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Sequencing Therapy in Castrate-Resistant Prostate Cancer

Insights From: Daniel Petrylak, MD, Yale University; Nicholas Vogelzang, MD, Comprehensive Cancer Center
Published: Wednesday, Mar 18, 2020



Transcript:

Nicholas Vogelzang, MD: Moving on to the castrate-resistant space, let’s say that you’ve given a patient docetaxel and ADT [androgen deprivation therapy], and you’re 6, 12 months into it, and the patient’s PSA [prostate-specific antigen] is still 4 ng/mL and beginning to rise. Where do you go next?

Daniel Petrylak, MD: If the PSA starts rising, I will go then to a next-generation antiandrogen such as abiraterone or enzalutamide as the first treatment. I also think of SIP-T [sipuleucel-T] in that situation as well. Sipuleucel-T from the data should be given early, before the PSA gets to 22 ng/mL is one of the thoughts. Remember back to the IMPACT trial, there are patients who had chemotherapy on that study.

Nicholas Vogelzang, MD: I know. And the median PSA was like 100 ng/mL and something.

Daniel Petrylak, MD: Exactly. I think that it’s underused, and I think it’s underappreciated. But it is a process that has activity, and it has a proven survival benefit.

Nicholas Vogelzang, MD: At ASCO GU [the American Society of Clinical Oncology Genitourinary annual meeting] this year, there was an interesting database analysis showing in, not a multivariate but certain single variate, that the sipuleucel-T in the era of second antiandrogen therapy, was still showing a survival advantage.

Daniel Petrylak, MD: Absolutely.

Nicholas Vogelzang, MD: I think we’re still underappreciating and not fully understanding the important role of sipuleucel-T in these patients.

Daniel Petrylak, MD: Exactly. I think too in underserved populations such as African-Americans, we know that sipuleucel-T seems to have a better survival benefit. The same thing with chemotherapy, if you adjust for the different poor prognostic factors. I think it also lends to the fact that for patients from different ethnic backgrounds, we should consider that in terms of our treatment.

Nicholas Vogelzang, MD: Moving then to the refractory castrate-resistant space, or landscape, where do you see as having had the most impact in the last several years?

This would be after sipuleucel-T. Is it the radium? Is it cabazitaxel? Is it PARP [poly ADP ribose polymerase] inhibitors there?

Daniel Petrylak, MD: I think right now the PARP inhibitors are going to have the most influence. And in some of the patients who I’ve treated both on and off study, I’ve seen some fairly dramatic and long-term responses.

Nicholas Vogelzang, MD: But in small populations.

Daniel Petrylak, MD: Small populations. Again, the issue is really trying to assess, first, we all have to check our patients molecularly now. This is now an absolute, absolute. You have to check them for MSI [microsatellite instability]. You have to check them now for DNA repair mutations, because we can make an impact on our patient’s care by administering drugs based upon these particular markers.

Nicholas Vogelzang, MD: It’s interesting, I just found 2 patients with Lynch syndrome, just by molecular testing. Not a very strong family history at all. So it’s like, look at that. Therefore, you have the needle IPI [ipilimumab] or PEMBRO [pembrolizumab] option for those patients.

Daniel Petrylak, MD: Exactly.

Nicholas Vogelzang, MD: In the sequencing changing landscape, sipuleucel-T, you still have radium in there, and then you have Jevtana, cabazitaxel, and then you have the PARP inhibitors. What’s your preferred sequence at that level?

Daniel Petrylak, MD: My preferred sequence is to go first with next-generation antiandrogen after sipuleucel-T; then to docetaxel chemotherapy; then to cabazitaxel chemotherapy; and then radium at some point if they have bone-only disease. Or if perhaps between the time they’ve had docetaxel and cabazitaxel, if they need a break from that type of treatment.

Nicholas Vogelzang, MD: There was an intriguing work from Emmanuel Antonarakis, MD, looking at sipuleucel-T and radium. I was intrigued by that because there were 4 PSA [prostrate-specific antigen] steep declines in a small population of patients, which we don’t usually see with either radium or sipuleucel-T. What’s your take on that?

