Reply to: Xaluritamig: a first step towards a new target, new mechanism for metastatic prostate cancer

We thank Dr. Raychaudhuri and his colleagues for their thorough and thoughtful commentary on the development of xaluritamig (1). We fully agree with their perspective that xaluritamig holds significant promise as a potential first-in-class T-cell engager in the prostate cancer treatment landscape. The initial clinical results are encouraging but naturally raised numerous questions, ranging from its mechanism of action to optimal drug delivery strategies. Fortunately, as xaluritamig continues to advance through multiple early- and late-phase trials, we expect to gain deeper insight into its efficacy and broader applicability for patients living with prostate cancer (2-4).

Dr. Raychaudhuri et al. highlight the resource-intensive nature of the phase I study for patients with metastatic castration-resistant prostate cancer (mCRPC), particularly the requirement for weekly hospitalizations during the initial 4-week step-up dosing period (5). We agree that hospitalization may limit uptake of this therapy in resource-constrained settings worldwide. As noted in the commentary, the incidence of cytokine release syndrome (CRS) was 72%; however, most events were low-grade and occurred with the initial priming dose. The ongoing registrational phase III clinical trials in the United States and Europe evaluating xaluritamig post-taxane in mCRPC have limited mandatory hospitalization to the first priming dose. We are also encouraged by the data emerging from other cohorts exploring fully outpatient dosing in the first-in-human trial. Given that CRS is generally low-grade, predictable, and manageable, we are optimistic that fully outpatient administration may be feasible in the future. Notably, CRS with T-cell engagers in general has been shown to correlate with the overall disease burden. Thus, CRS rates and severity may improve as xaluritamig advances into the earlier disease settings where the disease burden is typically less.

The underlying cause of the musculoskeletal toxicity remains unclear and warrants further study. In our experience, symptoms have emerged and resolved rapidly. The absence of elevated serum creatine kinase suggests that direct muscle fiber injury is not occurring, and is consistent with an absence of high six-transmembrane epithelial antigen of the prostate (STEAP1) expression on muscle fibers. Notably, some studies have reported STEAP1 expression on connective tissue (6), and further investigation may uncover whether this contributes to musculoskeletal toxicity. The current phase III studies use a biweekly dosing schedule (while maintaining favorable pharmacokinetics) instead of weekly dosing, where the majority of data in the first-in-human trial has been generated. In addition, with awareness and understanding of these events to prompt early recognition and treatment, a more prescriptive management plan has been deployed across the program. This plan includes the early use of acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) for pain symptoms, brief courses of steroids when necessary, treatment delays, and dose modifications to effectively manage these symptoms and to preserve patients’ quality of life while also maintaining maximal therapeutic benefit.

In addition, Dr. Raychaudhuri et al. suggest that prior lines of therapy, including cytotoxic chemotherapy and radioligand therapy (RLT), may impair immune function and blunt immune responses. The existing literature supports the notion that both treatment classes can exhaust peripheral and intratumoral immune cells (7,8). Ongoing studies will clarify the optimal placement of xaluritamig within the therapeutic armamentarium relative to chemotherapy and RLTs. Meanwhile, the ongoing phase III post-taxane mCRPC trial includes patients previously treated with RLT, with this subgroup factored into the design by stratifying for this parameter (3). Determining the dosing and timing of RLT in relation to xaluritamig will be crucial for maximizing synergy while minimizing T-cell exhaustion and should be part of future investigations. Such studies will help define the best strategies for treating advanced prostate cancer in the era of both RLT and xaluritamig. Notably, prostate-specific antigen (PSA) responses were observed in the majority of patients in the phase I study, despite these patients having received an average of four prior lines of therapy, with 86% having received at least one prior taxane and 49% having received 2 prior taxanes.

The authors also raise an important point regarding the heterogeneity of the prostate cancer surfaceome, including intra- and inter-patient variability in STEAP1 expression and the impact of prior treatment on antigen expression—factors that pose challenges for targeted therapies such as xaluritamig. Biomarker analyses of archival tissue from the phase I study showed that STEAP1 was broadly expressed in mCRPC, with over 95% of tumor biopsies containing at least 1% STEAP1-positive tumor cells, regardless of the number or types of prior therapies. STEAP1 expression appears to be retained throughout the treatment continuum, including during the development of castration resistance (9). Interestingly, neither STEAP1 immunohistochemistry (IHC) intensity nor the percentage of STEAP1-positive tumor cells correlated with response to xaluritamig (10). These findings suggest that a cytokine-mediated bystander effect may be driving—or at least contributing to—the robust anti-tumor responses observed. In our view, the emerging data with xaluritamig challenge the long-held notion that prostate cancer is an immunologically ‘cold’ tumor resistant to immunotherapy. Future work with xaluritamig and other innovative immuno-oncology agents will help refine our understanding of prostate cancer tumor immunogenicity in this context.

There is a strong biological rationale for combining androgen receptor (AR)- and STEAP1-directed therapies, particularly in earlier, hormone-sensitive prostate cancer. We agree that a more comprehensive understanding of the biology and regulation of STEAP1 expression in relation to androgen signaling is needed. Both clinical and preclinical data suggest that STEAP1 regulation involves a complex interplay of androgen-dependent and -independent mechanisms, underscoring the intricacies of AR signaling and STEAP1 modulation in prostate cancer (11). The growing interest in STEAP1 as a targetable tumor antigen has spurred research into how androgen signaling influences its expression, and strategies to modulate this target may soon be realized.

In conclusion, we fully share the enthusiasm expressed by Dr. Raychaudhuri and colleagues and remain optimistic about the continued development of xaluritamig—both as a significant advancement in prostate cancer immuno-oncology and as proof of principle for STEAP1-targeted therapy.

Acknowledgments

None.

Footnote

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

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-93/coif). K.K.Z. reports receiving grants from Amgen, IDEAYA, Johnson & Johnson/Janssen, and 858 Therapeutics; consulting fees from Pfizer; and payments or honoraria from OncLive and Association of Community Cancer Centers (ACCC). W.K.K. reports receiving grants from Amgen, Johnson & Johnson/Janssen, Bayer, Exelixis, Roche, Regeneron, SCRI, Endocyte, and Seagen; consulting fees from Fusion; patents planned/issued/pending with Merck; participation on the Data Safety Monitoring Board or Advisory Board for Janssen and Amgen; and leadership or fiduciary role in NCI GU Steering Committee. The authors have no other 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/.

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