Neeraj Agarwal: Hi. My name is Dr Neeraj Agarwal. I'm a Professor of Medicine and Director of the Genitourinary Oncology program at the Huntsman Cancer Institute, University of Utah. Today, I'm so pleased to have our two esteemed guests, Dr Elena Castro and Dr David Olmos, faculty in medical oncology in Madrid in Hospital Doce de Octubre or Hospital 12th of October.

Welcome to the two superstar medical oncologists in our field. And congratulations for your presentation in ASCO and simultaneous publication in Annals of Oncology.

Elena Castro: Thank you, Neeraj. It's very nice to be with you today.

David Olmos: Thank you, Neeraj, too. Thank you again, Neeraj, for having us today in UroToday. We are really pleased that we can share the results that, as you say, recently were presented at ASCO and published simultaneously in ESMO. This is the second cohort that we report on the CAPTURE study. This cohort is focused in metastatic hormone-sensitive prostate cancer.

And here, as you can see in the slide, we are showing the design of the study, in that we enrolled prospectively 556 patients from January 2018 to December 2023. We screened in both germline DNA and somatic DNA 11 mutations related to homologous recombination repair, including BRCA1, BRCA2, and the others that you can see in the slide. And we analyzed the main outcomes that were time to castration-resistant, radiographic progression-free survival, and overall survival, stratifying according to BRCA, non-BRCA status and HRR non-HRR status.

Elena Castro: Yeah. This is the breakdown of the population. We included 556 patients; 55% presented with high-volume disease and 45% with low-volume disease as per CHAARTED criterion. And here you can see the distribution of treatments in this series. Perhaps the most relevant part of it is that 13% of patients received ADT in monotherapy. This was more frequent among patients presenting with low-volume disease than patients with high-volume disease.

The use of chemotherapy was greater in the high-volume population, as expected. And the use of ARPis was greater in patients with low volume. And as you can see in this other graph, there was an increased use of ARPis between 2018 and 2023 in our population. And there is a very clear inflection point in 2020, because during the pandemic is when abiraterone was approved and reimbursed in Spain. And there was also the recommendation of not using chemotherapy in mHSPC to avoid as many complications as possible.

And that was a big change. So as you can see, since 2020, we have been using ARPi significantly more than docetaxel. The use of ADT monotherapy has been reduced in the last years. And the use of chemotherapy has changed, as expected, from monotherapy to triplet. And this is used in around 20% of our patients. So this is the distribution of the HRR, BRCA alterations in our patients. And David, I think the prevalence was very similar to our previous publication in mCRPC.

David Olmos: Exactly. What we have learned in this second study is that the prevalence in metastatic hormone-sensitive prostate cancer was very similar to the rates that we found in metastatic CRPC, with almost the same rate of BRCA1, BRCA2 alterations, slightly different individual genes among the homologous recombination repair non-BRCA genes.

But more surprisingly for us, overall, is that the frequency of alterations in high-volume disease and low-volume disease is very similar, around 13% and 11.5%, approximately, in low-volume disease, that we saw respectively in the mCRPC cohort, is a slight rise in the percentage of germline.

Especially, germline BRCA was almost 1% more frequent among the metastatic hormone-sensitive prostate cancer than mCRPC that is a mix of de novo patients that becomes CRPC, or patients that were diagnosed with localized disease later progressed to mCRPC. And also, but less important, is that we also saw a higher frequency of biallelic alterations among the metastatic hormone-sensitive prostate cancer compared with the mCRPC.

Elena Castro: And here we can see the outcomes of patients with BRCA versus non-BRCA alterations. There was no difference in the treatment these patients received. Clinicians didn't know the mutational status of patients when they were treated. But what we can see is a significant difference in RPFS, 13.5 months versus 13 months, and in overall survival, 26 months versus 55 months.

And for patients with HRR alterations, we also see a significant difference both in RPFS and overall survival. Although, as we have been consistently seeing in different studies, the differences between HRR and non-HRR are less evident than for BRCA patients, probably due to the heterogeneity of the HRR subgroup.

But to me, this is the most interesting part.

