Talazoparib plus enzalutamide shows improvement in PFS over standard of care in firstline HRR mCRPC

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Published: 6 Jun 2023
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Prof Karim Fizazi - Institut Gustave Roussy, Villejuif, France

Prof Karim Fizazi speaks to ecancer about the TALAPRO-2 phase 3 study of talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) harbouring homologous recombination repair (HRR) gene alterations.

This study reports the results of the prespecified, independently powered analysis of patients with mCRPC with HRR gene alterations from Cohorts 1 and 2 of the TALAPRO-2 trial.

The results of this study showed that talazoparib plus enzalutamide demonstrates a statistically significant and clinically meaningful improvement in rPFS over standard-of-care enzalutamide as a first-line treatment for patients with mCRPC and HRR gene alterations.

Prof Fizazi says that the toxicity of this treatment regimen was generally manageable and consistent with known safety profiles.

I presented here at ASCO 2023 the findings for TALAPRO-2 which is a phase III trial for men with metastatic castration resistant prostate cancer, first line, and evidence of DNA repair defects. This is a phase III trial that compares enzalutamide alone or in combination with talazoparib, a PARP inhibitor. So basically it’s not actually just one trial but it’s actually two different trials. I’m saying that because we first enrolled a population of men who are called all-comers, so no biomarker selection, and this was previously reported at ASCO GU this year. But then we carried on, enrolling more patients with DNA repair defects which consist of cohort 2 and this is the one I presented here at ASCO. So, again, two different populations of men.

For patients with HRR alterations, the primary endpoint was radiographic progression free survival and it was clearly met with a reduction of 55% in the risk of progression or death favouring the combination arm. When looking at subgroup analyses, we showed that pretty much all subgroups benefitted from the combination across the board. For example, this was true regardless of whether the patient had received docetaxel or abiraterone for castration sensitive disease or not. 

Now, when looking at a gene by gene analysis, and I think this is the key in the discussion, we saw that patients with BRCA alterations derive an enormous benefit from the combination with an 80% reduction in the risk of progression or death. This applied to both BRCA2 patients, as expected, but also to BRCA1 patients which is perhaps a new finding from the trial. On the other hand, patients with non-BRCA HRR alterations derived a more modest benefit with a hazard ratio of 0.68 and a p-value of approximately 0.6. 

Digging into more details, we saw that patients with CDK12 alterations actually may derive benefit from the combo with an approximately half reduction in the risk of progression or death, while patients with ATM or CHEK2 alterations just don’t benefit. 

At this interim analysis for overall survival, the data are probably mature. More than 75% of men were still alive when we did the analysis. Still, we see a clear trend for survival favouring the combination arm with a 41% reduction in the risk of death and a p-value which is almost significant. We will continue the follow-up of these patients, of course, and probably in a year’s time we will be able to provide the final analysis for survival. 

How can these results impact the future treatment of mCRPC?

For the future, we will have really to take into account the efficacy findings but also the safety profile of this combination. Indeed, what we saw was a 40% grade 3 or 4 anaemia rate which means that we should probably select patients who truly benefit from the combination to get it and try to avoid this combination in men who potentially don’t benefit. 

In my opinion, at least, we should probably in the future clearly treat patients with BRCA alterations, perhaps also those with CDK12 alterations and probably more data is needed for these men. Now, for patients with other HRR alterations and, of course, also for patients without HRR alterations, we need more data and a longer follow-up before we can really say that this is ready for prime time.

On top of that, for the future, talazoparib is being tested even earlier in the course of the disease in patients with metastatic castration sensitive disease, at least for patients with BRCA alterations, and this is really a key question for the future. There is a very good chance for PARP inhibitors to find their place in this setting but, of course, time will tell.