The 2025 ASCO Genitourinary Cancers Symposium (ASCO GU) was held from February 13 to 15 in San Francisco, California, bringing together leading experts and researchers in the field of genitourinary oncology. Among the key highlights was the final overall survival (OS) data from the TALAPRO-2 trial, presented by Dr. Neeraj Agarwal from the Huntsman Cancer Institute (HCI), University of Utah. The study drew widespread attention as it not only addressed a critical gap in first-line treatment for metastatic castration-resistant prostate cancer (mCRPC) using a PARP inhibitor in combination with next-generation hormonal therapy (NHT) but also reinforced the growing role of precision medicine in prostate cancer treatment.To explore the latest findings, clinical significance, and potential impact on first-line mCRPC treatment strategies, Urology Frontier spoke with Dr. Neeraj Agarwal for an in-depth discussion.
Urology Frontier: As the final stage of prostate cancer, what do you see as the key challenges in mCRPC treatment?
Dr. Neeraj Agarwal: Metastatic castration-resistant prostate cancer (mCRPC) represents the terminal stage of prostate cancer, characterized by high heterogeneity and poor prognosis. The median overall survival (OS) for patients receiving first-line next-generation hormonal therapy (NHT) is typically less than three years, and nearly 50% of patients do not make it to second- or later-line therapies, which is deeply concerning. I believe that the most pressing challenge is to extend survival and ensure that patients can access multiple lines of therapy, ultimately improving long-term outcomes.
However, even when we achieve positive results in clinical trials and publish in leading medical journals, if these findings are not effectively translated into clinical practice, their impact remains limited. We have already encountered this issue in metastatic hormone-sensitive prostate cancer (mHSPC), and it is an even greater concern in mCRPC. Delays in initiating effective treatment can lead to rapid disease progression within just two to three months, potentially resulting in patient death in a very short time. This urgency underscores the importance of combination therapy in prostate cancer, as well as in other malignancies. By administering two or more treatments simultaneously, we can significantly delay disease progression and improve patient outcomes, with the extent of benefit depending on the specific treatment regimen.
Urology Frontier: Several PARP inhibitors have been approved for mCRPC treatment. What do you think this means for advancing precision medicine in this field?
Dr. Neeraj Agarwal: PARP inhibitors have played a pivotal role in advancing precision medicine for mCRPC. Multiple clinical trials have confirmed a synergistic effect between PARP inhibitors and androgen receptor (AR) inhibitors, demonstrating significant survival benefits and delayed disease progression in both mHSPC and mCRPC.
At ASCO GU 2025, I presented the final OS data from the TALAPRO-2 trial, a global, multicenter, randomized, double-blind, placebo-controlled phase III study. This trial evaluated the efficacy of talazoparib, a PARP inhibitor, in combination with enzalutamide, compared to enzalutamide plus placebo as first-line therapy for mCRPC. The results were remarkable: the median OS for the entire study population reached 45.8 months, marking a significant breakthrough in first-line mCRPC treatment.
An important aspect of the study was its focus on homologous recombination repair mutations (HRRm) and the specific benefits in this subgroup. The findings provide strong evidence supporting precision medicine in prostate cancer treatment. In HRRm-positive patients, the median OS was extended by approximately 14 months, from 31.1 months in the placebo-enzalutamide arm to 45.1 months in the talazoparib-enzalutamide arm (HR=0.622, P=0.0005), reducing the risk of death by nearly 40%. Similarly, the median radiographic progression-free survival (rPFS) was significantly improved, reaching 30.7 months in the combination group versus 12.3 months in the control group (HR=0.468, P<0.0001).
Even in patients with non-BRCA HRR mutations, there was a positive trend, with median OS extending to 42.4 months in the combination group versus 32.6 months in the control group (HR=0.727, P=0.0665). In BRCA-mutant mCRPC patients, the OS benefit was even more striking: median OS was not reached (NR) in the talazoparib-enzalutamide arm compared to 28.5 months in the control arm (HR=0.497, P=0.0017). Across all HRRm-positive subgroups, talazoparib-enzalutamide significantly prolonged survival.
This study, which has spanned four years, has not identified any new safety concerns. Although adverse effects were observed, they were manageable and consistent with known safety profiles.
With a median OS of 45.1 months—nearly four years—compared to the previously accepted first-line OS benchmark of less than three years, this represents a significant advancement in the treatment of mCRPC. Given the success of multiple PARP inhibitors in mCRPC, PARP inhibitor-NHT combinations are now established as a first-line standard of care in authoritative guidelines. Talazoparib has also become the first and only PARP inhibitor approved in China for HRR-mutated mCRPC, providing an innovative and effective option for these patients. Considering the substantial survival benefit and the fact that patient quality of life was not compromised, this combination therapy deserves careful discussion in clinical practice. The key challenge remains ensuring that patients receive these therapies promptly to maximize survival benefits.
Urology Frontier: Are there any biomarkers that can predict the efficacy and prognosis of talazoparib-enzalutamide treatment in mCRPC?
Dr. Neeraj Agarwal: Genetic sequencing and next-generation sequencing (NGS) are essential tools for advancing precision medicine in prostate cancer. There is ongoing debate about whether NGS testing should be performed for all patients, and the answer is clear: every patient with metastatic prostate cancer should undergo NGS testing. This recommendation is supported by ASCO guidelines and nearly every major medical association.
NGS plays a critical role in multiple ways. For patients with BRCA1/2 or HRR gene mutations, NGS allows us to identify these mutations, enabling the use of targeted therapies such as PARP inhibitors. The TALAPRO-2 trial strongly supports this approach, demonstrating significant survival benefits with combination therapy in HRRm patients. Beyond individual treatment decisions, genetic testing is also crucial for family members, as many mutations can indicate hereditary cancer risk. Identifying these mutations enables early intervention and preventive strategies for at-risk relatives.
About Dr. Neeraj Agarwal
Dr. Neeraj Agarwal is a Professor of Medicine at the Huntsman Cancer Institute (HCI), University of Utah. He is a member of the NCCN, ESMO, and ASCO genitourinary oncology guideline committees, serves as Head of Early Therapeutics for SWOG GU, and is a member of the ASCO Genitourinary Oncology Advisory Group. He is also the Editor-in-Chief of ASCO Daily News.
The TALAPRO-2 trial marks a major milestone in mCRPC treatment, reinforcing the role of PARP inhibitors in first-line therapy and paving the way for a new standard of care in precision oncology.
