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Rashid Sayyid: Hello everyone, this is Rashid Sayyid. I'm a Urologic Oncology Fellow at the University of Toronto. And along with Zach Klaassen, Associate Professor and Program Director of the Medical College of Georgia, we'll be discussing the latest TALAPRO-2 publication that looked at talazoparib plus enzalutamide in men with first-line mCRPC, that was recently published in the Lancet.

So we know that patients with mCRPC have poor prognosis. And this has been shown in the COU-AA-302 abiraterone and the PREVAIL enzalutamide trials, where the median overall survival was only about three years. And this was within the context of a clinical trial. And if we look at real world data, and it was only about two years. So clearly, we need newer agents or combinations in this setting.

Patients with homologous recombination repair gene alterations, or HRR, are present up to 30% of mCRPC patients. These alterations are associated with a poor prognosis, and a resistance to current systemic therapies.

Within this subset, we have the patients with the BRCA1/2 mutations, and these patients specifically have increased sensitivity to PARP inhibition. And furthermore, this sensitivity may be further augmented by androgen receptor signaling inhibitors that downregulate DNA repair gene expression. And so, it's been hypothesized that the combination of a PARP inhibitor and an androgen receptor signaling inhibitor, may have synergistic potential. We'll talk about this a bit more in further slides.

Well, let's start with talazoparib. So talazoparib is a potent PARP 1/2 inhibitor. How do PARP inhibitors work? So they trap the PARP on a single strand DNA break, and they prevent DNA repair, leading to double-stand breaks, which may lead to cellular apoptosis.

And in the TALAPRO-1 trial talazoparib, one milligram per day, was shown to be associated with an objective response rate of 30% in mCRPC patients with an HR deficiency and with disease progression after one to two lines of taxane chemo and an ARSI, such as abi, enza, or both

What about enzalutamide? It's been around for a while. It's a second generation androgen receptor blocker, that prevents the translocation of the receptor into the cellular nucleus. And based on the results of the PREVAIL trial, showing an overall survival benefit, this has been approved in the first-line, meaning, the pre-chemo setting for mCRPC patients.

So let's talk a bit more about a combination of PARP inhibitor and an androgen receptor signaling inhibitor. So preclinical models suggest synergy for this combination. So PARP inhibitors upregulate AR signaling, enhancing this ARSI activity. Conversely, these ARSIs, such as abi or enza, inhibit the transcription of some HR genes, inducing an HR deficiency-like state, which has been commonly described as BRCAness.

And this combination isn't just unique to the TALAPRO-2 trial. There are other Phase III trials in this setting, in the mCRPC first-line treatment, that have looked at a combination of an ARSI and a PARP inhibitor. So we know about PROpel, which looked at abiraterone wither that olaparib, and this combination showed rPFS benefits in both the HRR and non-HRR mutated cohorts. And we also have the MAGNITUDE trial, that was recently published in JCO, that looked at the combination of abiraterone with niraparib. And in this trial, this combination was only shown to have rPFS benefits in the HRR mutated cohort.

So the study objective TALAPRO-2 two in this report, was to assess the safety and efficacy of combination talazoparib plus enzalutamide, versus placebo plus enzalutamide in the mCRPC first-line treatment setting.

And this is a brief overview of the study design, and we'll go into this into some more details in the next slides.
So this was a Phase III double-blind placebo controlled RCT across 223 centers with the following eligibility criteria. So patients were over 18, receiving ongoing androgen deprivation therapy, and had either asymptomatic or mildly symptomatic mCRPC, with an excellent to good performance status. Patients had progressive disease at study entry, defined by either PSA progression or imaging-based progression, and adequate bone marrow function.

Importantly, these patients had not received prior life prolonged systemic therapy for CRPC or mCRPC, meaning, this was a first-line treatment setting. Previous docetaxel, abiraterone, or orteronel was permitted in the castrate sensitive setting, but not in the castrate resistant setting.