Daniel Petrylak, MD: Well, I think it’s a very interesting biological observation. I think what also was interesting about that study is the fact that they looked at immune parameters. We would have expected that there would have been some upregulation of the immune function because of the abscopal effect that we see with radiation therapy. We saw actually the opposite, that there was a downregulation of some of the immune parameters they were looking at. I think the PSA observation is very intriguing. You do see some PSA declines with sipuleucel-T. I’ve seen it, and I’ve seen it with radium as well. The question really is, are we going to be getting more? And then mechanistically, what’s the  real issue here?

We’re seeing more and more now that we’re taking drugs and combining them that may have had little activity of single agents and seeing some very interesting synergistic patterns.

Nicholas Vogelzang, MD: He said, “We’re affecting the stroma. We don’t know much about the stroma and what that means in terms of supporting and allowing the growth of prostate cancer.” The bone marrow stroma is a target that really has not been addressed except potentially with Cabometyx.

Daniel Petrylak, MD: Exactly.

Nicholas Vogelzang, MD: And cabozantinib is an interesting drug. Where do you see those kind of drugs going, and particularly the TKI [tyrosine kinase inhibitor] combinations?

One of the most exciting abstracts at this meeting was a combination of cabozantinib along with atezolizumab. Both of these drugs really have, as an objective response rate and by PSA responses, a less than 10% rate. And we’re seeing a 28% rate of tumor shrinkage with responses in visceral sites such as liver. I think that we have to really understand more about the biology of the immune function. We know that cabozantinib can cause the reduction of myeloid suppressor cells, and this may be a way that we can convert a cold tumor to a hot tumor, and then we hit it with a checkpoint inhibitor. This is one of the fun things about being in this business right now, the biology is all coming to a focus, and we’re understanding more about how to take better care of patients.

Nicholas Vogelzang, MD: It’s a very complicated time because we’re now for the first time able to combine agents, and moreover, we’re seeing longer and longer response durations.

Daniel Petrylak, MD: Well, I think the fact that you mentioned about the stroma. We’ve always had tunnel vision of thinking about the tumor cell only. Now we have to think about this in terms of the environment and the actual patient and how there’s an interaction between the stroma and the tumor. And also, how the biology changes as you give drugs over time; the emergence of the neuroendocrine phenotype. This is evolution within the body. This is what’s so neat about looking at these particular systems, because they’re changing. And you can’t have unidimensional thought when you’re thinking about how to take care of these patients.

Transcript Edited for Clarity
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Transcript:

Nicholas Vogelzang, MD: Moving on to the castrate-resistant space, let’s say that you’ve given a patient docetaxel and ADT [androgen deprivation therapy], and you’re 6, 12 months into it, and the patient’s PSA [prostate-specific antigen] is still 4 ng/mL and beginning to rise. Where do you go next?

Daniel Petrylak, MD: If the PSA starts rising, I will go then to a next-generation antiandrogen such as abiraterone or enzalutamide as the first treatment. I also think of SIP-T [sipuleucel-T] in that situation as well. Sipuleucel-T from the data should be given early, before the PSA gets to 22 ng/mL is one of the thoughts. Remember back to the IMPACT trial, there are patients who had chemotherapy on that study.

Nicholas Vogelzang, MD: I know. And the median PSA was like 100 ng/mL and something.

Daniel Petrylak, MD: Exactly. I think that it’s underused, and I think it’s underappreciated. But it is a process that has activity, and it has a proven survival benefit.

Nicholas Vogelzang, MD: At ASCO GU [the American Society of Clinical Oncology Genitourinary annual meeting] this year, there was an interesting database analysis showing in, not a multivariate but certain single variate, that the sipuleucel-T in the era of second antiandrogen therapy, was still showing a survival advantage.

Daniel Petrylak, MD: Absolutely.

Nicholas Vogelzang, MD: I think we’re still underappreciating and not fully understanding the important role of sipuleucel-T in these patients.

Daniel Petrylak, MD: Exactly. I think too in underserved populations such as African-Americans, we know that sipuleucel-T seems to have a better survival benefit. The same thing with chemotherapy, if you adjust for the different poor prognostic factors. I think it also lends to the fact that for patients from different ethnic backgrounds, we should consider that in terms of our treatment.

Nicholas Vogelzang, MD: Moving then to the refractory castrate-resistant space, or landscape, where do you see as having had the most impact in the last several years?

This would be after sipuleucel-T. Is it the radium? Is it cabazitaxel? Is it PARP [poly ADP ribose polymerase] inhibitors there?

