Rucaparib, A PARP Inhibitor For The Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC) - Wassim Abida
June 3, 2020
Wassim Abida, MD, Ph.D. Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Charles J. Ryan, MD, The B.J. Kennedy Chair in Clinical Medical Oncology at the University of Minnesota and Director of the Division of Hematology, Oncology, and Transplantation.
FDA Approves First PARP Inhibitor Rucaparib for Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) - Charles Ryan
FDA Approves First PARP Inhibitor Rubraca for Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) and a Deleterious BRCA Mutation
Results from TRITON2: Treatment of mCRPC with Rucaparib - Alan Bryce
Molecular Genetic Testing in Prostate Cancer - Wassim Abida
Charles Ryan: Hello and welcome. I'm delighted today to be joined by Dr. Wassim Abida from Memorial Sloan Kettering Cancer Center, where he is an Assistant Attending and member of the cancer center there and is the lead author on a very exciting report that follows on or continues with the approval of rucaparib for metastatic castration-resistant prostate cancer. Dr. Abida, congratulations on this work. Exciting times for us who treat prostate cancer. Tell us about the findings and about the approval and what it means.
Wassim Abida: So they are exciting times indeed. Thank you, Dr. Ryan. And what the findings are of the study of a PARP inhibitor, rucaparib, in the selected patient population with prostate cancer that harbors mutations of BRCA1 or BRCA2. We know PARP inhibitors have been approved in other malignancies where we do find these types of mutations. So initially with ovarian cancer, subsequently breast and pancreatic cancer for other PARP inhibitors. And this was the first approval of a PARP inhibitor in BRCA deficient or BRCA mutated prostate cancer, which we have been anticipating. I think we can safely call it the first targeted approval in prostate cancer that in recent years if you don't count the pan-cancer approval of pembrolizumab and MSI high cancers.
Charles Ryan: Right, and clearly, it's the first approval of a drug that requires that genomic testing be performed beforehand. And that's really exciting. What's your feeling on that workflow and how that's going to disseminate across the world in terms of uptake in clinics and hospitals treating prostate cancer?
Wassim Abida: I think it's going to have a tremendous impact, frankly. We know that pembrolizumab is approved for MSI high prostate cancer, but I don't think the uptake has been that significant. And it could be that the label was pan-cancer. So it didn't bring specific attention to men with prostate cancer. However, this is prostate cancer-specific. I think it's been known now for a few years through genomic work that was sponsored by Stand Up to Cancer and Prostate Cancer Foundation that BRCA mutations do occur in men with prostate cancer. And they occur both in the germline, so it was inherited mutations as well as somatically. And this FDA approval really shows the clinical significance of having these types of mutations. So hopefully this will bring attention to the fact that patients should undergo genomic testing because there is a standard drug that targets these genomic alterations.
Charles Ryan: It's a key educational point that genomic testing should be done. I was fortunate enough to be part of the panel at the APCCC Conference last summer. And we were surprised that genomic testing is considered a standard of care, but its uptake across the world is not yet at what one would hope it would be. Academic centers are doing it, of course.
But I think this is a situation where we'll see a lot more uptake. So as that happens and clinicians who are listening, what should they be doing? Should they start with a tumor test? Should they be doing extra biopsies? Should they start with a germline test? How do you suggest that clinicians who are interested in evaluating their patients for PARP inhibitor therapy begin the process?
Wassim Abida: There are a lot of options. Certainly, there is a benefit of doing separate tumor testing or blood-based testing and germline testing, because finding a germline mutation has implications for family members as well. And the NCCN has had in its recommendations to discuss germline or inherited DNA testing for all men with metastatic prostate cancer. And that's been in the guidelines now for a couple of years. So, there is a benefit from having a specific discussion about germline testing versus somatic testing. But frankly, both are really important. If you do somatic only testing, so tumor testing alone, you may be missing inherited mutations.
And so, my recommendation is to have the discussion about both inherited testing and tumor-based testing. And if tumor tissue is not available or if it's too old and not accessible, then certainly one could fall back on testing with blood-based assays, so cell-free DNA or plasma-based assays, which granted are newer, but there's more and more data showing that you can select patients for targeted therapy using these types of assays.