Talazoparib dose was determined to be 0.5 milligrams daily. The usual was one milligram daily. And the reasons for that was that, the full one milligram dose was shown to have significant drug-drug interactions with enzalutamide 160 milligrams. And then the pharmacokinetics demonstrated similar talazoparib exposure levels, irrespective of whether it was 0.5 or one milligram. So for those reasons, the recommended drug dose for talazoparib was 0.5 milligrams.

Patients were randomized 1:1 to talazoparib 0.5 milligrams daily, plus enzalutamide full dose at 160 milligrams versus placebo, or enzalutamide one 60 milligrams daily, stratified by the prior novel hormonal therapy, or docetaxel exposure during the castrate sensitive state, yes versus no. And the HRR gene alteration status, whether that was deficient, non-deficient, or unknown. And treatment was continued until evidence of radiographic progression, an adverse event leading to permanent discontinuation, the patient decision to stop, or death. And it's important to highlight that the sponsor, the patients, and investigators, were all masked to other patients who received talazoparib or placebo.

Let's talk about patient enrollment for a bit. So there's a unique aspect to this trial. So enrollment began initially in cohort one of all comers, meaning, either patients with or without HRR gene alterations. So this was a biomarker, unselected, or non-selected cohort of patients.

After enrollment was complete in cohort one of all comers, enrollment in cohort two was restricted to patients with HRR gene alterations. And if we look at the image below, we see that in the all comers of cohort one, we had both the non-deficient, unknown, and the HRR mutated. And then, those HRR mutated patients, cohort one, the 169 patients, those also contributed to cohort two with the additional 230 patients for 399. So there's these 169 patients that overlap between cohort one and cohort two.

And then how do they determine the HRR gene alteration status? That's a question that's commonly asked. I'm considering a PARP inhibitor for my patient. What was the way that we can determine the HRR gene alteration status? So there's a couple of ways. So you can assess the solid tumor tissue, either it's de novo from a biopsy, or archival, from the time, let's say, of a prostatectomy or the biopsy, or it was blood-based, meaning a ctDNA. And we'll talk a bit more about what patients were, had the HRR gene alteration status determined via one, the other, or both.

And then, after we had that tissue, be it the solid tumor or the blood, these samples were evaluated for DNA damage response gene involved in HRR, most common of which are BRCA1/2, PALB2, ATM, CHEK2, et cetera. And they used the FoundationOne® CDx, or the FoundationOne® Liquid CDx, to ascertain the HRR gene alteration status. And then, patients were determined to have either a positive status, negative or unknown. What was unknown? Unknown meant, that either the sample was insufficient or inadequate, or it was not, meaning, it pre-specified quality control metrics, leading to the test failure.

Patients were followed with imaging, meaning, a CT chest plus abdomen/pelvis, or it could be an MR abdomen/pelvis, and a bone scan every eight weeks. So week 25, and then every 12 weeks, or three months thereafter. Underwent routine clinical lab evaluation and safety assessments, as for standard practice. And then PSA was followed every eight weeks, until evidence of radiographic progression.

The primary outcome of this study was radiographic progression-free survival, assessed by a blinded independent central review. This was evaluated using common criteria, the RECIST1.1 for soft tissue lesions, and the Prostate Cancer Working Group-3 for bone lesions. And then, they ran subgroup analysis by the HRR gene alteration status, which is very relevant to our clinical practice, looking at deficient versus non-deficient or unknown. In the second group. Also looked at the outcomes by the BRCA status. And they also looked at it by different baseline patient characteristics, which we'll go over in more detail later on.

Secondary outcomes were pretty standard; overall survival, objective response rate, PSA50, time to PSA progression, time to cytotoxic chemo, time to the next antineoplastic therapy, symptomatic skeletal events, opiate use, safety, and then, patient reported outcomes, which the investigators will report separately in a later publication. Of note, the overall type one error, or the false positive rate, was a split, equally between the all comers cohort, and then, the ongoing HRR selected population. And any comparisons were tested at a one-sided alpha of 0.025. And the reason being, usually, we do a two-sided alpha looking at these comparisons at 0.05. So if you look at the one-sided alpha, you split that to 0.025, and that 0.025 was subsequently split between those two cohorts. So each one got 0.0125. And again, this is emphasized in the later point.

