients actually can get a rash with this as well. It’s really thinking about all these different options, all of them actually being good options, but talking through what you would rather deal with, as a patient, in that clinical conversation.

Matthew R. Smith, MD, PhD: There have been really meaningful advances in the treatment of prostate cancer in recent years, with a variety of therapies that increase both progression-free survival and overall survival. But there remain significant unmet medical needs. Most patients who present with metastatic prostate cancer will go on to die of their disease. And while men are living longer and living better as a consequence of recently approved therapies, we really need to continue to improve our options for treating men and to allow them to live longer with the ultimate goal of actually curing at least some patients with metastatic prostate cancer.

Alicia Morgans, MD, MPH: There are multiple other drugs in development for metastatic castration-resistant disease that we do hope will move into metastatic castration-sensitive prostate cancer. The most exciting, at this point, is lutetium, which is a radiopharmaceutical targeting PSMA [prostate-specific membrane antigen] that delivers a radioactive payload that seems to be at least very effectively able to lower PSA [prostate-specific antigen]. There’s currently a phase III trial that is ongoing, but we’ll see if this can prolong overall survival. This is very exciting, and again, is something we’re moving into the metastatic castration-sensitive setting. Hopefully a trial will be launching next year related to that.

The other set of drugs that I think are furthest along and very exciting are the PARP inhibitors. Again, there are multiple PARP inhibitors available. These have been shown to improve radiographic progression-free survival in a recently reported trial. At least 1 of them has, and there are others that are coming along the way that look to have very promising results as well. These agents are coming, and I think we’re very excited. They seem to be for targeted populations, but we’ll see how we can use them either alone or in combination to really prolong lives of men with prostate cancer and hopefully make them feel better as well.

Matthew R. Smith, MD, PhD: The landscape for prostate cancer treatment continues to evolve in sometimes unpredictable ways. Some of the better understanding of the biology of prostate cancer in recent years has led us really in 2 directions. First, there’s an understanding that there is a small subset of patients who benefit from checkpoint inhibition. Those are patients with mismatch repair defects. Then there’s a somewhat larger minority of patients who have DNA repair defects. Preliminary evidence suggests that they benefit from use of PARP inhibitors. Really, that age of precision oncology has now come to prostate cancer, and 1 of the important parts of that in managing patients with advanced disease, particularly as they progress through some of our standard therapies, is to look for tumor mutations that would predict response or benefit to either a checkpoint inhibitor or a PARP inhibitor.

The progress that’s been made in prostate cancer in the last few years really would have been hard to predict a decade ago. We now have this abundance of new drugs that prove to treat the disease, and extension of the label of those drugs to settings that really weren’t previously appreciated. I anticipate that progress will continue and that we’ll have not only new drugs but a better understanding of the use of our currently available therapies.

Alicia Morgans, MD, MPH: My advice for medical oncologists and urologists who are treating metastatic castration-sensitive prostate cancer is that the landscape is becoming very, very crowded. What I would very strongly advise is that we have candid conversations with our patients about the adverse-effect profiles and the way we administer these drugs, the co-pays that patients have to pay, the time that they may need to stay out of work, and the things that matter to them in their daily lives that are different with all these drugs. This can really make a difference to them as they’re making this choice.

The other piece of advice that I would give—and I think many of us are already doing this—is that we, as a community treating men with prostate cancer, need to work together. Urologists and medical oncologists need to partner, because there are issues that might be best dealt with by a medical oncologist, as well as issues that might be best dealt with by a urologist, and sometimes by a radiation oncologist in this patient population. We owe it to them to give them the specialists they need to really work together, put our heads together, and get the best outcomes for our patients.


Transcript Edited for Clarity
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