Editor’s Note: Prostate cancer is one of the most prevalent malignant tumors in men worldwide. For localized cases, radical prostatectomy or radiotherapy can achieve a cure, but some patients experience biochemical recurrence (BCR). Salvage radiotherapy is the preferred treatment for these patients. Recently, next-generation androgen receptor inhibitors (ARIs) have expanded from treating advanced prostate cancer to addressing BCR-stage patients. However, clinical trials evaluating ARIs have varied in their endpoints, yielding inconsistent results. At the 14th Shanghai Uro-Oncology Academic Conference and the Annual Meeting of the Chinese Anti-Cancer Association Male Reproductive System Tumor Committee (CACA-GO) held December 6–8, 2024, Dr. Yanxia Shi from the Sun Yat-sen University Cancer Center presented a thought-provoking report titled “Should Biochemical Recurrence in Prostate Cancer Focus More on Metastasis-Free Survival (MFS) or Treatment-Free Survival (TFS)?” The key points are summarized below.Defining BCR and Advancements in NHT Therapy
Biochemical recurrence (BCR) in prostate cancer refers to a rise in PSA levels following radical treatment without evidence of imaging-detectable metastasis. BCR signifies the “premonitory stage” of local recurrence and distant metastasis, increasing prostate cancer-specific mortality. Approximately 53% of patients develop BCR within a median of 20 months after local therapy.
BCR definitions vary across guidelines:
- NCCN Guidelines: BCR is defined as PSA failing to drop to undetectable levels post-treatment, or an initial drop followed by two or more consecutive detectable rises.
- EAU Guidelines: PSA detected within 4–8 weeks after surgery is considered BCR. For post-radiotherapy patients, PSA exceeding nadir by >2 ng/mL constitutes BCR.
Treatment Approaches:
- Salvage Radiotherapy: The first-line treatment recommended by global guidelines.
- Novel Hormonal Therapy (NHT): New options such as enzalutamide ± leuprorelin are endorsed for high-risk patients with the following criteria: M0 confirmed via CT/MRI or bone scan PSA doubling time (PSADT) ≤9 months Post-radiotherapy PSA ≥2 ng/mL or post-prostatectomy PSA ≥1 ng/mL Ineligibility for pelvic-directed therapy
The CSCO Prostate Cancer Guidelines (2024) provide a secondary recommendation for ADT + enzalutamide for BCR patients.
Key Evidence from EMBARK and PRESTO Studies
- EMBARK Study: 1,068 high-risk BCR patients (PSA ≥1 ng/mL post-prostatectomy, PSA ≥2 ng/mL post-radiotherapy, PSADT ≤9 months). Results: Enzalutamide + ADT significantly improved MFS (HR 0.42; 95% CI: 0.31–0.61; P<0.0001) compared to ADT alone. Enzalutamide monotherapy also showed improvement (HR 0.63; 95% CI: 0.46–0.87; P=0.005). Secondary endpoints included delayed time to distant metastasis (HR 0.44; P=0.0002) and delayed time to symptomatic progression (HR 0.55; P<0.0001).
- PRESTO Study: Focused on BCR patients with PSA >0.5 ng/mL. Findings: Combination therapy with apalutamide + ADT (24.9 vs. 20.3 months, HR 0.52; P=0.00047) and apalutamide + ADT + abiraterone/prednisone (26.0 vs. 20.0 months, HR 0.48; P=0.00008) extended PSA progression-free survival (PSA-PFS) compared to ADT alone.
Quality of Life (QoL): Both EMBARK and PRESTO studies highlighted that next-generation hormonal therapies maintained patient QoL at the BCR stage, balancing efficacy and patient-centered outcomes.
Surrogate Endpoints in BCR Clinical Research
The U.S. FDA recognizes four main clinical trial endpoints:
- Overall Survival (OS)
- Tumor-based Endpoints
- Symptom-based Endpoints (QoL, functionality)
- Biomarkers
Surrogate Endpoints: Predictive metrics like PFS, time to progression (TTP), objective response rate (ORR), and MFS are often used in lieu of OS in early-stage studies.
- MFS: A meta-analysis published in JCP (2017) confirmed that MFS strongly correlates with OS in localized prostate cancer. When HR >0.72, OS is preferred; when HR <0.70, MFS is the optimal endpoint. The FDA officially accepted MFS as a primary endpoint in prostate cancer clinical trials, approving apalutamide for non-metastatic castration-resistant prostate cancer (nmCRPC) based on MFS data (NEJM, 2018).
- TFS: Proposed as a patient-centric endpoint for immune checkpoint inhibitors (ICIs) in JCO (2019). Studies like CheckMate 067/069 showed that TFS aligned well with OS outcomes, highlighting its potential to evaluate durable response without systemic therapy.
Conclusion
BCR signifies an early stage of prostate cancer progression, where timely intervention is crucial to reduce recurrence or metastasis risks. While patients with BCR generally have a good prognosis, high-risk cases benefit from intensified endocrine therapy (ADT + NHT) to extend MFS and PSA-PFS.
MFS, validated by FDA-backed studies, is now a reliable surrogate endpoint for evaluating therapeutic benefit in localized prostate cancer. TFS, as a patient-centered metric, is gaining recognition, particularly for immunotherapy. Future research must continue to balance survival benefits with treatment-related burdens to ensure optimal outcomes for prostate cancer patients.
About Dr. Yanxia Shi
- Roles: Chief Physician, Professor, Doctoral Advisor Vice Director, Department of Internal Medicine, Sun Yat-sen University Cancer Center
Professional Affiliations:
- Board Member, CSCO
- Youth Standing Committee Member, Chinese Anti-Cancer Association
- Vice Chair, Rare and Unknown Primary Tumors Division, Chinese Anti-Cancer Association
- Standing Committee Member, Clinical Chemotherapy Division, Chinese Anti-Cancer Association
- Chair, Breast Cancer Division, Chinese Elderly Health Association
- Committee Member, CSCO Breast Cancer Committee
- Chair, Guangdong Provincial Tumor Internal Medicine Division
- Chair, CMUP Committee, Guangdong Anti-Cancer Association
Achievements:
- Recipient of multiple honors, including the AACR-Asian American Award.
- Principal Investigator for several national and provincial research projects.
- Published extensively in Advanced Science, PNAS, Cancer Research, and Clinical Cancer Research.