When we're looking at the primary comparison in the all comers cohort, a lot of these calculations are not only based on the sample side number of patients, but also the number of events that occur. So the number of events drive the power analysis. So for 333 rPFS events, this study was adequately powered, 85% power. The usual is about 80 with these studies, to detect an improvement of about 30% at, again, the one-sided alpha of 0.0125. And the authors had that preplanned futility analysis when 50% of the events had occurred.

And of note, the overall survival outcomes would only be tested if the rPFS results were significant, and we'll see a bit more about that later on.

Again, survival analysis, looking at time to event outcomes, the authors used the classic Kaplan-Meier curves and Cox regression modeling. Then the safety analysis included patients who received at least one dose of the study drug. And at this point, I'll turn it over to Zach, to go over the results and discussion for this study.

Zach Klaassen: Thanks so much, Rashid, for that comprehensive introduction and methodological breakdown of the TALAPRO-2 study.

So this trial had 991 patients assessed for eligibility. Ultimately, 805 were randomized. This included 402 to talazoparib plus enzalutamide, and 403 to placebo plus enzalutamide. As you can see on the left, among the tala plus enza group, 245 patients discontinued talazoparib, and 227 discontinued enzalutamide. In the placebo plus enza group, 280 patients discontinued placebo, and 276 discontinued enzalutamide.

With regards to baseline patient demographics and characteristics, we can see the median age was well-balanced at 71 years. Roughly two thirds of patients were White and one third were Asian. In terms of baseline serum PSA, well-balanced as well, 18.2 for talazoparib group, compared to 16.2 in the placebo group. Majority of these patients, nearly three quarters, were Gleason greater than or equal to eight. And the majority, over 85%, had some component of bone disease, including a soft tissue component as well. And when we look at the additional disease sites, roughly 37 to 40% had lymph node involvement. And visceral involvement, including lung, was 11% in the talazoparib group, and 15% in the placebo group.

Not surprising for a Phase III trial, excellent performance status for these patients. Two-thirds were ECOG zero, one-third were ECOG one. Previous taxane chemotherapy, roughly 21% in the talazoparib group, 23% in the placebo group. 6% and 7% respectively in tala and placebo groups, had previous treatment with a novel hormonal therapy. When we look at HRR gene alteration status, 21% were deficient, and 79% in each group were non-deficient or unknown. And this included 7% BRCA1/2 alteration in the talazoparib group, and 8% in the placebo plus enzalutamide group.

Next several slides will look similar to these Kaplan-Meiers looking at rPFS, talazoparib plus enzalutamide in red, and placebo plus enzalutamide in blue. And this is rPFS for all patients. And we can see that the median was not reached in the talazoparib plus enzalutamide arm. And it was 21.9 months in the placebo plus enzalutamide arm. With a hazard ratio favoring talazoparib plus enzalutamide of 0.63, and a 95% confidence interval of 0.51 to 0.78.

This is rPFS in the HRR gene deficient cohort for talazoparib plus enzalutamide, median of 27.9 months. And for placebo plus enzalutamide, median of 16.4 months. With a hazard ratio, again, favoring talazoparib plus enzalutamide of 0.46. And a 95% confidence interval of 0.30 to 0.70.

This is HRR gene non-deficient or unknown. Median was not reached in the talazoparib arm, compared to 22.5 months in the placebo arm. Favoring the talazoparib plus enzalutamide arm, with a hazard ratio of 0.70, and a 95% confidence interval of 0.54 to 0.89.

And finally, this is HRR gene non-deficient by prospective tissue testing. Again, favoring talazoparib plus enzalutamide, with a hazard ratio of 0.66, and a 95% confidence interval of 0.49 to 0.91.

