Agarwal Discusses FDA Approval of Talazoparib Plus Enzalutamide in HRR Gene–Mutated mCRPC

For patients with homologous recombination repair (HRR) gene–mutated metastatic castration-resistant prostate cancer, additional data supporting the use of the combination of the PARP inhibitor talazoparib (Talzenna) with enzalutamide (Xtandi) is a welcome signal in the field, according to Neeraj Agarwal, MD.¹

The approval was supported by findings from the phase 3 TALAPRO-2 trial (NCT03395197), which enrolled 399 patients with HRR gene–mutated mCRPC and randomly assigned them to treatment with either enzalutamide 160 mg daily plus talazoparib 0.5 mg daily (n = 200) or enzalutamide 160 mg daily plus placebo (n = 199). The median radiographic progression-free survival (rPFS) was not evaluable (NE; 95% CI, 21.9-NE) compared with 13.8 months (95% CI, 11.0-16.7), respectively (HR, 0.45; 95% CI, 0.33-0.61; P < .0001).²

“The approval of enzalutamide plus talazoparib [is great news] for our patients with mCRPC who harbor any HRR gene mutations,” said Agarwal, who isPresidential Endowed Chair of Cancer Research, director of theGenitourinary Oncology (GU) Program and the Center of Investigational Therapeutics, as well as a professor of medicine, at the Huntsman Cancer Institute (HCI) of the University of Utah in Salt Lake City. “rPFS was the primary end point, [and] we saw that there was a 55% reduction in risk of progression or death with a combination of talazoparib plus enzalutamide vs enzalutamide alone. This is very impressive in my view; we also saw a strong trend for overall survival [OS] benefit, although OS data are not mature.”

In the discussion with OncLive®, Agarwal speaks on the significance of the approval and how the combination of talazoparib and enzalutamide will fit into the treatment landscape of HRR gene–mutated mCRPC.

OncLive: What were some of the other major findings from TALAPRO-2?

Aggarwal: Beyond rPFS and OS, those [other] end points are quite meaningful to our patients, [such as] time to delay of chemotherapy. The vast majority patients don’t want to be treated with chemotherapy in our clinics, and there was a 55% reduction in risk of [progression, so we could] delay chemotherapy.

Time to [prostate specific antigen]PSA progression is another meaningful end point to our patients. There was a 17-month delay in time to PSA progression with the combination of enzalutamide plus talazoparib vs enzalutamide.

If we look at time to deterioration of quality of life [QOL], as measured by standardized questionnaires—which are well validated and have been used worldwide in different trials—there was a significant delay in deterioration of QOL with the combination compared with enzalutamide alone. In my view, QOL data give us a summary of efficacy and toxicity. To see that QOL was maintained…gives me an additional level of confidence in this combination.

What were the key takeaways of findings from the exploratory analysis of patients with BRCA mutations from TALAPRO-2?

If we look at [patients with] BRCA1 and BRCA2 mutation who have mCRPC, we have always known that the efficacy of PARP inhibitors is highest in this subgroup. This is the most responsive patient population to PARP inhibitors. There were no surprises in the TALAPRO-2 trial. We saw an HR of 0.24 favoring the combination of talazoparib plus enzalutamide compared to enzalutamide, as far as rPFS is concerned, which translates into about 75% reduction in risk of progression or death with the combination.3

What was more interesting to me was the strong efficacy signal with enzalutamide plus talazoparib in patients who have other common mutations, such as CDK12 mutations. The HR for rPFS was 0.5, pretty much a 50% reduction risk of progression or death in patients with a CDK12 mutation.³

We also saw signal in PALB2-positive patients. We have always known that patients who have an RAD51 mutation, they seem to benefit. It was nice to see that even patients in smaller subgroups seem to be benefiting with the combination of enzalutamide and talazoparib.

However, given the small number of patients in each subset, any confirmation of rPFS or OS is going to be very difficult to establish. Having said that, it was quite impressive to see that combination of enzalutamide plus talazoparib performed well beyond the BRCA1- and BRCA2-[positive] patient population.

Are there any safety concerns clinicians should be aware of when using enzalutamide plus talazoparib?

The patient population which develops metastatic CRPC with an HRR [gene] mutation is facing an aggressive disease. Accordingly, looking at the number of patients who had grade 1 or 2 anemia, which is a known risk factor in metastatic CRPC, 55.6% patients had grade 1 or 2 anemia at baseline before enrolling on the TALAPRO-2 trial. We also know that hematologic toxicity and [gastrointestinal] GI adverse effects [AEs], such as nausea, vomiting, and decreased appetite, these are classic AEs of PARP inhibitors.

In TALAPRO-2, specifically, we saw 42% of patients developing grade 3 anemia, with the backdrop of 55% of patients already having grade 1 or 2 anemia before they receive treatment. Interestingly, only 4% of patients discontinued talazoparib [because of] anemia. For [most] patients who developed anemia—which happened within 3 to 4 months of starting talazoparib—if they reduced the dose in a timely fashion, 96% did not discontinue talazoparib because of anemia.

The biggest message here is: with talazoparib hematologic toxicities are common. They occur within the first 3 to 4 months. And we if we recognize them in time and decrease the dose of talazoparib for those 42% patients who are going to be developing grade 3/4 anemia, [most] patients will be able to continue to talazoparib without discontinuation.

The other AEs, such as grade 3/4 nausea and fatigue, were quite uncommon….The GI AEs are less common compared with other PARP inhibitors.

If you look at myelodysplastic syndrome or leukemia, we have not seen any incidence of those AEs in the PARP inhibitor. Even pulmonary embolism was reported in only 2% of patients compared with 1% in the control arm. Keep in mind that patients who were on talazoparib plus enzalutamide were on treatment for a much longer duration—almost twice as much.

[In summary], the AEs of the combination of enzalutamide plus talazoparib are mostly hematologic, which occurred early [in the treatment of] disease, and [patients] respond very well to symptomatic management. In those who develop grade 3 or 4 hematologic toxicities, if you decrease the dose in a timely fashion, more than 90% of patients are able to continue with the combination treatment without discontinuation.

How do you see talazoparib plus enzalutamide fitting into the current treatment paradigm of mCRPC?

Consistently we have seen real-world data showing that [most] patients, even in the early part of 2023, have not progressed on a novel hormonal therapy when they developed mCRPC. In fact, more than two-thirds of patients did not develop mCRPC in 2023 after disease progression on a novel hormonal therapy. The reason being many of these patients are developing mCRPC from the biochemically recurrent setting where they receive androgen deprivation therapy after prior surgery or radiation.

Many patients, even those with metastatic hormone-sensitive prostate cancer, do not receive treatment with novel hormonal therapies. So, the patient population, which developed mCRPC and who have not had disease progression on novel hormonal therapy and who harbor HRR mutations is still a large patient population. To have the new combination of enzalutamide plus talazoparib showing clear superiority to enzalutamide, which is one of the most used drugs in this setting, is going to be paradigm changing for many patients. That’s the biggest message coming out of this trial.

References

1. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer. News release. FDA. June 20, 2023. Accessed July 7, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-hrr-gene-mutated-metastatic-castration-resistant-prostate
2. Talzenna. Prescribing information. Pfizer; 2023. Accessed July 7, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/211651s010lbl.pdf
3. Fizazi K, Azad A, Matsubara N, et al. TALAPRO-2: phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations. J Clin Oncol. 2023;41(suppl 16):5004. doi:10.1200/JCO.2023.41.16_suppl.5004