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Metastatic Castration-Resistant Prostate Cancer and DNA Repair Gene Alterations

This is Part 3 of Updates in Prostate Cancer, a four-part video roundtable series. Scroll down to watch the other videos from this Roundtable.

In this video, Drs. Matthew R. Smith, Xin Gao, and Alicia K. Morgans discuss the role of PARP inhibitors in the treatment of metastatic castration-resistant prostate cancer and homologous recombination repair deficiency, focusing on data from the PROfound trial. Dr. Smith presents a case of a 67-year-old man with metastatic castration-resistant prostate cancer who experienced disease progression despite treatment with enzalutamide, and the faculty discuss the use of docetaxel vs olaparib when tumor genomic testing reports pathogenic mutations in BRCA2 or ATM.


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Transcript

Dr. Smith: Welcome to The ASCO Post Roundtable Series on Updates in Prostate Cancer. I'm Dr. Matthew Smith from the Massachusetts General Hospital Cancer Center in Boston. Joining me today are two of my colleagues. Dr. Gao: My name is Xin Gao. I'm an instructor in medicine at Harvard Medical School and a medical oncologist at Massachusetts General Hospital. Dr. Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and associate professor of medicine at Northwestern University in Chicago. Dr. Smith: Thank you, Dr. Gao and Dr. Morgans, for joining me. Today, we'll be discussing recent updates in prostate cancer, including data presented at the 2021 ASCO Annual Meeting, and integrating these new developments into four patient case studies. Our third installment will focus on the role of PARP inhibitors in the treatment of metastatic castration-resistant prostate cancer and homologous recombination repair deficiency or DNA repair deficiency. Here's our third case. So, this is a 67-year-old man with mCRPC and disease progression despite treatment with enzalutamide. Restaging demonstrates bone metastasis and retroperitoneal adenopathy. Tumor genomic testing, using a blood-based assay reports a pathogenic mutation in BRCA2. His past medical history includes hypertension and osteoarthritis. What do you recommend in this case as the next step: docetaxel, olaparib, or rucaparib? Dr. Morgans, how would you manage this patient? Dr. Morgans: Great, thanks. So, this patient has had progression of mCRPC after treatment with hormonal intensification. And because of that, I would say that rucaparib is kind of off the table in terms of our options. Rucaparib is really FDA approved for patients with BRCA1 and BRCA2, but it has to be after progression on an AR-targeted agent, as well as on a taxane chemotherapy. So, that really leaves us with olaparib and docetaxel, and in this setting, if the patient is progressing, has a BRCA2 mutation, and is interested in trying olaparib, I would be very comfortable trying that. There are few situations where I might suggest that docetaxel would be my preferred choice. If the patient had visceral crisis, was really declining rapidly, I often feel more comfortable with docetaxel. Not because of any data necessarily, but because as an oncologist we lean towards chemotherapy when we really need that rapid high response rate, and it's what we do. So, just to be clear, not based on data, but in general, I think olaparib is well tolerated, appreciated by patients, and with a BRCA2 mutation, I think there's a reasonable chance of response. Dr. Smith: Dr. Gao, what are your thoughts about this case, and how would you explain the choices to a patient in this situation? Dr. Gao: Yeah, I would say it really does come down to olaparib or docetaxel in this situation just in terms of the FDA label. For rucaparib, it is required that the patients have seen prior taxane therapy. But in terms of the decision between olaparib and docetaxel, I would say with olaparib, we have phase III data showing overall survival benefits, certainly, in patients with a BRCA2 mutation. We have good response rates, and a lot of the prostate cancer patients, they've become used to this hormone therapy, pills, injections, and I think taking the step from an oral therapy patient to an IV chemotherapy patient, for some people, is sort of a big step. That said, docetaxel is still an option for this patient. We really don't have robust data to say if docetaxel would be better first or if a PARP inhibitor like olaparib would be better first in this situation. So, I would talk about the pros and cons, the toxicities involved, and then certainly, harping back to financial considerations, certainly docetaxel. We worry less about that, whereas with olaparib, certainly sometimes we have patients where the co-pay would be unmanageable. Dr. Smith: Yeah, I think that's a good take by both of you. I would agree with your comments, and for most patients in this setting, I would favor olaparib, recognizing that docetaxel is not an incorrect choice. Part of the issue is that this is a discrete and relatively small subset, and