Editor’s Note: Prostate cancer is one of the most common malignant tumors of the male genitourinary system in China. Among these patients, metastatic hormone-sensitive prostate cancer (mHSPC) carries a particularly poor prognosis and remains a major clinical challenge. In recent years, novel hormonal therapies (NHTs), represented by enzalutamide, have continuously reshaped the treatment landscape of mHSPC. With the release of long-term follow-up data from landmark studies such as ARCHES and ENZAMET, the combination of enzalutamide plus androgen deprivation therapy (ADT) has demonstrated durable survival benefits across a broad range of subgroups, including high- and low-volume disease, synchronous and metachronous metastases, and patients treated before or after chemotherapy.However, Chinese patients with mHSPC present unique clinical characteristics, including a higher proportion of high-volume disease, advanced age, and frequent comorbidities. How to develop individualized treatment strategies that balance efficacy, safety, and adherence based on robust evidence remains a central issue in clinical decision-making. During this conference presentation, Professor Xu systematically reviewed the evidence supporting novel hormonal therapies represented by enzalutamide in mHSPC, shared valuable real-world clinical experience regarding treatment selection and safety management in Chinese patients, and offered insights into future biomarker-driven precision strategies involving HRR mutations, PSMA expression, and combination therapies.
Oncology Frontier – UroStream:
In your presentation, you comprehensively reviewed the evidence and clinical experience surrounding novel hormonal therapies represented by enzalutamide in mHSPC. In the current era of multiple combination strategies for mHSPC, which patient subgroups appear to derive the greatest long-term survival benefit from enzalutamide-based treatment?
Professor Tao Xu:
This is a very important question and one that sits at the center of current treatment decision-making for mHSPC.
Based on the most mature and longest-followed evidence available to date, next-generation hormonal therapies represented by enzalutamide have demonstrated stable and durable survival benefits across multiple mHSPC subgroups. I usually approach this question by focusing on several clinically meaningful populations with strong supporting evidence.
First, in both high-volume and low-volume disease, enzalutamide consistently delivers long-term overall survival (OS) benefits, with particularly notable absolute gains observed in high-volume disease.
The five-year follow-up results from ARCHES and more than eight years of follow-up from ENZAMET showed that enzalutamide plus ADT significantly prolonged OS in patients with high-volume mHSPC. Beyond the consistently favorable hazard ratios, there were also meaningful improvements in absolute survival time as well as five- and eight-year survival rates. This is especially important for high-volume patients, who generally carry a worse prognosis. Importantly, low-volume patients also demonstrated a consistent survival advantage, supporting enzalutamide as a broadly applicable foundational treatment regardless of disease burden.
Second, enzalutamide showed similarly durable survival benefits in both synchronous (de novo) and metachronous metastatic disease, making it particularly valuable for patients requiring intensified treatment early in the disease course.
A large proportion of patients enrolled in ARCHES and ENZAMET had de novo metastatic disease, and long-term follow-up demonstrated substantial reductions in mortality risk with enzalutamide in this subgroup. Clinically, this is highly relevant because patients presenting with metastatic disease at diagnosis often exhibit more aggressive biology. These data strongly support the early use of enzalutamide-based intensification strategies.
Third, from the perspective of chemotherapy exposure, enzalutamide demonstrated stable survival benefits both in patients treated before chemotherapy and in those receiving chemotherapy concurrently or sequentially. This flexibility is particularly important in the current era of multidrug treatment strategies.
Across both ARCHES and ENZAMET, the OS benefit associated with enzalutamide was not significantly influenced by prior or planned docetaxel use. In real-world practice, this gives clinicians considerable flexibility to build enzalutamide-centered strategies tailored to a patient’s age, comorbidities, and treatment tolerance without sacrificing long-term survival benefit.
A fourth increasingly important subgroup consists of patients who achieve deep PSA responses early during treatment.
The eight-year ENZAMET analysis showed that patients who achieved PSA ≤0.2 ng/mL at seven months experienced significantly better long-term survival outcomes regardless of treatment assignment. Enzalutamide substantially increased the proportion of patients achieving this deep PSA response early in therapy, helping more patients enter a favorable long-term survival trajectory. In practice, dynamic PSA monitoring early during treatment may further refine individualized decision-making.
