Rethinking evidence standards for men with metastatic prostate cancer in the post-androgen receptor pathway inhibitor setting: new insights from CONTACT-02

Metastatic castration-resistant prostate cancer (mCRPC) continues to carry a poor prognosis despite significant advances in therapeutic agents. For men with mCRPC that has progressed on an androgen receptor pathway inhibitor (ARPI), treatment sequencing beyond initial ARPI remains an area of unmet clinical need. Historically, a second ARPI or chemotherapy has been considered the standard of care; however, recent consensus and evidence have increasingly questioned the validity of ARPI switch as an appropriate control arm in modern clinical trials (1,2).

Agarwal and colleagues recently reported the final analyses from phase 3, open-label, randomised trial (CONTACT-02) that evaluated cabozantinib plus atezolizumab vs. ARPI switch after ARPI exposure in men with CRPC and measurable extrapelvic soft-tissue metastases (3). The authors reported that cabozantinib plus atezolizumab improved radiographic progression-free survival (rPFS) compared with a second ARPI (median 6.3 vs. 4.2 months). Subgroup analyses showed particularly pronounced efficacy of cabozantinib plus atezolizumab for those previously treated with docetaxel. However, the magnitude of benefit was modest—equating to roughly one imaging interval—and there was no improvement in overall survival (OS) at the time of reporting. Notably, grade ≥3 adverse events occurred in nearly half of men (48%), underscoring the substantial toxicity of this regimen.

Beyond efficacy outcomes, the trial design warrants critical reflection. The use of ARPI switch as a control arm has been widely debated and is no longer endorsed by contemporary guidelines, including the 2024 Advanced Prostate Cancer Consensus Conference and the European Association of Urology recommendations (2,4). Many experts have highlighted the limitations of such comparators, describing them as clinically obsolete and potentially confounding the interpretation of incremental benefit. Indeed, a recent correspondence questioned the scientific appropriateness of this study design (5), suggesting that cabozantinib plus atezolizumab was tested against an inadequately active regimen rather than a meaningful comparator. The authors replied that ARPI switch was consistent with other trials, but this justification may not reflect current evidence-based practice (6).

In addition, the trial population was highly selected, limiting the generalisability of the CONTACT-02 findings. Men with brain metastases, spinal cord compression, or cauda equina syndrome were excluded from the trial, whereas such complications often comprise a substantial proportion of those with real-world mCRPC. The objective response rate and prostate-specific antigen (PSA) response rate were modest (13% and 14%, respectively). These limitations, coupled with the absence of OS benefit, suggest that CONTACT-02 should be interpreted as hypothesis-generating rather than practice-changing.

When contextualising CONTACT-02 within the broader therapeutic landscape, it is essential to consider recent progress with other mechanisms of action. Radioligand therapy with ¹⁷⁷Lu-prostate-specific membrane antigen (PSMA)-617, as demonstrated in the PSMAfore trial, has shown meaningful improvement in rPFS amongst men with mCRPC after failure of an ARPI, along with a favourable safety profile and a preliminary OS signal (7). Similarly, combinations of poly(adenosine diphosphate-ribose) polymerase inhibitors (e.g., olaparib or rucaparib) and ARPIs (e.g., olaparib, niraparib, or talazoparib) have provided benefits in selected populations (8,9). An immune checkpoint inhibitor (ICI), although largely ineffective as monotherapy for mCRPC, continues to be explored in rational combinations, particularly in tumours with high tumour mutational burden or deoxyribonucleic acid repair deficiencies (10,11).

Novel systemic treatment strategies targeting prostate cancer biology are expanding rapidly. Recent studies have investigated mechanisms such as PSMA-targeted radioligands, bispecific T-cell engagers, and ICI-based combinations, further reshaping the therapeutic landscape of mCRPC (12-15). In this evolving context, the CONTACT-02 findings underscore both the potential and the pitfalls of an ICI plus multikinase inhibitor combination for men with mCRPC.

Quality of life (QoL) remains a key consideration in this population. Treatments combining an ICI and multikinase inhibitor can produce substantial adverse events, potentially leading to treatment discontinuation before disease progression. Although CONTACT-02 reported similar time to QoL deterioration between arms, more granular analyses are needed to ensure that any survival benefit is not achieved at the cost of tolerability.

In conclusion, CONTACT-02 provides valuable insights into post-ARPI treatment strategies for mCRPC but should be interpreted cautiously given the modest efficacy, substantial toxicity, and lack of OS benefit. Future trials should employ more relevant comparators, including taxanes, incorporate biomarker-driven selection, and prioritise endpoints. Ultimately, multidisciplinary collaboration and rigorous trial design will be critical to refining systemic treatment strategies for mCRPC.

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-2025-701/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-701/coif). The authors have no conflicts of interest to declare.

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