Editor's Note: In recent years, the treatment paradigm for advanced prostate cancer has undergone a profound transformation, shifting from conventional empiric treatment toward precision stratification. With the increasing availability of genetic testing and the emergence of novel targeted therapies, individualized treatment based on molecular characteristics has become an important direction in clinical practice. Oncology Frontier · UroStream invited Professor Xiaojie Bian of Fudan University Shanghai Cancer Center for an in-depth interview on treatment decisions guided by genetic testing, individualized treatment strategies, and potential future breakthroughs.From Genes to Proteins — Advances in Stratified Precision Treatment for Advanced Prostate Cancer
Oncology Frontier · UroStream: In recent years, the treatment of advanced prostate cancer has gradually shifted from conventional empiric therapy toward precision stratification. Based on the discussions at this conference, could you introduce some of the important advances in treatment decision-making based on genetic testing and protein expression?
Professor Xiaojie Bian: In recent years, with the continued development of precision treatment classification and the emergence of new technologies, prostate cancer treatment has gradually expanded from the genetic level to the protein level, creating a multidimensional precision treatment landscape.
At the genetic level, relatively mature treatment approaches are already available. PARP inhibitors targeting homologous recombination repair (HRR) gene alterations were among the earliest precision therapies developed at the genetic level. Based on phase III studies such as PROfound, PARP inhibitors including olaparib have been shown to significantly improve radiographic progression-free survival (rPFS) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) harboring HRR gene alterations such as BRCA1/2 mutations. The benefit is particularly pronounced in the BRCA-mutated subgroup, in which OS reached 20.1 months, representing a 5.7-month improvement compared with the control group.
In addition, for patients harboring mutations in the ligand-binding domain (LBD) of the androgen receptor (AR) pathway, AR-PROTACs (androgen receptor proteolysis-targeting chimeras) are currently being investigated. Unlike conventional antiandrogen therapies, which work through receptor antagonism, PROTAC technology directly degrades AR proteins through the ubiquitin-proteasome pathway and may therefore overcome resistance driven by AR mutations or splice variants.
At the protein level, considerable progress has also been made in recent years, providing a new dimension of treatment for patients with prostate cancer. One of the earliest approaches to enter clinical practice was radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA). Based on the phase III VISION study, ^177Lu-PSMA-617 combined with standard of care increased median rPFS from 3.4 months to 8.7 months and median OS from 11.3 months to 15.3 months in patients with PSMA-positive mCRPC, significantly reducing the risks of disease progression and death.
Meanwhile, the development of antibody-drug conjugates (ADCs) is progressing rapidly. In addition to PSMA, ADCs targeting several prostate cancer cell-surface antigens, including B7-H3, STEAP1, TROP2, and EGFR, are currently under clinical investigation. B7-H3 ADCs have attracted particular attention. Multiple candidates, including DB-1311/BNT324 and I-DXd (MK-2400), have demonstrated promising antitumor activity in early-stage studies, with some receiving FDA Fast Track designation or breakthrough therapy designation from China’s Center for Drug Evaluation (CDE).
Overall, protein-level therapies differ fundamentally from conventional gene-level targeted therapies in both their mechanisms of action and drug-development approaches. They provide additional treatment options for patients with prostate cancer and offer new hope for those who have experienced treatment failure across multiple lines of therapy.
Multidimensional Assessment — Strategies for Developing Individualized Treatment Plans for Advanced Prostate Cancer
Oncology Frontier · UroStream: For patients with advanced prostate cancer, faced with multiple treatment options including endocrine therapy, PARP inhibitors, radioligand therapy, and novel targeted agents, how should clinicians integrate molecular characteristics and disease features to develop individualized treatment strategies?
Professor Xiaojie Bian: We have now established a relatively comprehensive diagnostic and treatment framework, and this framework continues to evolve. Developing an individualized treatment plan requires consideration of multiple dimensions, including molecular and biological characteristics, clinicopathological features, and the patient’s physical condition.
First is stratification at the genetic level. For patients with HRR alterations identified through genetic testing, PARP inhibitors represent an established treatment option. The evidence of benefit is strongest for patients with BRCA1/2 mutations. Patients with alterations in other HRR pathway genes, including ATM, CDK12, CHEK1/2, and PALB2, may also derive benefit from PARP inhibitors according to clinical studies, although the magnitude of benefit may differ and should be assessed according to the specific genetic alteration.
