I think it's safe to say that we are currently in the area of targeted therapy. We have numerous PARP inhibitors that have been approved by the FDA for the treatment of patients with either metastatic castration-resistant or -sensitive prostate cancer. And as you can see in the table here, we have all the agents as well as the disease states where they're approved, and with pivotal trials, led to these approvals.
I'm not going to bore you by going through each one of them, but I do want to highlight one combination that is approved and that is talazoparib plus enzalutamide that was approved in 2023 for the treatment of homologous recombination repair positive mCRPC patients in the first-line mCRPC setting based on the results of TALAPRO-2. And as a refresher, TALAPRO-2 was a phase-three randomized double-blind placebo-controlled trial that included patients being treated for mCRPC in the first-line setting, and they were randomized one-to-one to talazoparib plus enzalutamide versus placebo plus enzalutamide with a key secondary endpoint overall survival and a primary endpoint of radiographic progression-free survival.
And as we see here in the overall population with regards to the primary outcome of rPFS, this trial was positive with a hazard ratio of 0.63 and meeting statistical significance. But importantly, we saw such a divergent preferential benefit in the HRR-deficient patients with the hazard ratio was down to 0.46.
Comparatively, those that were HRR intact or non-deficient, we saw a hazard ratio more modest of 0.7. So truly, we see here that biomarker selection in the form of identifying those that are HR division really led to a preferential benefit. And based on these results, we saw the combination of talazoparib plus enzalutamide approved specifically for those with HRR deficiency.
And as always, the question is, can we move up these drugs and these combinations earlier along the disease continuum, so that we give our patients this benefit early on, and help improve survival outcomes even further. And so the study objective of TALAPRO-3 was to investigate the efficacy and safety of this combination versus placebo plus enza, specifically in HRR-mutated metastatic castrate-sensitive prostate cancer. And I want to note from a semantic standpoint based on the recent output from the Prostate Cancer Working Group Four, now not referred to as mCSPC anymore, but androgen pathway modulation-sensitive or APMS disease.
And I want to note that nearly 30% of patients with mCSPC or thereafter mAPMS harbor this HR mutation, and it's important to note that these patients have worse survival independent of disease volume or the treatment received. So it's really important that we identify this 30%, and we help target with PARP inhibitors as we'll see in the next few slides.
So this was a phase-three double-blind placebo-controlled trial. It was designed as sponsored by Pfizer. In terms of eligibility, patients had to have metastatic APMS, prostate cancer, mCSPC, prostate cancer, and conventional imaging. All patients were required to have an homologous recombination repair or HRR mutation, be it on blood, meaning germline mutation or tumor, which could be either germline or somatic mutation. And from a practical standpoint, do you need fresh tissue or could this be archived tissue? Either/or. Archived or new, not an issue, which makes it much easier to recruit these patients into this trial.
With a 12-gene panel, our listeners are well familiar with these: ATM, BRCA, CDK, CHEK2, FANCA, et cetera, et cetera. And the prior ADT for up to three months plus or minus an ARPI was allowed, but prior docetaxel as of a protocol amendment in September 2021 was not allowed.
Here, we see the study design of TALAPRO-3. As we mentioned, key eligibility criteria, HRR-mutated mCSPC. They have metastatic disease as defined by conventional imaging, good performance status, and allowed three months or less of prior ADT plus or minus an ARPI. They underwent stratified randomization to talazoparib plus enza or placebo plus enza. And the primary endpoint similar to TALAPRO-2 was rPFS by investigator assessment. The key secondary endpoint was overall survival, which was alpha-protected, and we have other key secondary endpoints, which included objective response rate, soft tissue response, PSA response, PSA progression, time to subsequent therapy, symptomatic skeletal events, safety and patient reported outcomes.
At this point, turnover to Zach, we'll go over the results and discussion of this very important trial.
Zachary Klaassen: Thanks, Rashid. Let's look at the demographic and disease characteristics for TALAPRO-3. We see the median age in both groups was roughly 70 years of age. This was a global trial, so just over half of the patients were White and about over one third of patients were Asian. And we dropped down to median serum PSA, 3.6 for both groups. Over 80% of patients had a Gleason score equal to or greater than eight. We look at the disease localization at screening. Roughly one third were bone only. Around 10% were soft tissue only. The majority were both bone and soft tissue. ECOG performance status was excellent. ECOG 0 in nearly two-thirds of patients. This was de novo metastatic disease. In majority of patients, roughly 85%, high-volume in almost three quarters of patients. And then we look at the HRR gene alterations. Roughly one-third were BRCA1 or 2 and the remaining were other HRR alterations.
