Rana McKay: Thank you so much for that kind introduction. And honestly, it's really excellent to be able to share the data from the ARASEC study with you all. The ARASEC study was a US prospective open label phase two that was a pretty novel design trial that utilized an external control arm. So why was the ARASEC study designed? There was really a call for data on efficacy of darolutamide in the MHSPC setting not linked with chemotherapy. However, the landscape had changed and patients were now receiving ADT/ARPI doublets as the new standard of care in MHSPC. So conducting a trial with a prospectively enrolling ADT monotherapy arm in the US was really not feasible. So the ARASEC study was designed, which was a US open label study comparing darolutamide plus ADT versus the ADT arm from CHAARTED. The inclusion exclusion criteria aligned with that of CHAARTED, the schedule of events aligned with that of CHAARTED.
And the primary endpoint, which was progression-free survival, also aligned with that of CHAARTED. These were patients with metastatic hormone-sensitive prostate cancer with a ECOG of zero to two. Now to account for differences in the baseline characteristics from the ARASEC and the CHAARTED patients, they were matched one to one using propensity scores for the key variables of age, ECOG, extensive disease, prior local therapy, Gleason score and PSA. And after matching, this really ensured that the patients with similar scores were compared. The baseline characteristics were well-matched in the treatment arms across these key parameters. ARASEC was a positive trial that met its primary endpoint demonstrating a statistically significant improvement in PFS with the combination versus ADT. The hazard ratio for PFS was 0.29.
Additionally, one of the key secondary endpoints was overall survival and there was a statistically significant improvement in overall survival with the combination with a hazard ratio of 0.5.
And when we think about this OS benefit, it was really achieved despite proportionally more patients receiving subsequent lines of therapy in the ADT monotherapy arm. Other key secondary endpoints included time to mCRPC and radiographic progression-free survival, both of which were improved with combination therapy. Additionally, we've seen some evolving data around PSA nadir and the significance of PSA nadir of less than 0.2 in the MHSPC setting. And in the context of this trial, nearly 70% of patients were able to achieve an undetectable PSA at any time on treatment. To address limitations in the study design, we conducted several sensitivity analyses. The ADT arm from CHAARTED was not a contemporary ADT arm, so we asked ourselves how would the combination perform utilizing a contemporary ADT arm. And for this, we turned to the ARANOTE study, which ARANOTE was a trial looking at ADT darolutamide versus ADT in a non-US population.
And again, we see here that the sensitivity analysis versus a contemporary phase three cohort strongly supports the ARASEC study findings. We see a statistically significant improvement in PFS and OS when utilizing the ARANOTE control. We also conducted a second sensitivity analysis to ensure that our matching did not necessarily create a bias in patients analysis. And so we did an analysis using the entire unmatched population of all of those enrolled on ARASEC and all the CHAARTED ADT patients. And again, similarly, the data are consistent and strongly supports the ARASEC study findings. With regards to safety and tolerability, the CHAARTED study did not control adverse events in the ADT monotherapy arm. And so we again looked at the side effects from ADT monotherapy from ARANOTE and overall this was a safe and tolerable combination with low rates of treatment discontinuation at 8.1% with the combination. And when we referenced that to ADT discontinuation, that was 9% in ARANOTE.
So I think in conclusion, the ARASEC really provides further evidence of the efficacy and safety of darolutamide plus ADT and MHSPC resulting in a significant improvement in PFS, OS and PSA responses and the sensitivity analyses utilizing the contemporary ARANOTE trial also speak to the robustness of these results. The other key thing is that honestly, this is one of the first studies in prostate cancer to utilize external phase three trial control arms to really advance getting efficacy data. This design really avoids having a placebo arm, alleviates patient concerns about that, results in more efficient accrual and more rapid time to actually getting data. So thank you for allowing me to go through the study findings.
Sam Chang: Fantastic presentation. Now to start asking some provocative and perhaps questions that we don't know the answers to. Will this kind of study design using a prospective arm and then using propensity-based scoring, are we going to be able to get a compendium listing or a different FDA type of approval? What's the next step in terms of, okay, we see a benefit. Will it lead to further validation through government processing? Do you have any idea regarding that?
Rana McKay: So very good question. This study was actually designed in context with the FDA and was designed as a complementary study to the phase three ARANOTE study that was enrolling XUS. So this study didn't just happen in a silo. The phase three was happening outside the US in a more traditional ADT DARO versus ADT. This study was designed to complement that looking at the activity of DARO in a US population. And actually the label has already been expanded for darolutamide to be given with ADT in the US by the FDA without necessarily chemotherapy based off of these results.
Sam Chang: Got it. Got it.
Rana McKay: I think... Yeah.
Sam Chang: It was basically to help verify what was happening outside the US without having to go through a separate phase three trial. And obviously unfair, but if you look at the results just as the different sensitivity analysis you did, they pretty much verify the same story.
Rana McKay: Yeah.
Sam Chang: So as a urologist, I don't want to say simple-minded, but limited-minded urologist as we go through treatment algorithms for advanced prostate cancer in different treatment situations, it seems that in this metastatic hormone-sensitive cohort of patients, it's pretty clear singlet has been or ADT monotherapy or ADT in general has been replaced by doublet as well as possibly a triplet. When do you or how do you decide regarding using docetaxel in addition to the ARPIs with ADT? And would you consider standard of care? Again, looking at PC1 and ARASENS, clearly more potent ARPIs plus ADT plus doce is very effective treatment, slightly different cohorts, et cetera, but effective treatment. So how do you decide when you have a patient coming in now with de novo metastatic disease, what to do? Because urologists, I'm going to tell you the vast majority probably still do ADT monotherapy and I think we need to get the message out regarding the importance of intensification of care, but how do you come up with a treatment regimen?
