Prostate cancer is one of the most common malignancies affecting the male genitourinary system, and in China, a significant proportion of newly diagnosed patients present with advanced disease. Since late-stage prostate cancer is symptomatic and not curable, alleviating symptoms, delaying disease progression, and improving quality of life have always been priorities for both patients and physicians in China. In 2024, several groundbreaking studies on advanced prostate cancer, including metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC), were published in leading medical journals and presented at international conferences, reshaping treatment paradigms. With a retrospective look at the past year, Oncology Frontier invited Dr. Dingwei Ye from Fudan University Shanghai Cancer Center to share insights on these advancements.

The Growing Challenge of Prostate Cancer Diagnosis and Treatment

The global and domestic burden of prostate cancer has been steadily increasing, presenting a serious challenge in clinical practice. According to data from China’s National Cancer Center, prostate cancer ranked as the sixth most common malignancy among Chinese men in 2022. Although the five-year relative survival rate for prostate cancer patients in the United States has reached 97.0%, China lags significantly behind. Between 2003 and 2005, the five-year survival rate in China was 53.8%, which improved to 66.4% between 2012 and 2015. However, disparities in healthcare infrastructure remain a major issue. The uneven distribution of medical resources is evident not only between urban and rural areas but also among different regions of China, affecting access to medications, advanced medical equipment, insurance coverage, and standardization of treatment protocols. Ultimately, this inequality translates into significant survival disparities among patients.

China faces a low early detection rate and a high proportion of advanced prostate cancer cases. In the United States, over 80% of newly diagnosed prostate cancers are early-stage, with less than 5% of cases diagnosed at an advanced stage. In contrast, in China, only 40% of newly diagnosed cases are detected at an early stage, while 30% are intermediate-stage, and 30% are advanced-stage at initial diagnosis.

With a deeper understanding of the biological mechanisms of prostate cancer and advancements in precision medicine, drug development for advanced prostate cancer has made significant strides in recent years. New therapeutic approaches, including next-generation androgen receptor inhibitors (ARi), radioligand therapy, and PARP inhibitors, have provided more options for patients. The latest research findings in mHSPC and mCRPC have shaped the current treatment landscape and will be the focus of this review.

Advances in Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

The ARANOTE trial, presented at the 2024 ESMO Congress, is a global, multicenter, randomized, double-blind, placebo-controlled Phase III trial evaluating darolutamide in combination with androgen deprivation therapy (ADT) for patients with mHSPC. The study enrolled 669 patients across 15 countries and regions, including 90 patients from mainland China. Participants were randomly assigned to either the darolutamide plus ADT group (N=446) or the placebo plus ADT group (N=223). The median age of patients in the darolutamide group was 70 years, and 32.3% were Asian. At baseline, the median PSA level was 21.3 ng/mL, and 71% of patients were diagnosed with high-volume disease.

The initial results showed that radiographic progression-free survival (rPFS) was significantly improved in the darolutamide group compared to the placebo group (HR 0.54; P<0.0001). The benefit was consistent across all predefined subgroups, regardless of whether patients had high- or low-volume disease. Secondary endpoints also demonstrated a trend toward clinical benefit. In terms of safety, treatment-related adverse events (TEAEs) were low and comparable between the two groups. The ARANOTE trial confirmed that darolutamide plus ADT offers significant efficacy and favorable safety in patients with mHSPC. Alongside findings from the ARASENS study, darolutamide has demonstrated clinical benefit with or without chemotherapy in this patient population.

Another key study, the China ARCHES trial, was a Phase III, multicenter, double-blind, randomized controlled study conducted across 27 centers in China, enrolling 180 patients with mHSPC. Patients were randomized 2:1 to receive either enzalutamide plus ADT or placebo plus ADT, with the primary endpoint being time to PSA progression (TTPP). The initial results showed that enzalutamide significantly reduced the risk of PSA progression by 87% (HR 0.130; P<0.0001). Additionally, enzalutamide reduced the risk of radiographic disease progression by 67% (rPFS: NR vs. 19.4 months, HR 0.330; P<0.001) and the risk of castration resistance by 82.8% (NR vs. 8.3 months, HR 0.172; P<0.001).

At the 2024 ESMO Congress, further findings from the China ARCHES study were presented, focusing on the patient-reported outcomes of enzalutamide plus ADT in mHSPC. Among the 180 patients enrolled, 120 received ADT plus enzalutamide, while 60 received ADT plus placebo. A decline in quality of life was observed in 69% of patients (83/120) in the enzalutamide group and 57% (34/60) in the placebo group. However, the time to deterioration did not differ significantly between the groups (HR 1.2; 95% CI: 0.8–1.8). In terms of pain progression, 62% of patients (74/120) in the enzalutamide group and 55% (33/60) in the placebo group experienced at least a 30% increase in pain. Additionally, 45% (54/120) of enzalutamide-treated patients and 38% (23/60) of placebo-treated patients reported a pain increase of ≥2 points.

