Editor's Note: Patients with advanced prostate cancer whose disease continues to progress despite multiple lines of treatment urgently need new therapeutic options. At the 2026 European Society for Medical Oncology (ESMO) Congress, the Phase I study of SHR-4394, an antibody–drug conjugate (ADC) targeting prostate-specific membrane antigen (PSMA), attracted considerable attention. Oncology Frontier – UroStream invited Professor Zhenhua Liu of West China Hospital, Sichuan University, to discuss the clinical needs addressed by this study, patient selection, safety and preliminary antitumor activity, as well as future directions in drug design and combination therapy.Patient Selection: Addressing the Urgent Needs of Patients After Multiple Lines of Treatment
Oncology Frontier – UroStream: SHR-4394 selects PSMA as its therapeutic target. Which key treatment challenges is it primarily intended to address? What were the major considerations in patient selection for this study?
Professor Zhenhua Liu: There are currently substantial unmet clinical needs in advanced prostate cancer, particularly among patients whose disease continues to progress after multiple lines of treatment. In the Phase I clinical study of SHR-4394, more than 40% of participants had previously received four or more lines of therapy. Exploring effective subsequent treatment strategies for this population is important for improving quality of life and prolonging survival.
The selection of PSMA as a therapeutic target is supported by previous research. Early investigations of PSMA-targeted antibody–drug conjugates (ADCs), as well as PSMA-targeted radioligand therapy represented by ^177Lu-PSMA-617, have provided a rationale for developing this target in advanced prostate cancer. The specific efficacy of different drugs still depends on their molecular design and therapeutic payloads, but PSMA itself is a promising target that warrants further development.
The participants in this study were primarily patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously received novel androgen receptor pathway inhibitors. This population closely reflects an important area of unmet clinical need. During patient screening, the study used PSMA PET imaging, together with parameters such as standardized uptake value (SUV), for evaluation. These assessment methods are consistent with current patient-selection practices for PSMA-targeted therapies.
Early Findings: Balancing Antitumor Activity and Safety
Oncology Frontier – UroStream: What notable findings emerged from this Phase I study regarding safety and preliminary antitumor activity? What implications do these signals have for subsequent research?
Professor Zhenhua Liu: The efficacy and safety of PSMA-targeted drugs need to be evaluated with consideration of both the characteristics of the target and the therapeutic components carried by the drug. Different payloads and linker designs can significantly influence antitumor activity and adverse event profiles.
Previous ADCs using monomethyl auristatin E (MMAE) as their payload encountered challenges such as peripheral neurotoxicity during early-stage drug development. The underlying mechanisms may be related to insufficient linker stability or off-target effects. For PSMA-targeted radioligand therapy, adverse events such as dry mouth and suppression of bone marrow hematopoiesis require particular attention.
SHR-4394 uses a topoisomerase I (Topo I) inhibitor as its payload. The findings from this study showed that its adverse event profile was generally within the expected range. Although almost all participants experienced adverse events of varying degrees, the incidence of Grade 3 or higher adverse events was below 50%, with the main manifestations being hematologic toxicities such as decreased white blood cell counts.
One Grade 5 adverse event was recorded during follow-up. The patient had previously received multiple lines of antitumor therapy and entered the study on an every-two-week dosing schedule. However, the disease continued to progress. Against the background of multiple contributing factors, including anemia and an excessively high tumor burden, the patient developed shock and eventually died. A retrospective review of the patient’s entire clinical course suggests that this adverse event was more likely attributable to the combined effects of multiple factors. At present, no clear strong association with direct administration of the investigational drug has been established. Attribution of this event needs to take the patient’s previous treatment history and disease status at enrollment into comprehensive consideration.
In terms of antitumor activity, the study observed substantial reductions in prostate-specific antigen (PSA) levels in some participants, with a proportion achieving deep PSA responses. For patients with mCRPC who have already received multiple lines of treatment, these preliminary efficacy signals warrant further investigation.
The current observations regarding safety and activity support the continuation of clinical development. However, there remains room to improve the efficacy of monotherapy. Where feasible, future studies should explore combinations with other drugs or treatment modalities in the hope of achieving better therapeutic outcomes.
Future Development: Optimizing Drug Design and Exploring Combination Strategies
Oncology Frontier – UroStream: As SHR-4394 progresses from early clinical signals toward further development, which questions would you most like to clarify? Regarding the relationship between PSMA expression, drug exposure, and efficacy, what validation is needed to enable more accurate dose selection and identification of patients who may benefit?
Professor Zhenhua Liu: This study used a dose-escalation strategy to investigate different dosing schedules, including administration once every two weeks and once every three weeks. At this stage, clear antitumor activity has been observed with both dosing schedules. However, many details still require further investigation. We cannot simply assume that a particular drug design is optimal based solely on our understanding of the PSMA target.
The selection of the payload and the number of payload molecules attached to each antibody are key aspects that require continued optimization. Based on the current findings, topoisomerase I (Topo I) inhibitors represent a class of payloads with considerable research value. However, the appropriate number of payload molecules conjugated to each antibody—that is, the drug-to-antibody ratio (DAR)—still needs to be systematically explored in light of the specific activity and toxicity characteristics of each drug.
Linker stability is equally important. If the linker breaks prematurely and releases the payload into the peripheral circulation, unexpected toxicities may occur. The binding activity and specificity of the antibody for its antigen also directly affect drug distribution and the risk of off-target effects.
In addition, some ADCs carrying Topo I inhibitor payloads can exert a bystander effect. This may have potential therapeutic value in patients whose tumors exhibit substantial heterogeneity in PSMA expression. However, the specific patient population that may benefit from this effect remains to be defined through further research.
Combination therapy is another important area for exploration. Clinical studies in other solid tumors have demonstrated the initial potential of combining ADCs with immune checkpoint inhibitors. Prostate cancer, however, is generally considered an “immunologically cold tumor” because of the low immunogenicity of its tumor microenvironment. Previous immunotherapy-based combination strategies have not yet achieved the level of clinical benefit originally anticipated in this disease.
Looking ahead, further studies are needed to determine whether combining ADCs with immunotherapy can produce differentiated efficacy in mCRPC. It is also worth investigating whether additional combinations with radioligand therapy or radiotherapy could lead to better overall treatment outcomes.
Conclusion
The Phase I clinical study of SHR-4394 enrolled patients with mCRPC who had received multiple previous lines of treatment. Its preliminary findings provide a clinical research rationale for the further development of PSMA-targeted antibody–drug conjugates.
Professor Zhenhua Liu emphasized that subsequent research should continue to evaluate the drug’s safety and antitumor activity while optimizing its characteristics through improvements in payload selection, drug-to-antibody ratio, and linker design. The feasibility of combination treatment strategies should also be explored to further define the patient population most likely to benefit and clarify the drug’s potential clinical value.
Professor Zhenhua Liu
