Co-inhibition of poly(ADP-ribose) polymerase (PARP) and androgen receptor (AR) signalling could lead to effective antitumour activity in patients with metastatic castration-resistant prostate cancer (mCRPC), irrespective of alterations in genes involved in homologous recombination repair (HRR). Recently published in The Lancet, the primary analysis of the TALAPRO-2 trial revealed a significant improvement in radiographic progression-free survival of mCRPC patients receiving the combination of the PARP inhibitor talazoparib plus the AR signalling inhibitor enzalutamide, compared to enzalutamide alone.
Prostate cancer is the second most common cancer diagnosed in men and ranks as the fifth leading cause of cancer-related death worldwide. Approximately a quarter of men with advanced/metastatic prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC), harbour somatic and/or germline DNA damage response (DDR) alterations in a number of genes. Poly (ADP-ribose) polymerase (PARP) inhibitors have shown efficacy in patients with mCRPC harbouring this type of DDR alterations. Additionally, multiple preclinical studies and clinical evidence suggest the potential for PARP inhibitors to target tumours regardless of DDR alteration status when combined with an androgen receptor (AR) signalling inhibitor. Based on these data, the TALAPRO-2 trial evaluated the combination of the PARP inhibitor talazoparib with the AR signalling inhibitor enzalutamide as first-line treatment for patients with mCRPC, with or without DDR alterations.1,2
The phase 3 TALAPRO-2 trial was conducted across 223 sites from 26 countries in North America, Europe, Israel, South America, South Africa, and the Asia-Pacific region. Eligible patients were men (age ≥18 years or ≥20 years in Japan) receiving ongoing androgen deprivation therapy. In total, 805 patients were randomly assigned (1:1) to talazoparib or placebo, both combined with enzalutamide (n=402 and 403, respectively). The primary endpoint was radiographic progression-free survival (rPFS).2
At the planned primary analysis, the median rPFS was not reached for talazoparib plus enzalutamide, while it was reported at 21.9 months for placebo plus enzalutamide (HR[95%CI]: 0.63[0.51-0.78; p<0.0001). In the talazoparib group, the most common treatment-emergent adverse events were anaemia, neutropenia, and fatigue. The most common grade 3/4 event was anaemia (46% of patients), which generally improved after a dose reduction. Overall, only 8% of patients discontinued talazoparib due to anaemia. There were no treatment-related deaths in the talazoparib group as compared to two cases (<1%) in the placebo group.1,2
In conclusion, the combination of talazoparib and enzalutamide demonstrated a clinically meaningful and statistically significant improvement in rPFS compared to standard enzalutamide as a first-line treatment for mCRPC patients. Further analysis of final overall survival data and additional long-term safety follow-up will provide more insights into the clinical benefits of this treatment combination for patients with and without tumour HRR gene alterations.2
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