ONCAlert | Upfront Therapy for mRCC

Case 3: Selecting Therapy For Recurrent Disease

Targeted Oncology
Published Online:12:35 PM, Wed June 5, 2019


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Robert L. Coleman, MD: Shannon, these are 3 drugs that have very similar actions. But what kind of differences do we see? Or are they all tolerated the same?

Shannon N. Westin, MD: Overall, they’re generally well tolerated, as we talked about before in the last case. There are a proportion of patients who are going to require a dose interruption and a dose reduction. There are some subtle differences. There are certain class effects that we see across all PARP [poly (ADP ribose) polymerase] inhibitors. The GI [gastrointestinal] toxicity, nausea, anorexia, GERD [gastroesophageal reflux disease] symptoms—we’re going to see those kinds of things across all the PARP inhibitors. Fatigue is definitely a class effect and is definitely seen across all 3 FDA-approved drugs. But then you start to see little things that are a little bit different. You may see myelosuppression, in general. It does seem as if maybe there’s a little bit more anemia with olaparib, and definitely more thrombocytopenia, depending on the dose, with niraparib. The liver function test elevation that’s seen with rucaparib is typically somewhat unique, although, importantly, it is generally not associated with liver toxicity. It’s a lab value that you just have to kind of ride out. I think those are the major things. The only other thing I’d mention is that we’ve seen quite a bit of elevated creatinine. Many times, you see that someone maybe is not as comfortable or doesn’t really know the class effect of these drugs and doesn’t realize that this is all related to the renal transporters of creatinine across the membrane. And so you could see this elevation of creatinine again without a renal toxicity, similar to what we see with the liver. You just again have to ride that out and potentially check the true GFR [glomerular filtration rate] with a nuclear medicine study. But you don’t necessarily even need to dose interrupt for that.

David O’Malley, MD: Niraparib had a higher rate of thrombocytopenia, but it is the only commercially available product with once-a-day dosing. So it’s a little bit more convenient but clearly is a bit of an outlier on the hematologic toxicity.

Robert L. Coleman, MD: Yeah. We’ve also seen some of the hypertension issues show up.

Susana M. Campos, MD, MPH: But to your point—the RADAR data, Weights and Plates [baseline weights and baseline platelets]—I think when they first marketed this drug at 300 mg every day, it was probably way too high for a certain select group of individuals. Although it’s interesting. I think they never actually fail to surprise me. I had a young woman who I started the olaparib. She was beet-red 24 hours after giving olaparib. These are new drugs to all of us, and I think that’s the other thing you have to always keep in mind. There are surprises around the corner each time, so pay attention.

Robert L. Coleman, MD: I think Shannon even had a patient with a rash that we saw that I don’t think I’ve seen since.

Shannon N. Westin, MD: It was the craziest rash. It didn’t look like any TKI [tyrosine kinase inhibitor] rash. It didn’t look like a chemotherapy rash.

Robert L. Coleman, MD: Thick plaques.

Shannon N. Westin, MD: These blotchy plaques.

David O’Malley, MD: And not only that, we’re seeing them pop up after a prolonged period. So I think the chronicity and the toxicities, as we see patients on these for years, may change over time.

Shannon N. Westin, MD: And that brings up MDS [myelodysplastic syndrome].

Robert L. Coleman, MD: Yeah, I was just going to ask about that. How long do you guys treat?

Shannon N. Westin, MD: And AML. So with the long-term toxicity data, you see about a 1% rate, or less than 1%, across all 3. What we don’t know is if you continue the PARP longer, do you have an increased rate? I haven’t seen data around the duration.

Robert L. Coleman, MD: If there are any, they will come out in the Study 19 data.

Susana M. Campos, MD, MPH: Exactly, yeah.

Robert L. Coleman, MD: Because they’ve had it for so long. I know there are patients on them for 4 or 5 years.

Shannon N. Westin, MD: And I think when they reported, they updated MDS, AML [acute myeloid leukemia]. They didn’t see an increase from what they initially reported.

Robert L. Coleman, MD: Right.

David O’Malley, MD: It’s unbelievably consistent across the class—1% plus or minus a half. But when we look at previous platinum as a background risk, it’s pretty close to that.

Robert L. Coleman, MD: Exactly.

Susana M. Campos, MD, MPH: I think it’s also confounded by the number of cycles of therapy that this patient has gotten over the course of time. Is it really truly going to isolate that effect for that particular drug or not? Perhaps it’s a summation of all the drugs that they’ve actually had?

David O’Malley, MD: If we’re using a PARP earlier, are we actually going to see the MDS drop because they’ll have less platinum?

