We presented the overall survival results of the phase III trial investigating talazoparib plus enzalutamide versus enzalutamide in patients with metastatic castrate resistant prostate cancer who had not received any treatment for castration resistant disease. This study was in unselected patients with metastatic CRPC which means they were not selected based on underlying alterations in the homologous recombination repair genes.

What was the study design?

TALAPRO-2 was  a large phase III trial and it was essentially two trials in one trial. So the first portion of the trial which comprised 805 patients, we also call it cohort 1, it comprised patients who were unselected for HRR gene alterations in their tumours. They were prospectively assessed, they had tumour tissue testing done and they were enrolled, regardless of whether they had HRR gene alterations or not. Among these 805 patients there were 169 patients who had HRR gene alterations which is reflective of what we would expect from an mCRPC, or metastatic castrate resistant prostate cancer, population.

After this enrolment in this cohort 1 was over, we recruited an additional 230 patients with HRR gene alterations in their tumours which is called as cohort 2. So cohort 1 had this 805 all-comer patient population unselected for HRR gene alterations and then cohort 2 comprised all patients with HRR gene alterations, so 169 patients from cohort 1 and 230 patients additionally enrolled after completion of enrolment in cohort 1, so we call it cohort 2. So I’ll talk about the efficacy data and the side effects data from both cohorts.

In the cohort 1 all-comer patient population, 805 patients were randomised to talazoparib plus enzalutamide versus enzalutamide. The randomisation was stratified by prior abiraterone or docetaxel chemotherapy use in the metastatic hormone sensitive setting and presence of HRR gene alteration status by deficient or non-deficient or plus unknown. Now, if you look at the primary endpoint it was radiographic progression free survival which was positive, as we reported in 2023. In this meeting, in the 2025 ASCO GU Symposium, we presented an update on radiographic progression free survival, overall survival which was the key secondary endpoint, so the trial was statistically powered to look for overall survival so we reported that, and then we reported several other secondary endpoints and quality of life data.

So let’s talk about the cohort 1 progression free survival which was the primary endpoint and we updated that. So there was a 33% reduction in risk of progression or death, the radiographic progression free survival was 33 months in the combination arm of talazoparib plus enzalutamide and it was 19.5 months in the active control arm of enzalutamide plus placebo. It is about a 14 month improvement in progression free survival, or radiographic PFS, which is quite meaningful in patients with metastatic CRPC because disease progression in mCRPC is associated with pain, suffering, fractures and so on.

Now let’s talk about the overall survival which was the primary focus of this presentation in 2025 and we saw a 20% reduction in the risk of death with a more than 8 month improvement in median overall survival with talazoparib plus enzalutamide versus enzalutamide. If you look at the absolute values they were about 46 months overall survival with talazoparib plus enzalutamide and 37 months with enzalutamide. That basically, as I said, translates into 8.8 months improvement in overall survival.

If we look at the subgroups enrolled in the trial, such as patients with high Gleason score versus low Gleason score, patients who received abiraterone or docetaxel chemotherapy in the hormone sensitive setting, all these are small numbers of patients, about 20% of these patients, are patients who had de novo disease at the time of initial presentation of hormone sensitive metastatic disease. The combination seemed to benefit in all groups, so none of the subgroups did not show benefit although magnitude of benefit differs. For example, in HRR deficient patients the magnitude of benefit was higher than in patients who did not have HRR deficient tumours or were unknown status and I will come to that in a moment. If you look at the patients who were not detected to have any HRR gene alterations by both ctDNA and tissue testing, so I would like remind the viewers that ctDNA testing was not prospectively done in these patients so we did a post-hoc analysis and we looked at both ctDNA testing and tumour tissue testing and we only selected those patients who did not have HRR gene alterations by both ctDNA and tissue testing, and we found that the hazard ratio was 0.78 for overall survival, meaning a 22% reduction in the risk of death in patients who did not have any of these alterations by both ctDNA and tumour tissue testing with talazoparib plus enzalutamide. If you look at absolute values, 46.6 months overall survival versus 37.4 months favouring the talazoparib, over 9 months difference or improvement in overall survival with talazoparib.

If we look at time to cytotoxic chemotherapy, one of the key secondary endpoints quite meaningful to our patients, there was a 44% reduction in the risk of chemotherapy, so there was a delay in chemotherapy with talazoparib. If we look at adverse events of special interest we reported initially one case of MDS and one case of acute leukaemia in the talazoparib arm in 2023. At the time of data cutoff we did not see any more of these cases which is quite comforting. We didn’t see any additional thromboembolic events. In 2023 we reported 2.4 events per 100 participant years, we didn’t see any new findings after a longer follow-up, four years’ follow-up now.

