Rana McKay: Thank you so much for having us. It's a pleasure to be here.
Deepak Kilari: Thank you again, Neeraj and UroToday. We really appreciate the opportunity.
Neeraj Agarwal: So Rana, Deepak, we are going to talk about the ASPIRE study, the Phase III trial for patients with metastatic hormone-sensitive prostate cancer. We just got activated through Alliance Network. Please tell us more about the trial.
Deepak Kilari: Thank you, Neeraj. Dr. Agarwal and UroToday, we really appreciate the opportunity to discuss our trial, which is the Alliance 032302 trial, which is a Phase III trial evaluating the role of docetaxel in metastatic castrate-sensitive prostate cancer. The trial is also known as ASPIRE, and it's jointly sponsored by Alliance and ECOG-ACRIN. This is our study team, and all of the members on this team have been instrumental in moving this study forward. So all of us know that ADT intensification with docetaxel became the standard of care after the publication of the CHAARTED and the STAMPEDE trials. Given that these studies were presented earlier, ADT and docetaxel became the control arm by de facto for PEACE-1 and ARASENS trials. And in both of these trials, triplet regimens demonstrated improved outcomes compared to the doublet. And the question that we're trying to ask ourselves is, when using a backbone of ADT and an ARPI, we really don't know the benefit of docetaxel to justify its toxicity.
We and others, I think Dr. Agarwal, you've done multiple studies in this space, such as looking at TSG alterations in prostate cancer, and multiple studies have shown that TSG alterations, mainly alterations in PTEN, TP53, and RB1, portend a poor prognosis. And we also have seen retrospective data from multiple studies looking at whether ARPIs are effective or not, and they clearly are less effective for patients with TSG alterations. So we should determine as a group whether genetic alterations assist in selecting therapy. And also, can we better define who, if anyone, benefits from docetaxel-proven therapy in the pre-ARPI era? So the question that we're trying to ask through the ASPIRE trial is, is the addition of docetaxel to androgen deprivation therapy and apalutamide associated with improved outcomes for patients with metastatic hormone-sensitive prostate cancer? So this is the schema for the Phase III ASPIRE trial. The key eligibility criteria is highlighted on the left-hand side. So anyone with high-volume disease or de novo low-volume metastatic castrate-sensitive or hormone-sensitive prostate cancer are eligible to go on the study. We intentionally have excluded patients with recurrent low-volume MCSPC because we do not think they would benefit from a triplet. Patients could have received androgen deprivation therapy with the androgen receptor pathway inhibitor of their choice for up to 120 days prior to registration. They should have a good performance status of ECOG 0-2.
They should all be candidates for docetaxel, and the results of the next-generation sequencing should be available. And these patients are randomized in a one-to-one pattern to the triplet, which is the investigational arm of ADT, apalutamide, and docetaxel, or the doublet, which is ADT and apalutamide. Janssen is providing apalutamide for this study, and patients on this study will continue treatment until disease progression or withdrawal and will be followed up for long-term survival. In this study, docetaxel will be administered every three weeks for six doses, and apalutamide will be administered at standard dose. 1200 patients will be randomized in a one-to-one manner, and the stratification factors for this study are the presence or absence of tumor suppressor gene alterations. And tumor suppressor gene alterations will be defined as a copy number loss or deleterious alteration in one or more of the TSGs, mainly TP53, PTEN, and RB1 on tissue-based testing alone, not blood-based testing from any CLIA-based assay. The primary endpoint of the study is overall survival.
The secondary endpoints include radiographic progression-free survival, time to castrate-resistant prostate cancer, PSA response at six months in relation to RPFS and overall survival, safety and tolerability, quality of life as measured by FACT-B, BPI-SF, EQ-5D-5L. We are working with different companies, including Artera, Trellix, and Decipher in developing a couple of exploratory endpoints. Thank you.
Rana McKay: This is a really critically important study. I think we've seen the evolution of treatment intensification in the MHSPC setting, first with the introduction of ADT-docetaxel, then with the introduction of ADT ARPIs. And more recently, triplet therapy when compared to the backbone of ADT-docetaxel, and I think one of the critical questions in the field that we all are facing is who needs to get triplet therapy? What's the contribution of docetaxel when using an ADT ARPI? And this is going to really help try to answer that question in a meaningful way. And so I think we're super excited about the trial and super excited about launching this through the NCI. Really, it's available across the entire network of NCTN. All the study materials for anybody that is a part of the NCTN, any site that's a part of the NCTN, all of the materials are on the CTSU website. You can readily access the protocol, the consent documents, and resources and shuttle it through your activation pipeline. This is a really critical study and also is going to be integrating some integrated biomarkers that'll answer some additional questions about the genomic profiling and how that could impact treatment escalation.
Neeraj Agarwal: This is such a pertinent study. As you said, Rana and Deepak, we know triplet therapies are better than ADT plus docetaxel combination. And ADT plus ARPI has never been shown to be inferior to ADT plus ARPI plus docetaxel chemotherapy. And we have struggled with this decision-making in our clinics for the last many years, ever since these triplet therapy data were published. So my question to you is, if someone has not had NGS testing done... So I'm just going through the nuances of trials because you have already explained the trial so well. So first of all, I like to emphasize that patients who have been on an ADT plus ARPI regimen, they can still go on the trial as long as they have not received the ARPI for more than six months. Is that correct?
