The efficacy of deutenzalutamide in extending rPFS was significantly superior to that of placebo, as evidenced by the statistically significant improvement observed in this study. The HR for rPFS was 0.58 (95% CI, 0.44–0.77; P = 0.0001), indicating a 42% reduction in the risk of progression or death in the deutenzalutamide arm compared to the placebo arm. Although the median rPFS improvement with deutenzalutamide over placebo is modest (1.8 months), deutenzalutamide maintains a marked long-term rPFS advantage, with 29% vs 6% rPFS at 12 months and 18% vs none at 24 months. The rPFS benefit was consistent across all prespecified subgroups, including age, presence of visceral metastases, and prior docetaxel treatment. Central imaging results aligned with local investigator findings, offering additional assurance of therapeutic efficacy. Exploratory OS analyses revealed promising outcomes with deutenzalutamide. While the final OS analysis at the time point did not reach statistical significance, sensitivity analyses adjusting for subsequent antitumor therapies demonstrated a survival benefit with deutenzalutamide over placebo (HR ~ 0.65–0.73). These findings highlight that deutenzalutamide can offer a viable treatment option for patients with mCRPC who have not responded to prior therapies, particularly when considering the confounding effects of subsequent treatments on OS.
The management of mCRPC, particularly in the context of sequential use of ARSIs such as abiraterone following enzalutamide or vice versa, is complicated by cross-resistance due to their action on the same signaling pathway. While the overall clinical benefits are often limited, some patients experience long-term advantages.6 Our study is the first to demonstrate the efficacy of deutenzalutamide in improving rPFS and showing a positive OS trend in a well-designed, double-blind pivotal trial, with similar efficacy observed in patients regardless of prior docetaxel treatment (Fig. 3).
There is an unmet medical need for mCRPC patients post-ARSI and chemotherapy, particularly in China, where abiraterone and docetaxel are widely used.10,11 Initial investigations suggest that enzalutamide offers clinical benefits for patients unresponsive to abiraterone/docetaxel.6,12 Our research confirms the efficacy of deutenzalutamide in this setting, reinforcing its potential as a viable treatment option.
Cabazitaxel, approved for mCRPC after docetaxel treatment, may present as an alternative treatment in this setting (CARD study).13 Despite its longer median rPFS (8.0 months) compared to deutenzalutamide (5.6 months), deutenzalutamide offers a substantially better long-term rPFS rate at 24 months (18.8% vs. ~5%). Additionally, while the median OS is comparable between the two treatments, deutenzalutamide shows a notably higher long-term OS rate (~30% vs <2% at 30 months). However, cabazitaxel’s association with increased risks of neutropenia, infections, and gastrointestinal toxicities remains a significant concern. Recent developments in Lu-177 PSMA therapy provide another treatment avenue for mCRPC patients with PSMA-positive disease by delivering targeted radiation to PSMA-expressing tumor cells.14 Despite its promise, the limited availability and specialized requirements pose challenges for widespread adoption.
Deutenzalutamide, a deuterated variant of enzalutamide, shows promise in addressing CNS-related safety issues associated with enzalutamide and other AR inhibition therapies in mCRPC. By modifying the pharmacokinetic profile of enzalutamide, deutenzalutamide reduces brain exposure to the active drug, potentially decreasing the incidence of CNS-related adverse effects7. Our comparative analysis between deutenzalutamide and historical data from the pivotal AFFIRM trial of enzalutamide reveals a significant improvement in the CNS-related safety profile of deutenzalutamide (Supplementary Table 2).15,16 Specifically, deutenzalutamide demonstrated lower frequencies of fatigue, dizziness, and abnormal sensations. Notably, no cases of epilepsy, falls, or anxiety were observed in patients treated with deutenzalutamide. Additionally, the occurrence of grade 3 fatigue was significantly reduced with deutenzalutamide (3.3%) compared to enzalutamide (9%). It is important to acknowledge the limitations of comparing data from different trials. However, the present study showed that deutenzalutamide exhibited a favorable safety profile, with adverse events consistent with those common in the mCRPC patient population.
This study has several limitations to consider when interpreting the results. First, there was no active comparator (e.g., cabazitaxel, enzalutamide, or Lu-PSMA-617), which was not approved in China at the time of study design. Although the median rPFS with deutenzalutamide was similar to that reported for enzalutamide in post abiraterone mCRPC (5.55 months in this study vs. 5.7 months in TRANSFORMER and 5.55 months in PSMAfore),17,18 deutenzalutamide appears to offer a substantially better long-term rPFS than enzalutamide. This suggests a potential advantage for deutenzalutamide, particularly since TRANSFORMER and PSMAfore enrolled only patients who progressed on abiraterone, whereas our cohort included patients who had progressed on both abiraterone and docetaxel.
Second, adjustment of OS based on subsequent therapies was not predefined in the protocol. Given the absence of a standard therapy for this population in China at the start of the study, crossover was not an option. To fully understand the main factors contributing to the OS results, in addition to the previously described IPCW and RPSFTM analyses, comprehensive sensitivity analyses were conducted using common methods on OS analyses, including accelerated failure time (AFT) models, stratified proportional hazards models, two-stage estimation, and analyses excluding patients receiving subsequent antitumor therapies. All analyses largely converged on the conclusion that OS benefits persisted after adjustment for subsequent therapies. While these sensitivity analyses were not prespecified, they provided valuable insights into the treatment effect on OS.
Third, this study does not specify the treatments patients received during the mHSPC phase. It is plausible that many participants underwent androgen deprivation therapy, with abiraterone and docetaxel introduced upon progression to mCRPC. Explicit documentation of prior therapeutic regimens and disease context would enhance the interpretability and generalizability of the findings. Future work should routinely report prior therapeutic regimens and disease context to better contextualize AR-targeted responses.
Additionally, patients were not prescreened for AR mutations and tumor burden. In late-stage mCRPC patients, resistance often involves AR mutations and/or tumor burden. A recent study indicated that patients with circulating AR alterations may not benefit from continuing enzalutamide.19 Future work should integrate prospective molecular and clinical stratification to define subgroups most likely to benefit from AR-targeted therapy. Given the observed 24-month rPFS benefit in a subset of long responders, incorporating biomarker-driven selection (e.g., AR mutational status, AR signaling activity and tumor burden) could sharpen patient enrichment, personalize treatment and enhance the translational impact of AR-targeted strategies in this setting.
In conclusion, deutenzalutamide, a novel AR antagonist with an enhanced safety profile and reduced drug‒drug interaction effects, has been validated as a viable treatment for mCRPC patients who have shown resistance to abiraterone and docetaxel therapies. These results highlight its potential as a valuable addition to the AR-targeted therapy arsenal, particularly in settings where post abiraterone/docetaxel options remain limited.