so once you identify a patient who's a candidate for a PARP inhibitor, you really like to provide them the earliest possible chance to benefit. And as we all know, the approval of olaparib was based on the results of the PROfound study. This included patients with mCRPC and disease progression on a prior novel hormonal therapy who had gene alterations in one of the homologous recombination repair genes or DNA repair genes. Prior chemotherapy was allowed but not required, and about half of the patients had received prior docetaxel. The analyses were broken down into cohort A, or cohort A+B. Cohort A included BRCA1, BRCA2, and ATM alterations. Cohort B included other alterations. And in the primary analysis of cohort A, there was a marked improvement in rPFS as well as clinically and statistically significant improvement in overall survival. And now I'm going to pose a bit of a more challenging question, I think, which is that let's consider a similar patient, similar disease characteristics, but in this case, his tumor genomic testing reports of pathogenic mutation in ATM instead of BRCA2. So, how would you manage this patient? Would you proceed to docetaxel or directly to olaparib? Dr. Morgans? Dr. Morgans: Thanks. So in most cases, actually with an ATM alteration, I would typically proceed with docetaxel. The reason is just that in an exploratory analysis—instead to be clear, these are not definitive analysis, given that the numbers are so low—but in an exploratory analysis within the mCRPC trial, as well as within the TOPARP-B trial, patients who had ATM were not necessarily responsive to olaparib in the same robust way that patients with BRCA2 seem to be, really suggesting that these individual homologous recombination repair alterations are not the same. They're not all created equal, and there can be differences even in the drugs that we choose. So, there may be differences between rucaparib and olaparib, as well as the other PARP inhibitors, when we think about these individual operations. So a lot of work still to be done, but ATM does not seem to be an alteration that is really robustly responsive to olaparib, which would push me in the other direction. And one other piece that I would mention is that in cell-free DNA, or circulating tumor DNA in these analyses, I think ATM sometimes can give us a false positive. So, something for us to be aware of, if we're not doing tumor tissue analysis, looking for ATM specifically. Dr. Smith: All good points. And just to expand briefly on that exploratory gene-by-gene analysis from PROfound. There were a total of 86 patients with ATM mutation as well. So, it's a modest sized group, but a decent amount of data to reach some conclusions. And in that ATM-altered cohort, olaparib really showed no meaningful improvement in overall response rate, PSA response rate, or rates of CTC conversions. And then for rPFS and OS, there was really no meaningful difference between olaparib and control with hazard ratios that were 1.04 for rPFS and 0.93 for OS. So Dr. Gao, is this data from this gene-by-gene analysis sufficient for you to conclude that you would just not use a PARP inhibitor in patients with ATM mutations, or how do you think about that data? Dr. Gao: I think it's really intriguing data. I think it's a modest size sample; it's not huge. If you look at the waterfall plots, there are certainly patients who have pretty good response in terms of the target lesions at the very least. But I do agree that ATM mutations do not seem to behave the same as BRCA2 and BRCA1, to some extent. And I think that the data for PROfound really was driven by those with BRCA2 mutations. And with ATM mutations and BRCA1 mutations, the data is not as robust, I'll put it that way. I think that the specific ATM mutation matters and how we define ATM mutations. And I think there's a lot of work to be done in terms of biomarker development in this area. Dr. Smith: Yeah, I agree. And for the time being, I take this exploratory analysis from PROfound as at least sufficient for me to make decisions about sequencing. So, for a patient with an ATM mutation, like I described, I would generally treat with docetaxel before going on to olaparib, whereas for a BRCA2-altered patient, I would be very enthusiastic about using olaparib prior to docetaxel. So let me conclude with a few clinical takeaways from both this case, the data, and the faculty comments. DNA repair gene alterations are relatively common in metastatic prostate cancer, and both germline and somatic testing is recommended. PARP inhibitors have demonstrated efficacy in mCRPC, and both olaparib and rucaparib are now FDA approved. Patients with distinct DNA repair gene alterations have different sensitivities to PARP inhibitors with the greatest activity for patients with BRCA2 and BRCA1 mutations. This brings us to the end of this case. Please see the other segments for further discussion about the latest data in prostate cancer, or visit ascopost.com.
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