If we look at the most common grade 3/4 adverse events it was mostly anaemia in 49% of these patients. So if we look at the baseline status of these patients, 49% of these patients had grade 1/2 anaemia before starting treatment with talazoparib at baseline. So the trial had relaxed eligibility criteria in the sense that it allowed grade 2 anaemia as eligible. Patients who had grade 2 anaemia were eligible to enter the trial, to enrol in the trial. After 3.3 months of median duration of protocol treatment these patients developed grade 3/4  anaemia. So 49% had grade 1/2 anaemia at baseline, 49% of these patients developed grade 3/4 anaemia after 3.3 months of median protocol treatment and then they underwent protocol mandated dose reduction after developing grade 3/4 anaemia. Once you reduced the dose they seemed to tolerate the talazoparib well as evident by a long median treatment duration of talazoparib which was about 20 months and only 8.5% of these patients discontinued talazoparib because of anaemia.

But then you look at those other grade 3/4 side effects which really impact quality of life such as nausea, vomiting, anorexia, fatigue, these are quite rare. One or two, 4% of these patients, had these grade 3/4 events and this reflected in quality of life data. So if we look at the patient-reported global health status quality of life for standardised EORTC QLQ-C30 scale, there was no compromise on quality of life. Quality of life was maintained in the talazoparib plus enzalutamide arm versus enzalutamide plus placebo arm. So there was no deterioration in the quality of life with talazoparib.

So we concluded by saying that TALAPRO-2 is the first PARP inhibitor plus ARPI combination therapy to show a statistically significant and a clinically meaningful improvement in overall survival versus standard of care enzalutamide, an active control in mCRPC in patients who were unselected as well as selected for HRR gene alterations.

So if we look at the patients that were cohort 2 data, again a very similar side effect profile, but there was a 14 month improvement in overall survival with talazoparib. So if you look at the enzalutamide only arm the median overall survival in patients who were selected, who had positivity for HRR gene alterations, it was 31 months and with talazoparib it was 45 months. So a 14 month improvement in overall survival with a 40% reduction in risk of death. It’s quite remarkable.

So we concluded by saying that TALAPRO-2 shows improved overall survival in an all-comer patient population as well as HRR gene altered patients who had these alterations in their tumours. The median overall survival with talazoparib plus enzalutamide was pretty similar in the intention to treat population, patients who had HRR deficient disease, who did not have HRR deficiency, and all ranging from 46 to 47 months. It tells me that adding talazoparib somehow negates, seems to negate, the negative prognostic aspect of HRR gene alterations in that cohort but we also see benefit in an all-comer patient population.

Of course, I would like to remind the viewers that median radiographic progression free survival was delayed by about 15 months, 13.6 months to be precise, about 14 months, in the talazoparib arm which is quite meaningful because 14 months delay in disease progression means a delay in pain, fractures and suffering in our patients. We did not see any new safety signal.

So I would like to conclude that these data support talazoparib plus enzalutamide as a standard of care treatment option for patients with metastatic castrate resistant prostate cancer.

What is next for this study and what is the clinical significance?

It’s great to have overall survival benefit in any study and it is very gratifying to see such magnitude of overall survival benefit. In every group we see a survival benefit of about 9 months. When was the last time we saw this magnitude of overall survival benefit in many randomised controlled trials in the metastatic castrate resistant prostate cancer setting? So that’s number one, overall survival is the gold standard in an endpoint, if you meet it it’s very gratifying, great news for our patients. That’s our overarching overall conclusion.

But then the second question which came up within the meeting also – do we do NGS testing and the answer is yes. I can repeat it three times that we have to do NGS testing because, number one, NGS testing also tells us about the possibility of germline testing. So many patients miss germline testing. So if you are in the clinic and you are ordering NGS testing, many of these patients may be harbouring germline mutations which may have an effect on their family members or implications for their family members. So we need to do both testings as also supported by ASCO guidelines, we just came up on January 9th. So that’s number one but then, number two, we also have other mutations which can be detected, such as TMB high status, MSI high status, and hopefully many other trials which are ongoing which will also show more benefit in many new drugs. So not to make these patients eligible for other options like pembrolizumab but also to make them eligible for any other clinical trials which could be ongoing which could be available for these patients.

Of course, number three, the magnitude of difference in overall survival in patients who have BRCA1/BRCA2 mutations, so who had HRR gene alterations or did not have HRR gene alterations, all seemed to benefit but the magnitude is different. It is important to have this information in the clinic.

Lastly, the side effects which we saw did not seem to affect quality of life in the adverse fashion and all of these side effects were, especially with anaemia, grade 3/4 anaemia happens early on. So I tell my patients, tell my colleagues not to decrease the side effects of PARP inhibitors up front because dosing matters. I suggest doing the CBC, obtaining the haemoglobin level every month for the first three or four months. You  will know who is going to develop grade 3 or 4 anaemia and you can decrease the dose in those patients. Many patients do not require dose reduction of talazoparib so we should optimise dosing because dosing matters, not only with PARP inhibitors but most cancer therapies.

Lastly, quality of life was maintained while overall survival was significantly improved with talazoparib which is another great news for our patients.