Robert L. Coleman, MD: It might be, yeah. That’s an interesting point. In the SOLO-1 data, we gave it for 2 years. In the recurrent setting, do we have an upper limit?

David O’Malley, MD: I don’t stop. In the recurrent setting, if they’re benefiting, I will continue indefinitely.

Robert L. Coleman, MD: So you’re going to titrate the dose to make sure they can stay on?

David O’Malley, MD: Correct. I think it’s about managing symptoms.

Robert L. Coleman, MD: Let me just cover 1 quick point here. She was wild type when she came in. And before we started, we didn’t know what her response rate was going to be. We have that whole bevacizumab-versus-PARP question, right? And I know how you feel about this. You’re going to say, “Well, if we don’t give it now, we’re never going to give it to her.” Is that the most effective option?

Shannon N. Westin, MD: I think you’ve kind of alluded to this: Pure response. If you want to get them to maintenance, you have a higher response rate when you give chemotherapy in combination with bevacizumab in the BRCA wild-type population. In the ARIEL2 data, you saw an 80% response rate in that BRCA-mutant population. But for OCEANS, for GOG-213, you can get from about a 50% response rate up to about an 80% response rate.

Robert L. Coleman, MD: That’s right.

Shannon N. Westin, MD: And so, those patients actually can go to maintenance. So there’s a lot of impulse to potentially do that.

Susana M. Campos, MD, MPH: There’s always this question of the obsolete in a couple of years when we have the results of other trials.

Robert L. Coleman, MD: Like PAOLA-1, right?

David O’Malley, MD: A brilliant friend of mine once coined a phrase “switch maintenance” but then refuses to talk about switch maintenance…

Robert L. Coleman, MD: I don’t who you’re talking about. It wasn’t me.

David O’Malley, MD: Give them bevacizumab with the cytotoxic drug. Get your highest CR [complete response] and your highest PR [partial response] with bevacizumab. There’s nothing wrong with switch maintenance. I have zero data.

Robert L. Coleman, MD: But that’s never stopped you before.

David O’Malley, MD: Exactly. But I do think in a wild-type population, we know a certain percentage are going to benefit markedly from these medications. In a wild-type population, the only time they’re going to be able to get that medication, in our current data, is in the maintenance, platinum-sensitive setting.

Susana M. Campos, MD, MPH: At the end of the day, they’ll either tolerate it and respond or not.

Transcript edited for clarity.


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Robert L. Coleman, MD: Shannon, these are 3 drugs that have very similar actions. But what kind of differences do we see? Or are they all tolerated the same?

Shannon N. Westin, MD: Overall, they’re generally well tolerated, as we talked about before in the last case. There are a proportion of patients who are going to require a dose interruption and a dose reduction. There are some subtle differences. There are certain class effects that we see across all PARP [poly (ADP ribose) polymerase] inhibitors. The GI [gastrointestinal] toxicity, nausea, anorexia, GERD [gastroesophageal reflux disease] symptoms—we’re going to see those kinds of things across all the PARP inhibitors. Fatigue is definitely a class effect and is definitely seen across all 3 FDA-approved drugs. But then you start to see little things that are a little bit different. You may see myelosuppression, in general. It does seem as if maybe there’s a little bit more anemia with olaparib, and definitely more thrombocytopenia, depending on the dose, with niraparib. The liver function test elevation that’s seen with rucaparib is typically somewhat unique, although, importantly, it is generally not associated with liver toxicity. It’s a lab value that you just have to kind of ride out. I think those are the major things. The only other thing I’d mention is that we’ve seen quite a bit of elevated creatinine. Many times, you see that someone maybe is not as comfortable or doesn’t really know the class effect of these drugs and doesn’t realize that this is all related to the renal transporters of creatinine across the membrane. And so you could see this elevation of creatinine again without a renal toxicity, similar to what we see with the liver. You just again have to ride that out and potentially check the true GFR [glomerular filtration rate] with a nuclear medicine study. But you don’t necessarily even need to dose interrupt for that.

David O’Malley, MD: Niraparib had a higher rate of thrombocytopenia, but it is the only commercially available product with once-a-day dosing. So it’s a little bit more convenient but clearly is a bit of an outlier on the hematologic toxicity.

Robert L. Coleman, MD: Yeah. We’ve also seen some of the hypertension issues show up.

Susana M. Campos, MD, MPH: But to your point—the RADAR data, Weights and Plates [baseline weights and baseline platelets]—I think when they first marketed this drug at 300 mg every day, it was probably way too high for a certain select group of individuals. Although it’s interesting. I think they never actually fail to surprise me. I had a young woman who I started the olaparib. She was beet-red 24 hours after giving olaparib. These are new drugs to all of us, and I think that’s the other thing you have to always keep in mind. There are surprises around the corner each time, so pay attention.