Overall, in today’s era of multiple combination approaches for mHSPC, enzalutamide-based therapy appears particularly suitable for patients with high disease burden, de novo metastatic disease, biologically aggressive tumors, or those seeking deep early tumor control to maximize long-term survival.
Its greatest strengths are the durability of benefit, broad applicability, and compatibility with various treatment combinations, making it a strong evidence-based foundation for precision stratified therapy.
Oncology Frontier – UroStream:
Considering the clinical characteristics of Chinese patients with mHSPC—especially those with high- or low-volume disease, advanced age, and multiple comorbidities—how do you develop individualized treatment strategies based on the evidence supporting enzalutamide? What are your key experiences regarding long-term safety management and treatment adherence?
Professor Tao Xu:
In Chinese clinical practice, the overall profile of patients with mHSPC differs somewhat from that seen in many international trials. A large proportion present with extensive metastatic disease at diagnosis, particularly bone metastases, and many are elderly with hypertension, diabetes, cardiovascular disease, or other comorbidities.
Because of this, when selecting treatment strategies, I focus heavily on two principles. First, treatment should be intensified early, but it also needs to remain sustainable over time. Second, the regimen must realistically fit the long-term needs of Chinese patients.
From an evidence standpoint, the data supporting enzalutamide in mHSPC are extremely robust. Both ARCHES and ENZAMET demonstrated clear improvements in progression-free and overall survival across disease-volume subgroups, providing strong support for stratified clinical decision-making.
High-Volume vs Low-Volume Disease
For patients with high-volume mHSPC, disease progression tends to occur rapidly, so the therapeutic goal is very clear: delay the development of castration resistance as long as possible.
If a patient has limited performance status or concerns about early chemotherapy, I often favor ADT plus enzalutamide because it provides strong evidence-based intensification while remaining relatively manageable for long-term use. One major practical advantage is that meaningful disease control can be achieved without relying on chemotherapy.
In low-volume disease, my focus shifts more toward long-term treatment sustainability and quality of life. These patients often live for many years, making treatment persistence critically important. Enzalutamide provides demonstrated survival benefits in this subgroup as well, while its relatively simple oral administration helps patients maintain long-term adherence.
Use in Elderly Patients and Those with Multiple Comorbidities
A particularly striking feature of Chinese mHSPC practice is the large proportion of elderly patients. In these individuals, treatment decisions extend far beyond antitumor efficacy alone and must include considerations such as polypharmacy, metabolic burden, and long-term tolerability.
Enzalutamide fits many of these needs well. It does not require chronic concomitant steroid use, which is especially beneficial in patients with diabetes or cardiovascular disease because it reduces additional metabolic stress. In real-world practice, most patients tolerate treatment well when early follow-up and communication are properly managed.
Long-Term Safety and Seizure Risk
One unavoidable topic when discussing long-term enzalutamide safety is seizure risk associated with second-generation AR pathway inhibitors.
As the first extensively studied second-generation ARPI, enzalutamide was initially associated with seizure signals in the AFFIRM study. Subsequent ARPI trials therefore excluded patients with seizure histories, and prescribing information has continued to include warnings regarding this issue.
However, subsequent reports have shown extremely low seizure rates, generally comparable to placebo arms in most studies. This suggests that the actual real-world risk is very low.
Importantly, enzalutamide has a unique advantage in that post-marketing evidence specifically evaluated this concern. The UPWARD study examined patients with known seizure risk factors and found that enzalutamide did not significantly increase seizure incidence. In addition, a Chinese post-marketing observational study involving 385 patients reported no seizure events, which aligns closely with my own clinical experience.
In routine practice, simply screening for epilepsy history, traumatic brain injury, stroke, or brain metastases before prescribing, combined with appropriate follow-up, allows the vast majority of patients to use the drug safely and continuously. Over time, my concerns regarding seizure risk in elderly or long-term treatment populations have decreased substantially.
Long-Term Management and Treatment Adherence
From practical experience, adherence often determines whether intensified therapy truly delivers its full value.
When prescribing enzalutamide, I repeatedly emphasize from the beginning that this is a long-term disease-control strategy rather than a short-term trial. I also encourage patients to communicate promptly about adverse effects rather than independently adjusting or discontinuing treatment.
The simplicity of oral administration itself also improves adherence. For many elderly patients, a straightforward treatment process with manageable burden becomes a key factor supporting long-term continuation.
