Efficacy at a cost?—quality of life implications of PARP inhibition in the homologus recombination repair (HRR) cohort of TALAPRO-2

Patients with metastatic castration-resistant prostate cancer (mCRPC) with alterations in genes involved in the homologus recombination repair (HRR) pathway, particularly in BRCA1/2, have poor clinical outcomes when conventionally treated (1). To date, poly (ADP-ribose) polymerase inhibitors (PARPi) alone or in combination are the only agents that have demonstrated to improve the prognosis of these patients (2). However, the HRR subgroup exhibits heterogeneity in both, prognosis and response to PARPi. The phase III trial TALAPRO-2 demonstrated that the addition of talazoparib to enzalutamide prolongs the overall survival of mCRPC patients with HRR defects (1,2), with the greatest improvement observed in patients with BRCA2 and CDK12 alterations and less clear benefit in those patients harboring other HRR alterations (3). Therefore, the potential efficacy of a PARPi must be weighed against its safety profile for the different subgroups of patients.

In TALAPRO-2, the addition of talazoparib to enzalutamide was associated with an increased burden of adverse events (AEs), particularly hematologic toxicity. Grade ≥3 anemia occurred approximately four times more frequently in the combination arm than with enzalutamide alone (4). Other side effects associated with PARPi such as fatigue, neutropenia, and thrombocytopenia, were also more frequent in the experimental arm. Importantly, no correlation between toxicity and efficacy has been established and similar safety profiles have been reported in patients with and without HRR defects (5). These adverse effects are clinically relevant in a population already experiencing multifactorial symptomatology, particularly since contemporary evidence underscores that cancer-related anemia meaningfully worsens fatigue and health-related quality of life (HRQoL) and is associated with downstream increases in healthcare resource utilization (6-8). Therefore, given the observed differences in efficacy by mutational status, it is important to assess the impact that PARPi has on our patients’ quality of life.

TALAPRO-2 incorporated a rigorous assessment of HRQoL through a suite of validated patient-reported outcome measures (PROMs), including the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-PR25, Brief Pain Inventory-Short Form (BPI-SF), and EuroQoL 5-Dimension 5-Level questionnaire (EQ-5D-5L). PROMs capture the subjective dimension of treatment by directly reflecting patients’ perceptions of their functional status, symptom burden, and well-being—factors often underestimated in investigator-assessed endpoints. Their inclusion represents an essential complement to traditional efficacy and safety data, contextualizing therapeutic benefit in terms of lived experience.

A report by Fay et al. provides a comprehensive account of PROM outcomes in TALAPRO-2 in the subgroup of patients with HRR defects (9). In these patients, the addition of talazoparib to enzalutamide conferred longer time to definitive deterioration in global health status (GHS) and quality of life (QoL) physical, emotional, and cognitive functioning, pain, nausea and vomiting, appetite loss, and constipation per EORTC QLQ-C30, as well as in urinary symptoms per EORTC QLQ-PR25, was delayed with talazoparib plus enzalutamide versus placebo plus enzalutamide. These results suggest that a more durable disease control with the addition of talazoparib led to a delay in deterioration of symptoms and overall quality of life. As data from different subgroups have not been reported, it is unknown if a greater benefit in QoL is observed in those patients harboring HRR defects most likely to be sensitized to talazoparib. However, the absence of detectable deterioration in fatigue or anemia-related domains—despite a 38% higher incidence of grade ≥3 anemia in the combination arm—suggests that the PROM instruments used may lack sensitivity to fully capture the QoL consequences of transfusion dependence and treatment-related anemia. The EORTC-PR25 used in this study is recommended to measure the core domains of urinary, bowel, sexual function, hormonal symptoms and health-related quality of life in prostate cancer patients. This tool was developed over 25 years ago and does not fully reflect new treatment modalities and their associated toxicities, particularly in advanced prostate cancer setting. EORTC has launched an initiative to update the tool, enabling it to capture all the important factors affecting the QoL of men with advanced prostate cancer (10). Similar to TALAPRO-2, the phase III trial MAGNTITUDE also investigated the benefit of adding a PARPi (niraparib) to an androgen receptor pathway inhibitor (abiraterone) as first line of treatment for patients with mCRPC and HRR alterations. The study demonstrated an rPFS benefit from the addition of niraparib in patients with BRCA and HRR alterations that did not translate into an overall survival (OS) advantage (11). The combination has been approved by Food and Drug Administration (FDA), European Medicines Agency (EMA) and other regulatory agencies for the treatment of patients with BRCA1/2 alterations. Grade ≥3 anemia and any grade fatigue were observed in 28% and 26% of patients treated with niraparib, respectively. FACT-P, BPI-SF and EQ-5D-5L were used to evaluate disease symptoms, HRQoL and treatment side-effect bother (12). No clinically significant differences in HRQoL were observed with the addition of niraparib to abiraterone. Although it is reassuring that a new therapy does not have a negative impact on QoL, it is also possible that FACT-P also fails to capture new symptom domains or new treatment specific concerns.

Importantly, several methodological caveats warrant careful interpretation of the PROM outcomes reported by Fay et al. First, although missing data were managed in accordance with prespecified scoring manuals and deaths were treated as censoring events, the risk of informative missingness cannot be excluded: patients experiencing early toxicity or rapid disease progression may have been underrepresented in later assessments, biasing time-to-deterioration analyses. Second, given the median follow-up period of approximately 22 months, estimates of median time-to-deterioration that extend beyond this timeframe are inherently uncertain. Finally, no correction for multiplicity was applied to the PROM analyses, as these endpoints were excluded from the hierarchical testing framework. Consequently, some nominally significant results may reflect statistical noise rather than genuine treatment effects.

In conclusion, patient reported outcomes from TALAPRO-2 and other phase III trials indicate that adding a PARPi to an ARPi to treat mCRPC patients with HRR defects does not affect QoL and may even delay definitive deterioration. This is a reassuring outcome, particularly given the anticipated toxicity burden of PARPi-based regimens. However, these results should be interpreted with caution as it is unclear whether the tools currently available are able to capture the impact of the side effects associated with therapies not available when these tools were developed.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-645/prf

Funding: This work was support in part by a grant from Asocicación Española Contra el Cáncer (CLSEN223433) to EC.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-645/coif). J.E.V. receives grants or contracts from Astellas Pharma (research grant paid to collaborative group), payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas, Johnson & Johnson, MSD, Pfizer, BMS, and Recordati Rare Diseases and support for attending meetings and/or travel from Johnsson & Johnsson. E.C. receives grants or contracts from Johnson & Johnson, and Pfizer; consulting fees from Daiichi-Sankyo, Full-Life, and VIR; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas, AstraZeneca, Bayer, Johnson & Johnson, MSD, Pfizer, Medscape, PeerView, and Urotoday; support for attending meetings and/or travel from AstraZeneca, Pfizer, and Johnson & Johnson; participation on a Data Safety Monitoring Board or Advisory Board at Bayer, Johnson & Johnson, LinkinVax, MSD, Novartis, and Pfizer; and leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from ESMO: faculty, communication committee, precision oncology working group, EAU: Scientific Congress Office, ASEICA: Steering Committee. The authors have no other conflicts of interest to declare.

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