Source – FDA
On June 20, 2023, the combination of talazoparib (Talzenna) and enzalutamide (Xtandi) has been approved by the FDA for treatment in patients with metastatic HRR-mutated castration-resistant prostate cancer (mCRPC).
The Phase III TALAPRO-2 study (NCT03395197), in which the addition of talazoparib to enzalutamide significantly increased radiographic progression-free survival (rPFS) over enzalutamide alone in this cohort, served as the basis for the regulatory decision. In the investigational arm, the median rPFS was not yet attained (95% CI, 21.9-not evaluable), whereas with enzalutamide alone, it was 13.8 months (95% CI, 11.0-16.7) (HR, 0.45; 95% CI, 0.33-0.61; P .0001).
The hazard ratio for rPFS in patients with tumors harboring BRCA mutations (n = 155) was 0.20 (95% CI, 0.11-0.36) in favor of the talazoparib combination, according to data from an exploratory investigation of BRCA mutational status. In the investigative and control arms, the median rPFS was not evaluable as opposed to 11.0 months (95% CI, 8.3-11.1) in each case. The median rPFS was 24.7 months (95% CI, 16.4-NE) and 16.7 months (95% CI, 13.8-27.7) in individuals lacking these mutations, respectively (HR, 0.72; 95% CI, 0.49-1.07).
By using solid tumor tissue or next-generation sequencing tests, researchers prospectively evaluated the mutation status of the samples. At least one of the 12 genes implicated in the HRR pathway—ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C—had to be mutated in order for a participant to be eligible.
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Talazoparib, at a daily dose of 0.5 mg (n = 200), or a placebo (n = 199), together with enzalutamide, at a daily dose of 160 mg, were given to study participants by randomization. Treatment was continued until the disease got worse or the side effects became too bad. Notably, all patients had a gonadotropin-releasing hormone analogue or had bilateral orchiectomy surgery beforehand.
Prior docetaxel or CYP17 inhibitor therapy (yes/no) was a significant stratification factor. Participants in the research ranged in age from 41 to 90 and had a median age of 70. They were all men. ECOG performance status 0 (62%) and White (68%) predominance were both present at baseline. In addition, 15% of patients had visceral disease and 39% of patients had bone-only illness. 29% of patients had previously had docetaxel in the metastatic castration-sensitive scenario, and 9% had a CYP17 inhibitor. BRCA2 (34%) was the HRR gene with the highest frequency of mutations in this cohort, followed by ATM (22%), CDK12 (19%), CHEK2 (18%), and BRCA1 (6%).
The primary efficacy measures of the study were assessed through Blinded Independent Central Review (BICR) using RECIST v1.1 criteria and Prostate Cancer Working Group criteria. These measures included the assessment of radiographic progression-free survival (rPFS), and overall survival (OS) was also evaluated as an important efficacy outcome.
The findings related to rPFS were consistent among patients who had prior exposure to a CYP17 inhibitor or docetaxel and those who did not. However, the data on OS were not yet mature at the time of the rPFS analysis, with 24% of patients having died by that point.
In terms of treatment duration, 86% of patients who received talazoparib were exposed to the drug for at least 6 months, 60% for at least 12 months, and 18% for over 24 months.
Regarding safety, several common toxicities were observed in at least 10% of patients who received the talazoparib doublet. These included laboratory abnormalities such as decreased hemoglobin, neutrophils, and lymphocytes, as well as fatigue, decreased platelets, calcium, and sodium, nausea, decreased appetite, decreased phosphate, fractures, decreased magnesium, dizziness, increased bilirubin, decreased potassium, and dysgeusia.
Serious toxicities were reported in 30% of patients receiving the doublet, including anemia (9%) and fractures (3%). Fatal adverse reactions were experienced by 1.5% of patients, with causes including pneumonia, COVID-19 infection, and sepsis.
A total of 10% of patients discontinued talazoparib due to toxicities. The most common reasons for discontinuation included anemia (4%), fatigue (1%), bone fracture (1%), ischemic heart disease (1%), and spinal cord compression (1%).
Additionally, 58% of patients required dose interruptions due to adverse effects, and 52% needed dose reductions.