David Olmos: Yes, Elena. I completely agree with you. I think that the most striking finding is how much is the impact within the low volume. You will expect that BRCA patients that have poor prognosis are more frequent among the high-volume disease—we already show in the first slides that it is a similar frequency—but also the proportional impact in outcomes of BRCA alterations in the patients with low volume is much higher. It's a hazard ratio of 3.7 for radiographic progression-free survival, 3.4 for overall survival.

You can see the striking difference in the medians, 34.6 months in the BRCA low-volume patients compared with the 71 months that is quite similar to many studies that have been already reported in the non-BRCA patients with low-volume disease. It's also important for high volume. It's also a poor prognosis, but the difference is smaller.

In fact, we can say that high volume and low volume in BRCA is not as important as it is in the other patients, where the difference is clear between the non-BRCA, but for the BRCA, they are very similar. So we should probably start thinking about the low-volume BRCA and not being true volume disease—be more a high-volume disease.

Elena Castro: Yes. And the other important thing that we have observed is that PSA progression in BRCA patients occurs almost at the same time as radiographic progression, and time to castration-resistant is almost the same as time to radiographic progression. So I believe this is also important for the follow-up of these patients, because what we usually see in our patients, in non-BRCA patients, is that PSA progression occurs around six months before radiographic progression. But that doesn't seem to be the case for BRCA patients, for which everything seems to happen very fast.

David Olmos: Yes. We will be presenting data about the pattern of progression with more detail in the future, but something that I have been asked from many people who have read the article or have attended the poster presentation in ASCO is whether these patients are more neuroendocrine and progress without elevating the PSA. And the truth is that they elevate PSA, but they progress radiologically with less quantity of PSA.

So they might not meet the biochemical progression at the time that they are progressing radiographically or just have a small increase that meets the criteria and progress simultaneously in the radiographic evaluation. But they are not neuroendocrine. In fact, the frequency of neuroendocrine tumors, according to histology in this area, is about the same—it's around less than 2% of the patients in the non-BRCA and a similar rate in the BRCA cohort.

Elena Castro: And we can see here a summary of outcomes by HRR status. So here we see another summary of the data that we just presented for mHSPC and the data we have previously reported for mCRPC. And the idea is just to emphasize how the prognostic value of BRCA seems to be greater in the mHSPC space.

And this is probably because in mCRPC, the non-BRCA tumors also acquire other alterations that are associated with poor prognosis. Whilst in mHSPC, and particularly in our series, in which most cases were de novo metastatic, only 18% had metachronous metastatic disease. In our mHSPC series, those tumors that were not harboring BRCA alterations perhaps have not acquired other poor-prognosis factors that they may acquire over time. And this is why we see less difference in mCRPC.

David Olmos: So just to conclude our analysis, we looked at whether there was a difference between starting a treatment with a doublet with androgen receptor pathway inhibitors or a doublet with docetaxel, as are the two most frequent studies, and we performed the inverse probability weighting methods to control for the non-randomized nature of the study.

So according to this analysis, as you can see in the patients with—the patients that were non-BRCA, the RPFS was significantly worse for patients that did a doublet with docetaxel than those patients that were treated with a doublet with a novel androgen. And very similar results were shown by the STAMPEDE analysis comparing the arm with docetaxel and the arm with abiraterone.

However, when we looked to overall survival, this difference is compensated by the second line, and the survival for patients receiving hormone-sensitive disease docetaxel or hormones was almost the same, so reproducing the results of the STAMPEDE study. However, when we focus on the BRCA patients, as you can see here, both the patients treated with hormones and the patients with taxanes progress really quickly.

Median progressions are below a year and a half in both treatment options, and survival is almost the same—very poor outcomes compared with the non-BRCA patients—highlighting that even for RPFS, there is no difference between having a treatment with novel hormones or with taxanes, and probably these patients need better treatments and intensification, properly that we put together with the result of the AMPLITUDE. You even justify more, that we have to introduce, as early as possible, the treatment with PARP inhibitors in this population.

Neeraj Agarwal: So first of all, really striking data and really meaningful data for our practice. So first thing I noticed was that the presence of HRR mutations in your population with metastatic hormone-sensitive prostate cancer was 28%, so about one-third of these patients seem to have HRR mutations. The second finding, which I thought was quite striking, was presence of HRR mutations, meaning shorter time to progression and shorter overall survival with standard-of-care therapies, and even shorter in patients who have BRCA1 and BRCA2 mutations.