And then when we look at the right side of the screen, looking at the specific HR gene alterations, roughly 30% BRCA2, and up to 30%, almost an ATM. Our CDK12, roughly 20%, CHEK2, 15%. And then we see the remainder of the HRR mutations listed below.
In terms of imaging-based progression-free survival, the primary endpoint in the intention to treat population was a hazard ratio of 0.48, 95% confidence interval of 0.36 to 0.65, favoring the talazoparib plus enzalutamide arm. We can see an early and consistent splitting of the Kaplan-Meier curve here on the left. If we move to the right side, the BRCA subgroup, again, not a surprise here. Hazard ratio of 0.37 favoring the tala plus enzalutamide arm. And what's important here in the non BRCA subgroup, we also see a significant benefit for the talazoparib plus enzalutamide arm, hazard ratio of 0.57, 95% confidence interval of 0.39 to 0.82.
Some important secondary efficacy endpoints. On the left, we see overall survival. This is early data for OS. Kind of trending towards talazoparib plus enzalutamide, we see a splitting of the curves at about 12 months. The median not reached in either arm. The early stratified hazard ratio of 0.77. PSA progression, we see a benefit for the talazoparib plus enzalutamide arm. Again, the median not reaching each, but the hazard ratio 0.51, 95% confidence interval, 0.37 to 0.71, favoring the talazoparib plus enzalutamide arm.
Jumping down to the bottom left, subsequent antineoplastic therapy, median not reaching neither arm. The hazard ratio again favoring the tala plus enza arm, 0.51, 95% confidence interval, 0.38 to 0.70. When we look at objective response, which is in the bottom right, we see an ORR of 75% for talazoparib plus enzalutamide compared to 67% for placebo plus enzalutamide. What's important here, we see 23% complete responses for tala plus enza versus 14% for placebo plus enza, and we see no progressive disease in the talazoparib plus enzalutamide arm compared to 6% of patients in the placebo plus enzalutamide arm.
In terms of adverse events, any adverse event was 81% Grade 3+ in the tala plus enza arm compared to 44% in the placebo plus enza arm. Serious adverse events, 37% versus 27%. When we look at resulting in dose reduction, majorities were all grade, no grade three for talazoparib plus enzalutamide, 60%, although had a dose reduction in talazoparib. And we look at grade five events, 3% in each arm. What's important here, and we know this from the previous talazoparib plus enzalutamide trials, that anemia is by far the most common adverse events. So 71% all grade anemia for talazoparib plus enza compared to 51% for Grade 3+. This is certainly much lower than we see in the placebo plus enzalutamide arm. So we know that anemia is the most common in this combination. We've seen this in TALAPRO-2, and we're seeing it in TALAPRO-3.
So TALAPRO-3 showed that talazoparib plus enzalutamide versus placebo plus enzalutamide improved imaging-based radiographic progression-free survival with a hazard ratio of 0.48 in patients that are APMS with HR mutations. We also saw benefit in BRCA2, hazard ratio of 0.35, but also other HRR genes, including CDK12, hazard ratio of 0.28, and ATM hazard ratio of 0.43. We already have an approval in this space at AMPLITUDE, same patient population with HRR mutations, niraparib plus abi and prednisone versus abi and prednisone. This had an improved imaging based rPFS hazard ratio of 0.63 compared to 0.48, which we saw on TALAPRO-3.
The findings from TALAPRO-3 and AMPLITUDE really highlight the importance of molecular testing in the mAPMS patients. This does enable biomarker-driven treatment strategies as important take-home message from these two trials as we have to do the molecular testing for these patients. As I mentioned previously, half of the patients receiving talazoparib plus enzalutamide had grade 3-4 anemia as an adverse event.
These events did occur early and was managed with close monitoring, treatment interruption, dose reduction at the hemoglobin remained less than eight, and RBC transfusion if needed. With this combination of management, dose reduction allowed continued talazoparib use, and only 5% of patients discontinued talazoparib because of anemia.
So for take-home messages, talazoparib plus enzalutamide led to significantly better imaging-based progression-free survival versus placebo plus enzalutamide among mAPMS patients with HRR mutations. Serious adverse events were certainly more common with talazoparib plus enzalutamide than with placebo plus enzalutamide. I think this will continue to evolve into discussions in management, especially as we see these PARP inhibitors moving up in the prostate cancer landscape.
We thank you very much for your attention. I hope you enjoyed this TALAPRO-3 discussion presented at ASCO, subsequently published in the New England Journal of Medicine.