Deepak Kilari: Yes, it's four months, 120 days. So as long as it's less than 120 days, they can subsequently transition into the study. So they could have started on darolutamide, enzalutamide, or abiraterone, and once they register, they can switch over to apalutamide, which is provided by Janssen.
Neeraj Agarwal: Which is an equally efficacious drug and is associated with excellent outcomes based on the TITAN study. That's great. Do we need NGS testing results to be available prior to enrollment in the trial?
Deepak Kilari: One of the stratification factors is the presence or absence of tumor suppressor gene alterations either in PTEN, TP53, or RB1. So the reason why we built in the 120-day window is because we do understand that it takes time to get the results of the NGS. So providers and patients are always anxious about waiting for the results to go on a trial, but by building this 120-day period in there, they could get NGS. It might take three weeks or four weeks, and then eventually they can go on study. So it's a stratification factor, and really we are trying to understand who, if anyone, benefits from a triplet with ADT, apalutamide, and docetaxel.
Neeraj Agarwal: And I just want to clarify, Rana, they don't have to have TSG mutations. They just need to have results available from the NGS testing, from the tissue.
Rana McKay: That is correct. And I will say that now with the approval of niraparib and abiraterone for BRCA2-mutated metastatic hormone-sensitive prostate cancer, we are moving NGS testing into the hormone-sensitive setting. And so I think this is also going to help facilitate. The other piece to that is patients will be eligible even if they may have already started an ARPI, understanding that some patients may have started ADT with an ARPI. So it's not just ADT and exclusion if they received a couple days of abiraterone or something like that. They can have started an ARPI, and then if this trial is presented to them, there's some minimal washout periods, but that won't exclude somebody from going on.
Neeraj Agarwal: That's very important. So what is a maximum duration of ADT a patient could have had before being excluded from the trial?
Rana McKay: 120 days.
Neeraj Agarwal: So same for ADT and [inaudible 00:10:31]. That's great. Do you mandate any specific scans before patient started the ADT plus ARPI? Such as, do you mandate CT and bone scans?
Rana McKay: Yeah, we do. CT, bone scan, PSMA PET is not mandated. We're working on a PSMA PET substudy to hopefully integrate at a future time point, but just your routine CT, bone scan and patients... This trial is enrolling individuals that have high-volume disease by CHAARTED criteria and de novo low-volume disease, it is not enrolling patients with metachronous low-volume disease. So for those individuals, they are not eligible to enroll.
Neeraj Agarwal: Because we won't use triplet for most of them.
Rana McKay: Yeah.
Neeraj Agarwal: That's great. If somebody has had PSMA PET scan before starting ADT plus ARPI, and they are interested in this study, and they have not had CT and bone scans, but they have already started treatment with the ADT plus ARPI, are they still eligible or can they be eligible if they are willing to get CT and bone scans?
Rana McKay: Yes. If they're willing to get... You can potentially use the CT from the PET CT that was done if it's a diagnostic CT, but they will need a bone scan to enroll. We're still using Prostate Cancer Working Group 3. And I guess the nuance comes into play for those people that have bone-only disease that's visible only on bone scan. So that's not a lot of patients, but there's some individuals, so something to consider.
Neeraj Agarwal: So if I have a patient in Wyoming and they want to enroll in the study, how they can find out where to go, or is there a website they can look up?
Rana McKay: All of the materials are on ClinicalTrials.gov and as sites get activated across the NCTN, their information will be available on ClinicalTrials.gov. Our hope is that this trial is broadly open and available for individuals, both at academic centers and within the community. The NCTN has a large network of thousands of sites and hoping to leverage that to run this trial.
Neeraj Agarwal: And will apalutamide be provided? I think Deepak, you mentioned that, but I want to emphasize that point again. Will apalutamide, and these ARPIs can be expensive, be provided by the study?
Deepak Kilari: You're absolutely correct. I think Neeraj, there's a lot of patients that find the financial toxicity of these drugs very challenging. The good thing about this study is that apalutamide is provided by Janssen, and also there is no washout required. For instance, if a patient starts ADT and enzalutamide or ADT in a different ARPI, and once they register, they can immediately switch over to apalutamide. They don't need to have a washout of the prior ARPI before going onto the study.
Neeraj Agarwal: I think that's great news for our patients, and this is the question which is waiting to be answered for a long time. So congratulations to both of you for starting this very pertinent study and hopefully we'll get the answer in the very near future. So again, for our viewers, Phase III ASPIRE study, randomizing patients with metastatic hormone-sensitive prostate cancer to ADT plus apalutamide versus ADT plus apalutamide plus docetaxel chemotherapy. Thank you so much for being here.
Rana McKay: Thank you for having us.
Deepak Kilari: Thank you for having us, Neeraj.