These subgroup analyses from the China ARCHES study confirmed that enzalutamide plus ADT provides significant clinical benefit in mHSPC without compromising patient quality of life.

Patient-Reported Outcomes from the CHART Study

The CHART study, an international, multicenter Phase III trial led by Dr. Dingwei Ye from Fudan University Shanghai Cancer Center, was designed to evaluate the efficacy and safety of relugolix, a novel androgen receptor inhibitor (ARi) developed in China, in combination with androgen deprivation therapy (ADT) for the treatment of mHSPC.

Previous findings from the CHART study confirmed that relugolix plus ADT significantly improved radiographic progression-free survival (rPFS) in patients with high-volume mHSPC (NE vs. 25.1 months; HR 0.44, 95% CI: 0.33-0.58, P<0.0001), as well as overall survival (OS) (NE vs. NE; HR 0.58, 95% CI: 0.44-0.77, P=0.0001). These results, published in Lancet Oncology in 2022, have been incorporated into China’s clinical practice guidelines, offering a new treatment option for patients with mHSPC.

In 2024, a patient-reported outcomes analysis from the CHART study was published in Signal Transduction and Targeted Therapy, focusing on pain and functional health. Assessments using the Brief Pain Inventory-Short Form (BPI-SF) showed that relugolix plus ADT significantly delayed pain progression compared to bicalutamide (BIC) plus ADT, with median time to worst pain progression recorded at 9.2 months versus 6.4 months (HR 0.75, P=0.026).

The Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire further demonstrated that relugolix plus ADT significantly delayed functional deterioration compared to BIC plus ADT, with median time to functional decline recorded at 12.8 months versus 6.0 months (HR 0.66, P=0.002). Patients receiving relugolix also showed better physical, emotional, and functional well-being, with higher overall FACT-G scores, prostate cancer-specific subscale scores, and trial outcome index scores.

These findings suggest that beyond improving rPFS and OS, relugolix also effectively alleviates pain symptoms and preserves functional health, ultimately enhancing quality of life for patients with mHSPC.

UpFrontPSMA Study

The UpFrontPSMA study, published in Lancet Oncology in 2024, was the first randomized trial to demonstrate the benefit of 177Lu-PSMA-617 in mHSPC. The study aimed to compare the efficacy and safety of sequential 177Lu-PSMA-617 plus docetaxel versus docetaxel monotherapy in mHSPC.

Findings showed that the sequential treatment group had a significantly higher PSA undetectable rate at week 48 (41% vs. 16%, P=0.002) compared to the docetaxel-alone group. Additionally, sequential treatment significantly prolonged median PSA-PFS (30 months vs. 21 months, P=0.002) and median time to castration resistance (20 months vs. 16 months, P=0.033).

These results highlight the potential of radioligand therapy in mHSPC, warranting further exploration in clinical settings. With continued research, 177Lu-PSMA-617 may become an established treatment option for patients with mHSPC.

Advances in Novel Endocrine Therapy for mCRPC

The TALAPRO-2 study is an international, multicenter, randomized, double-blind, placebo-controlled Phase III trial evaluating the efficacy and safety of talazoparib plus enzalutamide versus enzalutamide alone as a first-line treatment for mCRPC.

In May 2024, the study published an analysis of the HRR-mutated cohort, revealing that talazoparib plus enzalutamide significantly improved rPFS compared to enzalutamide plus placebo (NR vs. 13.8 months; HR 0.45; P<0.0001).

By October 2024, the study reached its prespecified overall survival (OS) endpoint, demonstrating that talazoparib plus enzalutamide significantly extended OS in all patients (Cohort 1) and HRR-mutated mCRPC patients (Cohort 2). These findings confirmed the clinical benefit of combination therapy in prolonging survival.

At the 2024 ESMO Congress, data from the Chinese cohort of TALAPRO-2 were presented. Results showed that in Chinese patients, talazoparib plus enzalutamide significantly improved median rPFS compared to the control group (33.3 months vs. 10.9 months; HR 0.30; P<0.0001).

Among patients with homologous recombination deficiency (HRD), rPFS was 15.7 months versus 4.0 months (HR 0.16; P=0.0044), while for patients with non-HRD or unknown HRR status, rPFS was 35.9 months versus 13.8 months (HR 0.36; P=0.0018).

Overall, the Chinese cohort findings aligned with global study data, reinforcing that talazoparib plus enzalutamide provides substantial rPFS benefits, offering a promising new treatment option for mCRPC in China.

Radioligand Therapy in mCRPC

The PEACE-3 study, presented at the 2024 ESMO Congress, was a randomized, multicenter, open-label Phase III trial evaluating radium-223 plus enzalutamide versus enzalutamide monotherapy in patients with asymptomatic or minimally symptomatic bone-metastatic mCRPC.