For patients with mutations in the AR ligand-binding domain (LBD), conventional androgen receptor-targeted therapies are often less effective. For these patients, a different treatment strategy may be considered, such as enrollment in clinical trials investigating AR-PROTACs, from which some patients may benefit.
Second is treatment selection based on protein expression. PSMA expression is an important criterion for selecting patients for radioligand therapy. Assessment of tumor PSMA expression using PSMA PET/CT to identify patients suitable for ^177Lu-PSMA-617 has become part of the standard clinical pathway.
Third, patient clinical characteristics must be fully considered. For example, patients with liver metastases generally have a poorer prognosis and represent a clinically high-risk population. Of note, B7-H3 ADCs have demonstrated encouraging activity in patients with liver metastases, a particularly challenging subgroup with a poor prognosis, providing a new potential treatment direction. Therefore, treatment decisions should not be based solely on genetic or protein biomarkers; metastatic sites, tumor burden, and other clinical characteristics must also be incorporated into the overall assessment.
Finally, the patient’s physical condition and quality of life are also critical factors. For patients in good physical condition, more intensive combination therapies may be considered to achieve deeper tumor responses and longer survival. For patients with poorer physical status, supportive care should be strengthened alongside anticancer treatment, with careful consideration of treatment benefit and tolerability and priority given to maintaining quality of life.
In summary, individualized treatment for advanced prostate cancer requires comprehensive consideration of molecular subtype, clinical characteristics, physical condition, and many other factors in order to develop a precise treatment strategy tailored to each patient.
Multiple Explorations — Future Breakthrough Directions in Advanced Prostate Cancer Treatment
Oncology Frontier · UroStream: Drug-treatment strategies for advanced prostate cancer have continued to evolve in recent years. What major breakthroughs do you anticipate in the future?
Professor Xiaojie Bian: Looking ahead, breakthroughs in advanced prostate cancer treatment will likely come from several areas, including the expansion of new targets, the emergence of novel therapeutic modalities, and optimization of treatment strategies.
First, existing pathways will continue to be explored while new therapeutic targets are expanded. In addition to the AR pathway, PSMA, PARP inhibitors, and HRR-related targets, the AKT-mTOR pathway is another important area worthy of attention. The IPATential150 study and other research have suggested that patients with PTEN loss may derive benefit from combining an AKT inhibitor with androgen receptor pathway inhibition in the metastatic hormone-sensitive prostate cancer (mHSPC) setting. PTEN loss occurs in approximately 40%–50% of patients with mCRPC and can lead to abnormal activation of the PI3K/AKT signaling pathway, which is closely associated with poor prognosis. Precision treatment for this molecular subgroup remains an active area of investigation.
Second, immunotherapy may represent another area of breakthrough. Prostate cancer is generally considered an “immune-cold” tumor, and conventional immunotherapy has shown limited efficacy. In earlier years, the only tumor vaccine approved for mCRPC was sipuleucel-T, which was approved in 2010, although its clinical use has remained relatively limited.
In recent years, T-cell engager (TCE) therapies have brought potentially transformative developments to prostate cancer immunotherapy. TCEs are bispecific molecules that can simultaneously bind specific targets on prostate cancer cells, such as PSMA or STEAP1, and CD3 on T cells, thereby actively recruiting and activating T cells to kill tumor cells. TCEs targeting PSMA, STEAP1, and several other antigens are currently undergoing clinical investigation, and some early-stage studies have demonstrated encouraging antitumor activity.
Third, exploration of new targets for ADCs will continue. In addition to PSMA and B7-H3, ADCs targeting STEAP1, TROP2, EGFR, and other targets are being investigated. With continued advances in antibody engineering and linker-payload technologies, the efficacy and safety profiles of ADCs may be further improved.
Fourth, both monotherapy and combination strategies will continue to be explored. Combination treatment is an important future direction. Some combination approaches have already demonstrated advantages in terms of radiographic outcomes or survival, but combination therapies are often associated with a greater burden of adverse events, requiring active clinical management. Therefore, determining how to balance treatment efficacy, survival extension, and quality of life will remain an important area of future research.
In recent years, patient-reported outcomes (PROs) have received increasing attention, and quality of life has become an important dimension for evaluating treatment value. Patients themselves are also placing greater emphasis on quality of life. Therefore, future therapeutic development should not focus solely on tumor control and prolonging survival, but should also incorporate adverse-event management and quality of life, allowing us to identify better treatment strategies through multidimensional clinical decision-making.
Professor Xiaojie Bian
