PARP inhibitors plus ARSI in first-line mCRPC—a treatment for all patients?

The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has evolved substantially over the past decade with the integration of androgen receptor signaling inhibitors (ARSI), taxane chemotherapy, radioligand therapy, and molecularly targeted agents. Among the most relevant recent developments is the combination of poly(ADP-ribose) polymerase inhibitors (PARPi) with ARSI in the first-line mCRPC setting. This strategy is supported by a strong biological rationale, as androgen receptor signaling interacts with DNA damage repair pathways, and AR blockade may induce a “BRCAness” phenotype that enhances tumor sensitivity to PARP inhibition [1, 2]. Randomized phase III trials, including PROpel, MAGNITUDE, and TALAPRO‑2, have consistently demonstrated significant improvements in radiographic progression-free survival (rPFS) with PARPi–ARSI combinations [3–5]. However, overall survival (OS) outcomes remain heterogeneous and appear to depend largely on homologous recombination repair (HRR) mutation status. Patients with BRCA 1/2 alterations derive the most pronounced benefit, whereas evidence supporting use in unselected populations remains inconsistent, with no uniform demonstration of OS improvement [6, 7]. In addition, combination therapy is associated with increased hematologic toxicity, raising concerns regarding overtreatment in biologically less responsive subgroups. Taken together, current data support a biomarker-driven approach, positioning PARPi plus ARSI as a standard option for HRR-mutated mCRPC, while a generalized treatment strategy for all patients remains uncertain.