ASCO 2023

Metastatic prostate cancer with DNA repair gene mutations: a highly promising combination of hormone therapy and PARP inhibitor

The international TALAPRO-2 study could become the first-line standard of care for patients with hormone-resistant metastatic prostate cancer and alterations in a DNA repair gene. The results of this randomized, double-blind, phase 3 study show that combining talazoparib, a novel PARP inhibitor, with enzalutamide, a second-generation hormone therapy, versus placebo, reduces the risk of death or tumor progression by 80 %. TALAPRO-2 was presented in an oral session at ASCO by Pr. Karim Fizazi, Head of Gustave Roussy's Genitourinary Committee.

Abstract n° 5004 orally presented by Pr. Karim Fizazi on Sunday, June 4

With an average of 50 000 new cases per year in France, 10 % of which are immediately metastatic, prostate cancer is the most common cancer in men. Nearly a quarter of patients have altered DNA repair genes (most often homologous recombination repair, or HRR), and within that group, 8 % to 10 % have altered BRCA2 or BRCA1 genes, which have a poorer prognosis and require new therapeutic options. 

Second-generation hormone therapies (abiraterone, enzalutamide) have become the standard of care for hormone-sensitive or castration-resistant metastatic prostate cancers.  

Talazoparib is a novel inhibitor of PARP, an enzyme involved in the repair of cellular DNA damage. This compound is already approved in several countries as monotherapy in advanced breast cancer with BRCA1/2 mutation and HER2 negativity.

TALAPRO-2 is the first international Phase 3 trial to evaluate the efficacy of talazoparib plus enzalutamide as first-line treatment for patients with metastatic prostate cancer.

Major clinical benefits of this combination

In this large-scale comparative multicenter study (one of the largest ever conducted), 399 men with metastatic prostate cancer resistant to conventional hormone therapy and with alterations in a DNA repair gene (BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, CDK12) took part. Pr. Karim Fizazi, study coordinator, presents the results for these patients at the ASCO congress. All patients were randomly assigned to one of two groups : one receiving 0.5 mg talazoparib plus 160 mg enzalutamide once daily, the other receiving the same dose of enzalutamide plus placebo.

The results, after 17 months' follow-up, showed that radiological progression-free survival, the study's primary endpoint, was significantly improved, with a 55 % reduction in the risk of death or tumor progression in favor of the group receiving both drugs. The benefit of the enzalutamide/talazoparib combination was particularly noticeable in the subgroups of patients with BRCA2 and BRCA1 gene alterations, with an 80 % reduced risk of death or tumour progression. « Patients with CDK12 gene alterations, who generally have more aggressive disease, also appear to derive some clinical efficacy from this combination therapy. This is not the case, however, for other genes, » explains Pr Karim Fizazi.

The secondary endpoints of the TALAPRO-2 study - time to biological progression of the tumor, time without the use of chemotherapy and progression-free survival after a 1st tumor progression event - are also very positive. The response rate reached 67% in the group in which patients received the combination therapy. Anemia is the most frequent side effect, with around 40 % grade 3-4. Importantly, survival without deterioration in quality of life was also significantly prolonged for patients receiving the combination of the two drugs.

« In the non-comparative TALAPRO-1 study, talazoparib monotherapy showed durable antitumor activity in heavily pre-treated metastatic prostate cancer patients with DNA repair gene alterations, » explains Pr Karim Fizazi. « TALAPRO-2, along with other recent Phase III comparative trials, clearly establishes that a PARP inhibitor combined with second-generation hormone therapy should now become a therapeutic standard, at least for men with hormone-resistant metastatic prostate cancer and BRCA gene alterations ».

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