Charles Ryan: But in the TRITON2 study, what were the types of tests that were used that led to the eligibility of the patients?
Wassim Abida: The TRITON studies are fairly broad in allowing a variety of CLIA certified tests or tests that are run in CLIA laboratories. So they would allow standalone local germline testing or standalone local somatic testing through tissue or plasma. But the studies themselves did allow screening using both tissue-based testing and plasma-based testing, and patients were identified with either one of these tests. And the concordance was high for patients who had successful testing using one method or the other, which really does suggest that plasma-based testing is an appropriate way to identify patients who have BRCA alterations.
Charles Ryan: Yeah, very good. And that's certainly the easiest, least invasive way to go about doing it, in particular, when you have a situation of a patient with advanced disease and the prostate biopsy may have been years ago and may be hard to find. TRITON2, the study that led to the approval of rucaparib, has a couple of unique features associated with it I want to discuss. One of them is that it was a Phase II study essentially without a control arm. And this is unique in the setting of our disease, prostate cancer. Tell us about that design and why it's important to know.
Wassim Abida: Well, the study, as you said, is a single-arm study. However, it's in an advanced patient population. So it's patients who have received either abiraterone, enzalutamide, or both and at least one line of taxane, so docetaxel or cabazitaxel. Now that being said, of course, cabazitaxel, a patient may have received a dose of taxane may have been cabazitaxel-naïve. But the advantage of this study is that it really looked at the objective response rate, radiographic response rates in this patient population with advanced disease. And the response rate was 44%, which was quite substantial. We're talking about radiographic response and that's really how the FDA approved this drug. Now certainly PSA responses are even higher, but that was not what was quoted by the FDA for approval. An objective response rate of 44% is quite substantial.
A lot of these patients have had durable benefit from a drug that is generally considered well-tolerated. We have experience with this drug in other malignancies, the drug is approved in ovarian cancer and certainly, the toxicities do mirror what we see in ovarian cancer as well. So a well-tolerated oral drug that has for many patients a substantial clinical benefit. So we do, as I'm sure you do, welcome this approval because this is a drug that really has benefited some of our patients who have BRCA mutations.
Charles Ryan: Right, and it's such a great thing for patients who have very few treatment options available to them and were 44% likely to respond. This is a very interesting time with regards to FDA approval because of response rate, and others, critics out there, might look at these data and say, Well, I want to wait until there's survival data in this setting before I give the drug. But there are no other treatment options available for these patients, as you said because they had already progressed essentially after an AR-targeted drug in docetaxel. And so there are radium and other therapies that are available, but it is remarkable that this selected patient population was used to approve a drug in a new indication on response rate only.
So moving forward, what are the options for rucaparib? There is now a second drug approved in this space, olaparib, with a slightly different indication, and that's going to create a little bit of a choice for clinicians out there. How do you think the clinicians should look at the data from TRITON2 and think about prescribing this drug?
Wassim Abida: Well, I should say that those two studies are in different spaces. So, the PROfound study which led to the approval of olaparib was in the pre-taxane setting. It was at least post-abi or post-enzalutamide, whereas TRITON2 was post-abi or enzalutamide and post-one line of taxane chemotherapy. The PROfound study had PFS as its primary endpoint. It was a randomized study compared with abi or enza, did not compare to taxane chemotherapy, and the FDA approval mirrors those clinical settings. So certainly, I think ultimately physicians will have a choice between olaparib or rucaparib. And I think like with any other drugs that fall in the same category, the choice is based on a number of factors. My personal experience is the toxicities are relatively similar, again, personal experience with these two drugs. So I think physicians will have a choice.
Charles Ryan: Are you surprised at all at the 44% response rate? I mean, when we started out with the PARP inhibitors and thinking through this, we thought this is great. We've got a selection, we've got a mutation that is clearly associated with sensitivity to this therapy. Maybe I was overly optimistic as I'm frequently accused of being, but I would have expected nearly 100% of patients would have responded. Of course, that's naïve, and 100% of patients rarely respond to a therapy. Tell us what you know about the situations where the drug doesn't work as well as we might anticipate in a BRCA1, BRCA2 population.