Expert Summary
Overall, in Chinese patients with mHSPC—particularly those with high-volume disease, advanced age, and multiple comorbidities—enzalutamide offers a highly practical individualized treatment option due to its proven efficacy, durable tolerability, and validated safety profile in Chinese populations.
Through proper patient stratification, standardized follow-up, and ongoing communication, this approach can truly be “used long-term while maintaining durable disease control” in real-world clinical practice.
Oncology Frontier – UroStream:
mHSPC treatment has now entered the era of precision stratification. Based on your research and clinical experience, what future directions do you see for enzalutamide and other novel hormonal therapies in terms of combination strategies and biomarker-guided precision medicine?
Professor Tao Xu:
Indeed, mHSPC management is evolving from generalized treatment intensification toward increasingly refined stratified care.
As novel hormonal therapies move broadly into frontline treatment, the central question is no longer simply whether to intensify therapy, but rather how to intensify treatment more precisely, earlier, and more strategically.
Based on my own research and clinical observations, several major directions deserve further exploration.
1. Optimization of Combination Strategies and Exploration of “Chemo-Free” Approaches
Current evidence already supports ADT plus enzalutamide as a mature intensification strategy. The next step is not simply adding more drugs indiscriminately, but identifying the appropriate treatment depth and sequencing for different patient populations.
In real-world practice, many patients—particularly elderly individuals with multiple comorbidities—are unwilling or unable to tolerate chemotherapy. In these settings, oral enzalutamide-based regimens with minimal or no steroid dependence may provide a more balanced approach that preserves efficacy while improving long-term sustainability and treatment experience.
Future studies should also explore combinations between enzalutamide and agents with complementary mechanisms to further delay disease progression while maintaining acceptable safety profiles.
2. Biomarker-Driven Precision Therapy
At present, frontline mHSPC treatment remains largely based on clinical characteristics such as disease burden, metastatic distribution, and performance status. The next critical step is integrating molecular information into routine treatment decisions.
We need to better identify which patients derive particularly durable benefit from enzalutamide and which may require earlier strategy adjustments. This may involve not only genomic alterations but also dynamic biomarkers related to AR pathway activity.
Additionally, integrating imaging, blood-based markers, and molecular biomarkers may allow us to predict tumor biology more accurately during the mHSPC stage and optimize enzalutamide-centered treatment pathways accordingly.
HRR Mutations and PARP Inhibitors
PARP inhibitors are now moving earlier into the mHSPC setting as biomarker-driven intensification strategies.
Trials such as AMPLITUDE demonstrated that in patients with HRR-mutated mHSPC, adding PARP inhibition to intensified endocrine therapy significantly improved radiographic progression-free survival, with especially strong benefits observed in BRCA1/2-mutated disease.
Future research should focus on earlier HRR testing integration, refining mutation-specific benefit prediction, and determining optimal sequencing or combination approaches alongside ARPIs.
PSMA Expression and Radioligand Therapy
PSMA-based imaging and targeted radioligand therapy represent another exciting precision pathway.
Studies such as PSMAddition suggest that adding ^177Lu-PSMA-617 to standard ADT plus ARPI in PSMA-positive mHSPC significantly improves radiographic progression-free survival and disease-control endpoints.
Future work should better define PSMA positivity thresholds, address intrapatient heterogeneity, personalize dosing strategies, and determine optimal timing for combinations with ARPIs including enzalutamide.
Integrating Genomics and Molecular Imaging
Ultimately, precision treatment in mHSPC will likely rely on integrated molecular stratification.
HRR alterations may identify intrinsic vulnerabilities, while PSMA imaging reflects target expression intensity. Patients with HRR mutations but low PSMA expression may benefit more from PARP-focused strategies, whereas strongly PSMA-positive disease may favor radioligand approaches. Patients exhibiting both features may represent ideal candidates for highly synergistic combination strategies.
The Importance of a Strong Therapeutic “Backbone”
Regardless of how combination strategies evolve, the long-term sustainability of ARPI backbone therapy remains fundamental.
Beyond extensive global experience, Chinese real-world evidence has further strengthened confidence in enzalutamide’s safety. In one observational Chinese cohort, no seizure events were observed during treatment, reinforcing confidence in long-term use and earlier treatment intensification.
Ultimately, future progress will not depend on adding more treatments indiscriminately, but on ensuring the right treatment is given to the right patient at the right time—and on maintaining therapies patients can realistically continue over the long term.
Professor Tao Xu
