DNA-dependent protein kinase inhibition as a radiosensitizer in rectal cancer: toxicity must be evaluated in the context of organ preservation

We thank Drs. Kagawa, Watanabe, and Ando for their thoughtful editorial commentary on our phase Ib trial of the DNA-dependent protein kinase (DNA-PK) inhibitor peposertib combined with neoadjuvant chemoradiation in the treatment of locally advanced rectal cancer (LARC) (1,2). Their article appropriately situates peposertib within the broader landscape of emerging therapeutic strategies, including DNA damage response (DDR) inhibition, radiosensitization, immune checkpoint blockade, and multi-omics-driven patient selection. We write to extend that discussion by emphasizing a critical consideration for the clinical development of radiosensitizers in rectal cancer: the therapeutic index of these agents must be assessed in the specific population they are intended to benefit, patients pursuing organ preservation (OP).

As Kagawa et al. note, improving complete response rates through novel radiosensitization strategies remains an important unmet need, particularly because higher clinical complete response (cCR) rates may extend eligibility for nonoperative management (NOM) (1). We share this goal. However, treatment response alone is not sufficient. For patients managed with a watch-and-wait approach (WW), the rectum remains in situ; therefore, late rectal injury can determine whether an apparent organ-preservation benefit is durable, functional, and meaningful to patients.

In a recently published post hoc analysis of the complete subset of patients treated at Memorial Sloan Kettering Cancer Center on the parent phase Ib trial, we evaluated peposertib-enhanced chemoradiation specifically in the context of OP (3). The regimen produced a cCR in 3 of 6 patients and 3-year OP in 3 of 5 evaluable patients. However, late grade 3 or higher toxicity occurred in 3 of the 6 patients and was exclusively confined to the 3 patients who achieved cCR and entered WW. These complications were all rectum-specific and included severe chronic proctitis requiring blood transfusions and hyperbaric oxygen therapy, bowel fistulization and obstruction in the setting of grade 4 proctitis, and mucosal sloughing or necrosis on endoscopy. One patient who achieved a cCR and entered WW surveillance ultimately required palliative abdominoperineal resection for treatment-related morbidity despite having no evidence of local or distant recurrence and having a pathologic complete response on surgical pathology. No late grade 3 or higher toxicity was observed among the 3 non-cCR patients, although these findings should be interpreted cautiously given the small sample size, heterogeneous subsequent management, and post hoc design.

These observations have several implications for future trials. First, late toxicity to the retained rectum cannot be meaningfully assessed when patients proceed to total mesorectal excision. Trials composed primarily of patients planned for surgery may therefore underestimate the OP-specific morbidity of radiosensitizing agents. Second, treatment-related endoscopic findings, including mucosal ulceration, sloughing, necrosis, and fibrosis, can closely resemble local regrowth, complicating the surveillance that is fundamental to WW. For a radiosensitizer intended to facilitate NOM, surveillance ambiguity is not a minor inconvenience; it can affect clinical decision-making, patient anxiety, the need for increased biopsies or procedures, and the ability to sustain OP.

We therefore echo Kagawa et al.’s enthusiasm for continued investigation of DDR inhibitors, including DNA-PK inhibitors, while emphasizing that biomarker development in the era of OP should address both tumor response and normal-tissue susceptibility. Preclinical studies utilizing an ex vivo rectal cancer tumoroid model have already demonstrated the ability to quantitatively assess radiosensitizer effects in both tumor-derived and matched normal tissues, providing a framework for such biomarker development (4). These findings establish a patient-specific platform with the potential to predict both response and toxicity.

We also agree that multi-omic efforts from collaborative trials such as JANUS, ACO/ARO/AIO-18.1, and ENSEMBLE will be essential for identifying patients most likely to benefit from NOM (1,5). As novel radiosensitizers advance to clinical trials, protocols should prospectively define safety endpoints within the OP population specifically, incorporate long-term bowel function and quality-of-life measures, and report efficacy and safety separately according to definitive management strategy (e.g., NOM versus surgical resection). Particularly relevant endpoints include late grade 3 or higher rectal toxicity among WW patients, durability of OP, salvage surgery rates and indications, and interpretability of endoscopic and radiographic surveillance.

As rectal cancer treatment continues to evolve toward NOM, novel therapeutic strategies should not be evaluated solely through the lens of tumor response. The goal of OP is not merely to avoid surgery: it is to preserve a functional rectum and maintain quality of life. A cCR accompanied by severe proctitis or loss of rectal function is not a successful OP outcome. Future studies evaluating emerging radiosensitizers, intensified chemotherapy regimens, and novel immune modulators should therefore evaluate tumor response and late effects on normal tissue specifically in patients who achieve OP.

Acknowledgments

The authors acknowledge the assistance of Claude and ChatGPT in generating initial editorial suggestions and thank Jennifer Huber, PhD for her editorial support.

Footnote

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

Funding: This work was supported in part by National Institutes of Health/National Cancer Institute (NIH/NCI) Memorial Sloan Kettering Cancer Center (MSK) Support Grant (No. P30 CA008748).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0480/coif). W.Z. was supported by NIH/NCI training grant (No. T32CA009501-34). P.B.R. was supported by an anonymous UK donor and NIH/NCI grants (Nos. K08CA255574 and 1R37CA304010-01). P.B.R. received research funding and serves as a consultant for EMD Serono, received research funding from XRAD Therapeutics, and serves as a consultant for Faeth Therapeutics, Natera, Urogen, and Incyte. P.B.R. is a volunteer on the advisory board for the HPV Cancers Alliance and Anal Cancer Foundation non-profit organizations. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are 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/.

References

1. Kagawa Y, Watanabe J, Ando K. DNA-dependent protein kinase inhibitor as a sensitizer of radiotherapy in locally advanced rectal cancer. J Gastrointest Oncol 2024;15:2358-62. [Crossref] [PubMed]
2. Romesser PB, Capdevila J, Garcia-Carbonero R, et al. A Phase Ib Study of the DNA-PK Inhibitor Peposertib Combined with Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer. Clin Cancer Res 2024;30:695-702. [Crossref] [PubMed]
3. Zambare W, Ravella R, Li C, et al. Late toxicity after peposertib-enhanced chemoradiation in rectal cancer patients managed with organ preservation. Clin Transl Radiat Oncol 2026;58:101109. [Crossref] [PubMed]
4. ZambareWHuangHWuCLeveraging a Patient-Derived Tumoroid Platform for Precision Radiotherapy: Uncovering DNA Damage Repair Inhibitor-Mediated Radiosensitization and Therapeutic Resistance in Rectal Cancer.medRxiv 2025:2025.01.15.25320629. [Preprint]. Available online: https://www.medrxiv.org/content/10.1101/2025.01.15.25320629v1 10.1101/2025.01.15.25320629
5. Kagawa Y, Smith JJ, Fokas E, et al. Future direction of total neoadjuvant therapy for locally advanced rectal cancer. Nat Rev Gastroenterol Hepatol 2024;21:444-55. [Crossref] [PubMed]