Rana McKay: Yeah, no, very good question. So I think the new standard is ADT plus an ARPI, any ARPI. Pick the one that is your favorite, any ARPI. There's lots of nuances about the choice of ARPI, ABI, ENZA, APA, and now DARA is another agent that could be utilized. And a lot of the impetus around choice is dependent on what's the patient's comorbidities, what's the patient's CON meds, there's drug-drug interactions, do they have diabetes? Should they get prednisone? All these kind of nuances. So the first thing is ADT/ARPI. I will say you just can never catch up with regards to the OS benefit if you don't use the ARPI upfront. For those individuals that are doing sequential therapy, you will never be able to catch up from the effect size is just so big in the MHSPC setting that you just can't catch up in the mCRPC.
And when I think of MHSPC, this is your honeymoon period. This is your period where you can have several years, many years of limited touchpoints coming in, getting your labs, getting your injection or doing relugolix, getting your hormone therapy where people can really have really good sustained quality of life. And it's good for the doc, it's good for the patient to have that be as long as possible. And so you just can't make it up. The time to progression for ADT, median time to progression is a year and a half. You're going to at least double that with an ARPI, and that's huge for a patient. So that's the first take-home message is escalate. And then the question is, okay, which agent should I escalate with? And then I think the chemotherapy question is a little bit more nuanced. I think for those we don't have level one data comparing ADT/ARPI to ADT/ARPI/docetaxel.
So we don't know the contribution of docetaxel when you're using the backbone of ADT/ARPI. But I will say for those individuals that have visceral metastases, maybe they've got a genomically aggressive tumor, maybe they've got bulky disease, they're symptomatic, high-volume, those are the individuals where we're having that conversation around docetaxel. And again, the story is, how can I make it so that your MHSPC period is as long as possible? And docetaxel is only a short period of that. It's only maximum four months. And just because you give one dose doesn't mean you have to do all six. If somebody doesn't tolerate it, you can always stop, but give people the opportunity to make that choice.
Sam Chang: Yeah, I think that resignation regarding, oh, I've got to get all these treatments in the clarification regarding what you just said, that you don't have to maximally get this side effect profile for the benefit. And that choice and that possibility I think is really important because we have just by wrote and just by practice, we go through this and we exhaust and then we add something and exhaust. But hopefully I think this further elucidates the importance of that therapy upfront. Just like I love the how you phrase, you never catch up, you never catch up. And so the fact that we gained that benefit early on during this honeymoon phrase, as you put it, where you really do have, I don't want to minimize the treatments, but in terms of the visits and the burden of seeing doctors, other treatments, you've really actually have a lot of flexibility with combination therapies at this point.
All right, so where next? What do you think is going to be the most exciting next findings or readout or something that will influence your practice in this setting or in the castration resistance setting? Because I can tell you right now with the explosion, we've had explosions in prostate and then we faded a little bit. We had explosions in kidney and then now in bladder, I mean, we've got so much going on in all the different disease. What's the most exciting thing coming up then for prostate?
Rana McKay: Yeah, very good question. So I think right now we've been doing an all-comer strategy in the MHSPC setting, but how can we get a little bit more nuanced? We've seen data emerge from the AMPLITUDE trial of the role of niraparib for BRCA2 mutated prostate cancer. We're going to see data from TALAPRO-3, which is looking at talazoparib, enzalutamide in the MHSPC setting. We've already seen data from CAPItello regarding capivasertib for PTEN-deficient tumors. So how do we better tailor therapy based off of a biomarker in the MHSPC setting? So I think that's going to be, I think, the future. And there are some studies being conducted through the cooperative groups that are asking that million-dollar question of what's the contribution of docetaxel to the backbone of ADT/ARPI.
The ASPIRE trial being coordinated through the Alliance is currently enrolling patients to answer that critical question and does integrate tumor genomics in that analysis based off of tumor suppressor gene loss alteration. So a lot of really cool things happening. The field continues to evolve. It's really great. I think on that same note, I will say because of the data from AMPLITUDE, every man with hormone-sensitive prostate cancer should undergo both germline and somatic tumor profiling. There is now an indication for PARP inhibitor and MHSPC, so broadly test for both germline and somatic alterations.
Sam Chang: Yeah, I think that is becoming increasingly important as hopefully we're getting to this age of catching up with other cancers with personalized kind of care based upon really what's going on within that person's individual tumors. And we're learning a lot, we're getting better. Clearly it's the minority of patients with BRCA2 changes, but if they have them, the ability to focus care just with FGR3 changes in terms of bladder cancer and other things that we've got where we can actually utilize those changes. We've got to start off, we as urologic surgeons, you all as medical oncologists, you guys have been on top of this for years for decades.
We've got to start recognizing early on that we need to actually begin testing early on and actually in our younger patients obviously doing germline testing as well. So really excited about the future and really excited that you are one of the key individuals leading this wave of important research. And there was never a doubt. I've known Dr. McKay when she was like 10 years old. This was just a few years ago and she is now really a true-
Rana McKay: You're awesome, Sam.
Sam Chang: So thanks so much.
Rana McKay: Thank you so much.
Sam Chang: We look forward to catching up again and hopefully I can get out to sunny San Diego at some point.
Rana McKay: We'd love to have you. Thanks for having me.