Daniel Petrylak, MD: I think right now the PARP inhibitors are going to have the most influence. And in some of the patients who I’ve treated both on and off study, I’ve seen some fairly dramatic and long-term responses.

Nicholas Vogelzang, MD: But in small populations.

Daniel Petrylak, MD: Small populations. Again, the issue is really trying to assess, first, we all have to check our patients molecularly now. This is now an absolute, absolute. You have to check them for MSI [microsatellite instability]. You have to check them now for DNA repair mutations, because we can make an impact on our patient’s care by administering drugs based upon these particular markers.

Nicholas Vogelzang, MD: It’s interesting, I just found 2 patients with Lynch syndrome, just by molecular testing. Not a very strong family history at all. So it’s like, look at that. Therefore, you have the needle IPI [ipilimumab] or PEMBRO [pembrolizumab] option for those patients.

Daniel Petrylak, MD: Exactly.

Nicholas Vogelzang, MD: In the sequencing changing landscape, sipuleucel-T, you still have radium in there, and then you have Jevtana, cabazitaxel, and then you have the PARP inhibitors. What’s your preferred sequence at that level?

Daniel Petrylak, MD: My preferred sequence is to go first with next-generation antiandrogen after sipuleucel-T; then to docetaxel chemotherapy; then to cabazitaxel chemotherapy; and then radium at some point if they have bone-only disease. Or if perhaps between the time they’ve had docetaxel and cabazitaxel, if they need a break from that type of treatment.

Nicholas Vogelzang, MD: There was an intriguing work from Emmanuel Antonarakis, MD, looking at sipuleucel-T and radium. I was intrigued by that because there were 4 PSA [prostrate-specific antigen] steep declines in a small population of patients, which we don’t usually see with either radium or sipuleucel-T. What’s your take on that?

Daniel Petrylak, MD: Well, I think it’s a very interesting biological observation. I think what also was interesting about that study is the fact that they looked at immune parameters. We would have expected that there would have been some upregulation of the immune function because of the abscopal effect that we see with radiation therapy. We saw actually the opposite, that there was a downregulation of some of the immune parameters they were looking at. I think the PSA observation is very intriguing. You do see some PSA declines with sipuleucel-T. I’ve seen it, and I’ve seen it with radium as well. The question really is, are we going to be getting more? And then mechanistically, what’s the  real issue here?

We’re seeing more and more now that we’re taking drugs and combining them that may have had little activity of single agents and seeing some very interesting synergistic patterns.

Nicholas Vogelzang, MD: He said, “We’re affecting the stroma. We don’t know much about the stroma and what that means in terms of supporting and allowing the growth of prostate cancer.” The bone marrow stroma is a target that really has not been addressed except potentially with Cabometyx.

Daniel Petrylak, MD: Exactly.

Nicholas Vogelzang, MD: And cabozantinib is an interesting drug. Where do you see those kind of drugs going, and particularly the TKI [tyrosine kinase inhibitor] combinations?

One of the most exciting abstracts at this meeting was a combination of cabozantinib along with atezolizumab. Both of these drugs really have, as an objective response rate and by PSA responses, a less than 10% rate. And we’re seeing a 28% rate of tumor shrinkage with responses in visceral sites such as liver. I think that we have to really understand more about the biology of the immune function. We know that cabozantinib can cause the reduction of myeloid suppressor cells, and this may be a way that we can convert a cold tumor to a hot tumor, and then we hit it with a checkpoint inhibitor. This is one of the fun things about being in this business right now, the biology is all coming to a focus, and we’re understanding more about how to take better care of patients.

Nicholas Vogelzang, MD: It’s a very complicated time because we’re now for the first time able to combine agents, and moreover, we’re seeing longer and longer response durations.

Daniel Petrylak, MD: Well, I think the fact that you mentioned about the stroma. We’ve always had tunnel vision of thinking about the tumor cell only. Now we have to think about this in terms of the environment and the actual patient and how there’s an interaction between the stroma and the tumor. And also, how the biology changes as you give drugs over time; the emergence of the neuroendocrine phenotype. This is evolution within the body. This is what’s so neat about looking at these particular systems, because they’re changing. And you can’t have unidimensional thought when you’re thinking about how to take care of these patients.

Transcript Edited for Clarity
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