Phase I RAMP Study Evaluating the Combination of Enzalutamide and Rucaparib in mCRPC - Arpit Rao
February 23, 2021
A combination of enzalutamide and rucaparib was not associated with a clinically significant effect on pharmacokinetic profiles of either drug, and no dose-limiting toxicities were observed.
Arpit Rao, MD, MBBS, Assistant Professor of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA.
Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Clinical Trial Information: NCT04179396
ASCO GU 2021: Rucaparib plus Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer: Pharmacokinetics and Safety Data from the Phase Ib RAMP Study
Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so delighted to have here with me today, a friend and colleague Dr. Arpit Rao, who is an Assistant Professor of Medicine at the University of Minnesota and a GU medical oncologist himself. Thank you so much for being here with me today, Arpit.
Arpit Rao: Thanks, Alicia. A pleasure to be here.
Alicia Morgans: Wonderful. So Arpit, I wanted to speak with you a little bit about an abstract that you have published at GU ASCO 2021, really exciting, on the RAMP trial. Can you tell us a little bit about that?
Arpit Rao: Yeah. The RAMP trial is a Phase I study that's looking at the combination of enzalutamide and rucaparib in metastatic CRPC. And there's an interesting backstory to why this trial came about. But as you know, there has been, over the last few years, a surging interest in using synthetic lethality in therapeutic context in CRPC. Abiraterone or enzalutamide based combination approaches, we've known this, there's a big body of basic science literature that shows that "Hey, combining these two classes of drugs, even in patients who don't have an HRR or DDR alteration, or homologous recombination, or DNA damage response alteration, it still works preclinical models." And that's now being shown in a Phase II study. So this was really an effort to investigate whether this combination of enzalutamide and rucaparib is safe and also doesn't have any clinically significant drug-drug interactions.
Alicia Morgans: Fantastic. And as we know, when we want to use new combinations, we have to do these Phase I trials to, as you said, make sure that they're safe, that they're tolerable, that we understand those drug-drug interactions. And so what did you find on the RAMP trial that you did?
Arpit Rao: Men with metastatic CRPC, who had been exposed to zero to two lines of AR directed therapy and less than, or equal to two lines of chemotherapy for mCRPC. And we did a one-week run-in for rucaparib monotherapy. Now, for context, both rucaparib and enzalutamide are now FDA approved as monotherapies in mCRPC. So we did a week of run-in of rucaparib at 600 milligram BID, which is the FDA approved dose, and did a bunch of PKs in that run-in, and at the end of the run-in period. And then started the combination of rucaparib 600 BID and enzalutamide 160 milligrams once a day in 28-day cycles. And the dose assessment, the DLT period was the first two cycles. And we did serial PKs through that DLT assessment period.
The primary endpoint for the study was PK and the safety of the combination, but we were also looking at the secondary endpoint the PSA response rate. So we treated a total of eight patients in the initial cohort and seven were evaluable for PK assessment and six were evaluable for DLT assessment. And I'm really happy to say that we were able to meet the primary objective of the RAMP study in that first cohort. We did not see any DLTs in the first six patients and there were no clinically significant DDIs, drug-drug interactions between these two drugs. So that was really, really great finding right off the bat.
Alicia Morgans: I agree. And like you said, I think this combination of a PARP inhibitor plus an AR targeted agent that might confer efficacy of a PARP in patients who are wild type in terms of their DRD status is really, really exciting. So this kind of Phase I trial that really establishes that safety and helps us understand drug-drug interactions might allow you to do something bigger and really launch a trial that could look at the combination of the two in terms of efficacy in the population. So, as I understand that was the ultimate goal, is that true?
Arpit Rao: Yeah. A little bit concurrent or the other way round actually, where when we proposed the study, a large Phase III study of enzalutamide and rucaparib, there was a lot of skepticism amongst our peers that whether this combination would actually be tolerable and whether it will have significant drug-drug interactions, because when you look at all of the individual enzymatic conversions and interactions, there's a pretty significant red flag that, "Hey, this could happen between these two drugs, one could affect the concentration on the other."
So this study was really launched in response to that, "Yes, this is a theoretical possibility, but let's see if it actually happens." And the data will speak for itself. The poster will be out soon and people will be out in the next few months for everybody to see. But there was really no signal. There's no clinical signal that rucaparib is meaningfully changing the concentration of enza or its metabolite or vice versa. So that was really reassuring as we launched this thousand patient Phase III study that we have strong data to support the safety of this combination.
Alicia Morgans: Wonderful. So we'll talk about the Phase III in a separate conversation, but can you give just an overview very, very briefly of your Phase III, the CASPAR trial?
Arpit Rao: I guess I should also mention again with the big caveat that this is a small sample size, but we did want to see some robust efficacy signals. And in the eight patients who went on RAMP, we were able to see PSA responses in a majority of those patients. I think we had a 50% confirmed PSA response rate and the only patient with radiographically measurable disease had a complete response. And none of those patients had DDR alterations. So these patients are responding to this combination even after progressing on enzalutamide. So there's a lot of exciting early efficacy signals that are coming out of RAMP that we'll be sharing in the coming weeks and months.
The CASPAR study is a randomized Phase III placebo-controlled study that's run through NCI and Alliance and that's going to open soon. I have the distinguished honor of being the study chair for CASPAR. And so that's really exciting. It's exploring the option of enzalutamide and rucaparib combination versus enzalutamide plus placebo in first-line metastatic CRPC. So that's relevant as we start moving upstream with these novel anti-androgens, like abi/enza, apalutamide, et cetera. In the hormone-sensitive setting, we're going to need better options in CRPC when these patients get there. And so it's very relevant I think. I'm a little biased, but not a whole lot. But I think it's very relevant to the clinical challenges that we're going to face in the next five to 10 years in caring for these men with mCRPC.
Alicia Morgans: So fantastic work for you, Dr. Rao, and certainly to your colleagues on completing this body of work and helping us understand whether there is an interaction that could limit us. It seems like there is not. And I appreciate your time. And of course that you're launching a Phase III to help us understand whether the combination of rucaparib and enzalutamide may help men with mCRPC. Congratulations, and thank you for your time today.
Arpit Rao: Thank you, Dr. Morgans and UroToday for highlighting our work on RAMP and giving us the opportunity to talk about CASPAR. Really excited and looking forward to it.