It looks like, and of course, you are in a tertiary cancer hospital practicing with state-of-the-art medicine. It's heartening to see that most of your patients, close to 90% of your patients, are receiving ADT intensification with the combination of ADT plus docetaxel or ARPi and now triplets. Despite the fact that they were getting ADT intensification combination therapies, we are seeing inferior radiographic progression-free survival and overall survival, which is even worse in patients with BRCA1 and BRCA2.

So coming back to the implications of these findings, for our colleagues in the community across the world, what do you think is the importance of genomic testing of the tumors? We know, based on the results, less than one-third of our patients with metastatic prostate cancer are undergoing genomic testing. So what is the message for our colleagues out there when they see a patient with metastatic hormone-sensitive prostate cancer? How soon genomic testing should be done and germline testing should be done? Elena, maybe I ask you first.

Elena Castro: Well, I think what our data and others' data shows is that we currently base our treatment decisions for mHSPC on risk stratification based on disease volume and timing of metastasis. But we need to start considering biology as well, because in patients, like in these patients with BRCA alterations, disease volume doesn't really impact outcomes. These patients have poor outcomes regardless of how many metastases they have.

So I think once we have access to PARP inhibitors, that is the only therapy that has demonstrated to improve the outcomes of these patients. We may need to start profiling patients' tumors at the time of diagnosis, particularly for metastatic disease. And this is the only way we are going to be able to really make a good treatment decision.

Neeraj Agarwal: Great. So the first time when I see the patients with metastatic hormone-sensitive prostate cancer, I should be sending out the tissue and asking them to get germline testing done for both germline and genomic testing. I don't think these data and the data from the AMPLITUDE trial [INAUDIBLE] will have a PARP inhibitor available for these patients. There is no reason for us not to sequence or test these patients for germline and genomic testing. I agree with you.

Another striking point, David, which you showed was that especially in patients with BRCA1 and BRCA2 mutations, when they are progressing, they are progressing not only fast—quickly, quicker than patients who do not have these mutations—but the PSA progression may not reflect or precede the radiographic progression. Radiographic progression is happening almost at the same time as the PSA progression.

So it looks like in these patients, we may not really rely too much on PSA progression, and more frequent scans every three to four months may be needed now and in the community, and even in my practice. Many patients who are coming from long distances, they are mostly doing PSA every three months or every two months, and they may not be doing scans every three months.

And these data tell me that we may need to do CT and bone scans or other scans, whichever scans are available out there. If you are doing PSA or PET scan, I don't do that. I mostly do CT and bone scans. But we may need to do scans more often in these patients because PSA may not be reliable. Is that correct, David?

David Olmos: Yeah. You are completely right on that. I think that these patients, as I said before, they have PSA. They elevate PSA. But with less quantity of PSA, they have more disease—more disease volume. So the PSA is not telling us the complete history. And relying only on the PSA, we might delay the diagnosis of a clinically relevant progression or a radiographically relevant progression and delay disposition to the team. And we see how short are the windows of opportunity to change the treatment in these patients.

We agree that if we don't have access to PARP inhibitors, as demonstrated in the AMPLITUDE, it's a challenge for doing the screening, and having only a prognostic factor sometimes doesn't change our practice. But these data are showing that we have to monitor the patients differently, that we have to pay more attention to the imaging, to the clinical symptoms, and not just to the PSA in these patients.

Neeraj Agarwal: We really hope we have a PARP inhibitor available in the clinic for these patients. I'm really hoping that AMPLITUDE trial data will change that. And many other PARP inhibitor trials are coming up in the near future, fortunately, with TALAPRO-3, EVOPAR-Prostate01, with different PARP inhibitor, ARPi combinations. So ultimately, patients with HRR mutations have poor prognosis. They rapidly progress. They have inferior survival. And many of these patients may not have PSA as a good marker of disease progression.

So these data not only have implications on prognostication counseling, but also on how we monitor these patients in our clinic and, hopefully, in the near future, how we treat these patients with a PARP inhibitor. Well, thank you very much for joining us today. And congratulations to both of you for this impactful data and the publications in Annals of Oncology.

David Olmos: Thank you very much, Neeraj.

Elena Castro: Thank you.