The study enrolled 446 patients with a median age of 70 years and a median follow-up of 42.2 months. Findings showed that radium-223 plus enzalutamide significantly improved median rPFS (19.4 months vs. 16.4 months; HR 0.69; P=0.0009) and reduced the risk of disease progression by 31%.

In terms of overall survival (OS), the combination therapy significantly extended OS to 42.3 months, compared to 35.0 months in the enzalutamide monotherapy group (HR 0.69; P=0.0031). Additionally, time to next systemic therapy (TTNT) was significantly prolonged, with 24-month TTNT rates of 30% in the combination group versus 51% in the monotherapy group (HR 0.57; P<0.0001).

Regarding safety, ≥Grade 3 treatment-related adverse events (TEAEs) occurred in 28% of the combination group and 19% of the enzalutamide monotherapy group, with no treatment-related deaths.

These results indicate that radium-223 plus enzalutamide offers significant benefits in both rPFS and OS, providing a novel first-line treatment approach for mCRPC. The findings may reshape future clinical guidelines for mCRPC treatment.

The PSMAfore trial compared 177Lu-PSMA-617 versus ARPI switch therapy in PSMA PET-positive mCRPC patients who had progressed after initial ARPI treatment.

The study enrolled 585 patients across 74 countries, randomly assigning them to either 177Lu-PSMA-617 or ARPI switch therapy. The primary endpoint was rPFS, with patients in the 177Lu-PSMA-617 group receiving a median of six cycles of treatment.

Updated efficacy analysis showed that 177Lu-PSMA-617 significantly improved median rPFS (11.60 months vs. 5.59 months), reducing progression risk by 51%. These findings suggest that for patients with ARPI resistance, 177Lu-PSMA-617 may be an effective next-line treatment.

The VISION trial, a global, multicenter Phase III study, previously demonstrated that 177Lu-PSMA-617 plus standard of care (SOC) significantly improved OS in PSMA-positive mCRPC patients, extending OS by 4 months and reducing the risk of death by 38% (HR 0.62, 95% CI: 0.52-0.74).

A 2024 safety analysis, published in European Urology, confirmed that TEAE rates were consistent across treatment cycles, with no additional safety concerns in patients receiving more than four cycles. These findings reinforce the safety and efficacy of 177Lu-PSMA-617 in mCRPC, offering a new option for advanced disease management.

About Dr. Dingwei Ye

Dingwei Ye, MD, PhD

• Vice President, Fudan University Shanghai Cancer Center
• Chief Expert, Multidisciplinary Team for Urological Oncology
• Director, Shanghai Institute of Urological Oncology
• Director, Fudan University Institute of Prostate Oncology
• Executive Director, Integrative Prostate Oncology Committee, Chinese Anti-Cancer Association (CACA)
• Chairman, Chinese Anti-Cancer Association (CACA) Male Genitourinary Oncology Committee (CACA-GO)
• Chairman, Prostate Cancer Expert Committee, Chinese Society of Clinical Oncology (CSCO)
• Chairman, Urology Committee, China Primary Health Care Foundation
• Former Chairman, CACA Urological and Male Genitourinary Oncology Committee (CACA-GU)
• Vice Chairman, Tumor Group, Chinese Urological Association (CUA); Chairman, CPCC
• Vice Chairman, Urothelial Cancer Expert Committee, CSCO
• Vice Chairman, Renal Cancer Expert Committee, CSCO
• Vice Chairman, Immunotherapy Expert Committee, CSCO
• Chairman, Chinese Tumor Hospital Urological Oncology Collaborative Group (UCOG)
• Standing Member, Chinese Anti-Cancer Association & CSCO
• Deputy Editor-in-Chief, Chinese Journal of Oncology
• Committee Member, NCCN Asian Consensus Panel for Prostate Cancer, Kidney Cancer, and Bladder Cancer
• Committee Member, St. Gallen Advanced Prostate Cancer Consensus Panel
• Chairman, Urological Oncology Committee, Shanghai Anti-Cancer Association
• Vice President, Urological Surgery Branch, Shanghai Medical Doctor Association
• Former President, Asia-Pacific Prostate Society (APPS)
• Vice President, Asia-Pacific Society of Cryosurgery

Dr. Dingwei Ye is a renowned expert in urological oncology, with extensive contributions to the clinical management and research of prostate cancer, bladder cancer, and kidney cancer. He has played a key role in shaping China’s clinical guidelines for advanced prostate cancer and has led multiple national and international clinical trials on novel therapies, including androgen receptor inhibitors, radioligand therapy, and immunotherapy.

With numerous high-impact publications and leadership roles in oncology societies and guideline panels, Professor Ye continues to be at the forefront of innovative prostate cancer treatment strategies, advancing research and clinical practice on a global scale.