Neeraj Agarwal, MD, Huntsman Cancer Institute at University of Utah, Salt Lake City, Utah, discusses the results of the phase 3 TALAPRO-2 trial, which he first presented at the 2023 ASCO Genitourinary Cancers Symposium. This study compared enzalutamide plus talazoparib with enzalutamide plus placebo for patients with metastatic castration-resistant prostate cancer.

The study met its primary end point of improved progression-free survival (PFS). As Dr Agarwal stated, “We have convincing data that the combination of enzalutamide with talazoparib improves radiographic progression-free survival and delayed progression and death and deterioration of quality of life, compared to enzalutamide alone, which is a very active control arm.”

Transcript:

Hi, my name is Dr Neeraj Agarwal. I'm a professor of medicine and director of Genitourinary Oncology program at the Huntsman Cancer Institute at University of Utah in Salt Lake City in the United States of America. Today I'm going to be discussing the results of the phase 3 TALAPRO-2 trial, which I presented on behalf of my colleagues and investigators in the 2023 ASCO Genitourinary Cancers Symposium.

Let's start with the background: why we did the study. Despite advancements in therapeutics in last decade, metastatic castrate-resistant prostate cancer remains lethal. In fact, by the time our patients hit metastatic castrate-resistance state, the median survival is 33 months, less than 3 years, and this has not really changed in the first-line mCRPC setting in the last decade. In this context, TALAPRO-2 trial was conducted.

These were metastatic CRPC patients. They had not received any life-prolonging therapy for the metastatic castration-resistant prostate cancer setting, and they were randomized to enzalutamide, which is one of the most commonly used drugs in this setting, plus or minus talazoparib —patients either were randomized to enzalutamide plus talazoparib or enzalutamide plus placebo. The primary end point was radiographic progression-free survival by independent radiology assessment. Investigator assessment was also done, but the primary endpoint was independent radiology assessment.

Let's look at the primary endpoint first. The combination of enzalutamide plus talazoparib significantly improved radiographic progression-free survival and delayed progression and death by 37%, with a hazard ratio of over 0.63, favoring the combination arm. Quite impressive. The primary endpoint was met.

Now please remember that we recruited patients regardless of whether they had homologous recombination repair gene alterations or not. And I would like to bring to your attention that every patient was prospectively tested by tumor tissue testing for the presence or absence of these homologous recombination repair gene alterations. If you look at patients who were positive for these gene alterations, there was a 54% reduction in risk of death, with the combination treatment. If you look at patients who did not have these HRR alterations, or who had unknown status, even by tumor tissue testing, there was a 30% reduction risk of death. I also presented the analysis specifically in those patients who did not have gene alterations by prospective tumor tissue testing, and there was a 34% reduction in risk of death or progression. We can say here that the combination was able to delay disease progression or death convincingly, regardless of HRR alterations.

The other clinically meaningful endpoints such as delay in chemotherapy, delay in PSA progression, delay in deterioration of quality of life, how patients did on subsequent therapies, they were all favoring the combination of enzalutamide with talazoparib.

If you look at the side effects, we didn't see any new safety signals. Grade 3/4 anemia was present in 46% patients, but then 49% of patients had grade 1/2 anemia even before starting the protocol treatment. This was a metastatic CRPC state and, as expected, patients had grade 1/2 anemia, and we did not require dose reduction for grade 1/2 anemia, because otherwise, it would have compromised the optimization of the dose. The moment they hit grade 3, which is 1 point decrease from the 9 gram/dL hemoglobin which was the eligibility criteria for the trial, protocol required a decrease of the dose of talazoparib. And after that, patients tolerated the medicine very well, as evident by only 8% of patients discontinuing talazoparib because of grade 3/4 anemia. Grade 3/4 nausea, vomiting, anorexia, fatigue, all these side effects which are really known to impact quality of life, we saw these events in only 1% to 4% of patients.

Put it together, I think we have convincing data that the combination of enzalutamide with talazoparib improves radiographic progression free survival and delayed progression and death and deterioration of quality of life compared to enzalutamide alone, which is a very active control arm.

I look forward to the regulatory approval of this combination. I look forward to discussing the combination with my patients in the coming months.

Source:

Agarwal N, Azad A, Carles J, et al. TALAPRO-2: Phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. Published online February 21, 2023. doi:10.1200/JCO.2023.41.6_suppl.LBA17