Robert L. Coleman, MD: I think Shannon even had a patient with a rash that we saw that I don’t think I’ve seen since.

Shannon N. Westin, MD: It was the craziest rash. It didn’t look like any TKI [tyrosine kinase inhibitor] rash. It didn’t look like a chemotherapy rash.

Robert L. Coleman, MD: Thick plaques.

Shannon N. Westin, MD: These blotchy plaques.

David O’Malley, MD: And not only that, we’re seeing them pop up after a prolonged period. So I think the chronicity and the toxicities, as we see patients on these for years, may change over time.

Shannon N. Westin, MD: And that brings up MDS [myelodysplastic syndrome].

Robert L. Coleman, MD: Yeah, I was just going to ask about that. How long do you guys treat?

Shannon N. Westin, MD: And AML. So with the long-term toxicity data, you see about a 1% rate, or less than 1%, across all 3. What we don’t know is if you continue the PARP longer, do you have an increased rate? I haven’t seen data around the duration.

Robert L. Coleman, MD: If there are any, they will come out in the Study 19 data.

Susana M. Campos, MD, MPH: Exactly, yeah.

Robert L. Coleman, MD: Because they’ve had it for so long. I know there are patients on them for 4 or 5 years.

Shannon N. Westin, MD: And I think when they reported, they updated MDS, AML [acute myeloid leukemia]. They didn’t see an increase from what they initially reported.

Robert L. Coleman, MD: Right.

David O’Malley, MD: It’s unbelievably consistent across the class—1% plus or minus a half. But when we look at previous platinum as a background risk, it’s pretty close to that.

Robert L. Coleman, MD: Exactly.

Susana M. Campos, MD, MPH: I think it’s also confounded by the number of cycles of therapy that this patient has gotten over the course of time. Is it really truly going to isolate that effect for that particular drug or not? Perhaps it’s a summation of all the drugs that they’ve actually had?

David O’Malley, MD: If we’re using a PARP earlier, are we actually going to see the MDS drop because they’ll have less platinum?

Robert L. Coleman, MD: It might be, yeah. That’s an interesting point. In the SOLO-1 data, we gave it for 2 years. In the recurrent setting, do we have an upper limit?

David O’Malley, MD: I don’t stop. In the recurrent setting, if they’re benefiting, I will continue indefinitely.

Robert L. Coleman, MD: So you’re going to titrate the dose to make sure they can stay on?

David O’Malley, MD: Correct. I think it’s about managing symptoms.

Robert L. Coleman, MD: Let me just cover 1 quick point here. She was wild type when she came in. And before we started, we didn’t know what her response rate was going to be. We have that whole bevacizumab-versus-PARP question, right? And I know how you feel about this. You’re going to say, “Well, if we don’t give it now, we’re never going to give it to her.” Is that the most effective option?

Shannon N. Westin, MD: I think you’ve kind of alluded to this: Pure response. If you want to get them to maintenance, you have a higher response rate when you give chemotherapy in combination with bevacizumab in the BRCA wild-type population. In the ARIEL2 data, you saw an 80% response rate in that BRCA-mutant population. But for OCEANS, for GOG-213, you can get from about a 50% response rate up to about an 80% response rate.

Robert L. Coleman, MD: That’s right.

Shannon N. Westin, MD: And so, those patients actually can go to maintenance. So there’s a lot of impulse to potentially do that.

Susana M. Campos, MD, MPH: There’s always this question of the obsolete in a couple of years when we have the results of other trials.

Robert L. Coleman, MD: Like PAOLA-1, right?

David O’Malley, MD: A brilliant friend of mine once coined a phrase “switch maintenance” but then refuses to talk about switch maintenance…

Robert L. Coleman, MD: I don’t who you’re talking about. It wasn’t me.

David O’Malley, MD: Give them bevacizumab with the cytotoxic drug. Get your highest CR [complete response] and your highest PR [partial response] with bevacizumab. There’s nothing wrong with switch maintenance. I have zero data.

Robert L. Coleman, MD: But that’s never stopped you before.

David O’Malley, MD: Exactly. But I do think in a wild-type population, we know a certain percentage are going to benefit markedly from these medications. In a wild-type population, the only time they’re going to be able to get that medication, in our current data, is in the maintenance, platinum-sensitive setting.

Susana M. Campos, MD, MPH: At the end of the day, they’ll either tolerate it and respond or not.

Transcript edited for clarity.
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