Wassim Abida: Yeah. I think ultimately it's a matter of enrichment, and we certainly don't understand all the variants that really do allow for response versus non-response. So at first look, it doesn't look like there's a tremendous difference between germline and somatic BRCA mutations. So if you've ruled out a germline alteration BRCA and you have somatic only, it seems like you respond just as well. So I would not necessarily think that a patient with a germline alteration will benefit. For the study the qualification that was quite stringent, you had to have a deleterious alteration in one of these two genes to be able to enroll in the study. So certainly if it had been more lax, I would have understood, but these patients had deleterious alterations, alterations that either truncate the protein product or a full deletion of the gene or a well characterized, a missense mutation that really inactivates the protein product.
So it's not clear yet really what are the variants, or are there co-occurring alterations that cause resistance to the drug? That's certainly a possibility and that's something we're looking at. I think that will be possible as we have bigger and bigger numbers of patients, ultimately. You need a lot of patients to be able to determine whether there are co-occurring alterations that may promote resistance or really good response.
Charles Ryan: Right. And you're in a great position to help us to answer those questions. Your prior work has looked at RB1 deletion and other complicated biological and genetic alterations in prostate cancer that harbor drug resistance. And so it's probably something like that. In fact, as I'm sure you're aware, when we look at these mutations, we're frequently seeing perhaps a BRCA2 mutation in the context of other aberrations, other mutations in other things as well, not to mention other factors that can mediate drug resistance, such as PK variability, and metabolism and things like that. So there is a lot yet to learn, yet it's a very exciting time and one that we've been anticipating for quite some time.
Final question is, the TRITON2 study was based on eligibility that included BRCA1, BRCA2, and a whole host of other genes associated with DNA repair. Those aren't included in the FDA approval, and yet we are seeing some interesting findings. If you could tell us about those other findings and how those may impact future FDA approvals or future considerations for rucaparib.
Wassim Abida: So these are very interesting findings in the sense that with the initial genomic studies, we found that up to probably 25% of men with prostate cancer had a mutation or genomic alteration in a gene that's involved in DNA repair somehow, but we know that these aren't all created equal. BRCA2 is the most common, it's involved in homologous recombination repair. There are other genes that are more closely implicated with homologous recombination repair. So PALB2, for example, and BARD1 where you might imagine they might have the same susceptibilities as BRCA2. And then there are genes that are not really, they're involved in DNA repair of not quite homologous recombination. So ETM, CHEK2, CDK12 most recently, we've learned more about its function. Now, these genes were sort of lumped together initially, and so a lot of the PARP inhibitor studies included subsets of men who had genomic alterations and these genes.
Now, as you mentioned, Dr. Ryan, TRITON2 study, the main core was patients with BRCA2 and BRCA1 alterations. And that is where response rates were substantial, and that's where the FDA approval was. There was a signal of good response rates in a very small number of patients, for example, with PALB2 alterations, of patients with alterations on [inaudible], but not enough, I think to really draw a strong conclusion about response rate in the small subsets. So we'll certainly have to learn more about that.
And then there were genes such as ATM that are really mutated in 6% to 8% of men with prostate cancer. So substantial numbers where we saw low objective response rates with PARP inhibitors. And so we certainly have to learn more about the function of these genes and what their susceptibilities are. And the question is, Would we see more objective response rates with combination therapy, PARP inhibitor, and another agent? And we certainly need to learn more about the biology, so ATM, we know a lot about it, but CDK12, for example, has generally not been well characterized in terms of its function. And that's again, 68% of men with prostate cancer. So not an unsubstantial number.
Charles Ryan: Yeah. Great, great. Congratulations on these findings, your publication, and having your name on an FDA approval. That's a big deal. And I look forward to hearing more from you on the topic in the future.
Wassim Abida: Thank you, Dr. Ryan. It's been a pleasure working with you on this study TRITON2 to which you're a close co-author.
Charles Ryan: Likewise.