Patient-reported outcomes in TALAPRO-2 trial: addressing data integrity and comparative clinical benefit in mCRPC

We appreciate the opportunity to respond to the insightful editorial by Francini E recently published in Chinese Clinical Oncology (1), regarding our publication of patient-reported outcomes (PROs) from the TALAPRO-2 trial in Lancet Oncology (2). While the authors correctly highlight the complexities of interpreting PRO data in the context of combination treatment and potential unblinding, we believe certain methodological strengths of our study warrant further emphasis to ensure a balanced perspective for the clinical community.

Robustness of time to definitive deterioration (TDE) against potential unblinding bias

The editorial raises the possibility that the high rate of hematologic toxicities (notably Grade 3–4 anemia in 46% of the talazoparib group) could have inadvertently unblinded patients, thereby introducing an “expectation bias”. However, we argue that our choice of TDE as a primary PRO endpoint significantly mitigates this risk (3,4).

Unlike a “snapshot” analysis of mean scores at a single time point—which could indeed be influenced by temporary physical and psychological expectations—TDE measures a sustained, clinically meaningful decline in health status. In TALAPRO-2 trial, the combination arm demonstrated a statistically and clinically significant delay in TDE [hazard ratio (HR) 0.78; P=0.0003]. If unblinding bias were the primary driver of reported quality of life (QOL), one would expect the subjective burden of frequent blood transfusions and clinic visits required for anemia management to accelerate, rather than delay, the time to definitive deterioration.

Comparative superiority: lessons from PROpel and MAGNITUDE

To place our results in a broader clinical practice, it is essential to compare the TALAPRO-2 PRO data with results from other trials of poly ADP-ribose polymerase (PARP) inhibitor and androgen receptor pathway inhibitor (ARPI) combinations.

In the PROpel trial (olaparib plus abiraterone), despite achieving a significant rPFS benefit, there was no statistically significant difference between the treatment arms regarding the time to deterioration in Global Health Status (GHS)/QOL (5). Similarly, in the MAGNITUDE trial (niraparib plus abiraterone), the PRO benefits were predominantly confined to the homologous recombination repair (HRR)-mutated subgroup (6).

TALAPRO-2 is unique in demonstrating a significant QOL benefit in the all-comers population (unselected for HRR status). This suggests that the high PARP-trapping potency of talazoparib, when combined with enzalutamide, provides a magnitude of disease control that effectively “outpace” the negative impact of its toxicity profile, including anemia, across a wider range of patients, which might boil down to better PRO outcomes.

Sensitivity of fatigue scales and symptom compensation

Francini E noted the discrepancy between clinician-graded fatigue and patient-reported scores. We believe this “discrepancy” actually reflects the patient's lived reality: a trade-off between treatment side effects and cancer-symptom relief.

The EORTC QLQ-C30 is highly sensitive to functional changes. In our trial, the substantial delay in time to severe pain progression (HR 0.56) in the combination arm appears to act as a powerful compensatory factor. For a patient with metastatic castration-resistant prostate cancer (mCRPC), the prevention of bone pain and the delay of skeletal-related events (SREs) might be often perceived as more vital to their QOL than the manageable fatigue associated with PARP inhibition.

Individual variability and dose management

We totally agree with the editorial’s caution that group averages can mask individual experiences. However, our use of “Responder Analyses” which tracks the proportion of individuals achieving at least 10-point or more change (the established threshold for clinical relevance) confirms that the benefit was not limited to a few outliers but was consistent across the cohort (7). Furthermore, the protocol-mandated dose reductions for talazoparib allowed patients to remain on therapy while symptomatic toxicities were mitigated, effectively preserving the “window of wellness”.

Conclusions

Our PRO results from TALAPRO-2 trial provides high-level evidence that the intensified first-line treatment of mCRPC with talazoparib and enzalutamide does not come at the cost of the patient’s quality of life. By significantly delaying the deterioration of health status and pain, this regimen offers a clinical benefit regardless of HRR status that is statistically superior to that seen in other contemporary PARP-ARPI trials. While vigilant monitoring of hematologic toxicity, especially anemia is mandatory, our PRO data should provide clinicians with the confidence that they are extending life while preserving its quality.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0007/coif). N.M. receives Research funding (institution) from Bayer Yakuhin, Ltd., MSD K.K. Chugai, Pharmaceutical Co., Ltd., Eisai Co., Ltd., Astellas Pharma Inc., Janssen Pharmaceutical K.K., Pfizer Japan Inc., Amgen K.K., Takeda Pharmaceutical Co., Ltd., Novartis Pharma K.K., Eli Lilly Japan K.K., Seagen Inc., TAIHO Phamaceutical Co., Ltd., Novartis LLC., Telix, Inc. and BicycleTx Limited; Consulting fees from Janssen Pharmaceutical K.K., Pfizer Inc., Novartis Pharma K.K., Takeda Pharmaceutical Co., Ltd., CMIC Co., Ltd. and Amgen K.K.; Honoraria (personal) from Sanofi K.K.; speakers bureaus from Novartis Pharma K.K. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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