This is the rPFS subgroup analyses, and you can see generally, looking at overview of this figure, that all of these subgroups favor talazoparib plus enzalutamide, particularly for age, ECOG performance status, Gleason score, stage at diagnosis, progression at entry, baseline PSA, HRR status per randomization stratification, as well as previous taxane or novel hormonal therapy.
We do see a little bit less of a signal among patients that were randomized from Asia and from North America, as well as those that had soft tissue only sites of metastases. But generally speaking, amongst these subgroups, very good rPFS benefit for those receiving talazoparib plus enzalutamide.

This looks at the subgroup analyses by BRCA1 status, as well as HRR gene alteration status and prospective tumor status. As you would expect, as we can see at the top here, this is BRCA1/2 altered among HRR deficient patients. Very significant benefit, although small sample size, hazard ratio of 0.23. We see not as strong of a benefit among the non BRCA1/2 altered HRR deficient, with a hazard ratio of 0.66, 95% confidence interval of 0.39 to 1.12. In the non-BRCA1/2 altered or unknown in the intention to treat population, we do see a benefit for talazoparib plus enzalutamide, hazard ratio of 0.69. And again, by prospective tumor testing, benefit for talazoparib plus enzalutamide for HRR deficient and HRR non-deficient, with not a statistical benefit for the HRR unknown patients in the prospective tumor testing cohort.

This looks at the secondary efficacy endpoints, and we can see at the top, this is best overall response. A complete response rate of 38% for talazoparib plus enzalutamide, compared to only 18% for placebo plus enzalutamide. I've highlighted that all of these secondary endpoints benefited talazoparib plus enzalutamide, except for time to first symptomatic skeletal event. So the benefit was seen for objective response for PSA50, for time to initiation of toxic chemotherapy, for time to PSA progression, for time to antineoplastic therapy, and PFS too. So all of these benefited talazoparib plus enzalutamide, statistically significant, except for time to first symptomatic skeletal event.

When we look at adverse events, this is the safety population, and we'll focus primarily on the grade three adverse events. And we can see that in the talazoparib plus enzalutamide arm, 75% of patients had a grade three or greater adverse event, compared to 45% of patients in the placebo plus enzalutamide arm. And there's some significant differences in terms of these adverse events.

And so, when we look at anemia, 46% had a grade greater than or equal to three adverse events for anemia for talazoparib plus enzalutamide, compared to only 4% for placebo plus enzalutamide. Neutropenia, 18% for the talazoparib arm, compared to 1% for placebo arm. And also, for thrombocytopenia, 7% for talazoparib arm, compared to 1% for the placebo plus enzalutamide arm.

So across this all comer population in pre-specified subgroups, talazoparib plus enzalutamide resulted in a clinically meaningful and statistically significant benefit over enzalutamide plus placebo. Enzalutamide plus placebo performed in line with extended follow-up in the PREVAIL trial. So we did have a very good control arm to compare this to. Statistically significant and clinically meaningful improvements in rPFS were seen for the all comers population, which was the primary endpoint. HRR deficient subgroup and the HRR non-deficient or unknown subgroup, as well as the HRR non-deficient subgroup by prospective tumor testing only.

TALAPRO-2 two results are supported by those from the recent Phase III PROpel trial, which demonstrated improved PFS with olaparib plus abiraterone, over placebo plus abiraterone in patients with mCRPC.

So let's talk just a little bit more about the patients without an HRR gene alteration. In TALAPRO-2, talazoparib plus enzalutamide significantly improved rPFS in these patients. And this is in contrast to the recently published Phase III MAGNITUDE trial, which showed no benefit of adding niraparib to abiraterone in patients without HRR gene alterations.

So the reasons for these results are yet to be fully elucidated, and it may be related to trial design, and it may be related to the ability of each drug to trap PARP or DNA.

So in conclusion, results from the primary analysis of the all comers population of the TALAPRO-2 trial supported the consideration for talazoparib plus enzalutamide as first-line treatment options in patients with mCRPC. The final overall survival data and additional long-term safety follow-up, will further clarify the clinical benefit of the treatment combination in patients with and without tumor HRR gene alterations.

We hope you enjoyed this UroToday Journal Club of the recently published TALAPRO-2 trial in the Lancet.