Editor's Note: Prostate cancer is a common malignant tumor of the reproductive system, particularly affecting elderly men. Screening high-risk populations and tailoring treatment plans based on patient characteristics are crucial for improving cure rates and enhancing quality of life. Recently, the 2024 ASCO Annual Meeting unveiled numerous advancements in the treatment of prostate cancer. "Oncology Frontier" invited Dr. Fu Fu Zheng from The First Affiliated Hospital , Sun Yat-sen University to provide an in-depth analysis of these advancements and discuss the latest breakthroughs in prostate cancer. This article summarizes notable real-world research explorations and related poster presentations for readers.

Patient-Centered Real-World Exploration

MAST Study on Metformin Active Surveillance

Active surveillance is the standard management strategy for low-risk prostate cancer patients, typically involving close monitoring and initiating definitive treatment upon significant disease progression. Preclinical data suggest that metformin may slow prostate cancer progression. The MAST study enrolled low-risk localized prostate cancer patients randomized 1:1 to receive either metformin (850 mg BID) or a placebo for three years to evaluate metformin’s impact on disease progression during active surveillance. Baseline characteristics were consistent between groups. Results confirmed that active surveillance remains the standard treatment for low-risk localized prostate cancer; metformin did not alter the progression rate during active surveillance. Exploratory analyses indicated higher progression rates in men with higher BMI treated with metformin and more high-grade disease compared to the placebo group. Further research is needed to explore metformin’s direct impact on tumor metabolism/microenvironment and systemic metabolism.

Impact of Self-Help Cognitive Behavioral Therapy (CBT) on Hot Flashes and Night Sweats (HFNS)

Studies have shown that up to 80% of prostate cancer patients undergoing ADT experience hot flashes and night sweats (HFNS), affecting quality of life and ADT adherence. HFNS is associated with sleep disturbances, anxiety, depression, and cognitive impairment, but prospective data on non-pharmacological interventions are lacking. The MANCAN2 trial, a multicenter randomized controlled trial, assigned patients (1:1) to standard care or standard care plus CBT. The CBT intervention consisted of a 4-week self-help program (booklet and relaxation audio) with group workshops conducted by the prostate CNS team before and after the intervention. Baseline characteristics were consistent between groups. MANCAN2 confirmed that a 4-week CBT intervention improved HFNS in prostate cancer patients undergoing ADT at week 6, along with reduced anxiety and depression, although these differences were not observed at six months. Further research is needed to address the persistence of CBT’s effects.

HRQOL Analysis of the PRESTO Study

Approximately 30% of localized prostate cancer patients experience biochemical recurrence after radical prostatectomy or radiotherapy, with androgen deprivation therapy (ADT) being the standard adjunct treatment. However, patients with short PSA doubling times face higher risks of distant metastasis and prostate cancer-specific death. This study included patients with post-surgical PSA ≥0.05 ng/mL and PSA doubling time ≤9 months, randomized to receive ADT (control group), ADT plus apalutamide (test group), or ADT plus apalutamide and abiraterone acetate with prednisone (test group). In men with biochemical recurrence after primary treatment, apalutamide-enhanced androgen blockade improved PSA-PFS compared to ADT alone without increasing SAE, prolonging testosterone recovery time, or increasing common treatment-related symptoms: hormonal symptoms, sexual function symptoms, hot flash interference, and fatigue. Triple androgen blockade did not further improve PSA-PFS but increased SAE, prolonged testosterone recovery time, and increased hot flash interference.

CHAARTED2 Study

While early ADT combined with docetaxel benefits mHSPC patients, most will progress. For mCRPC patients, should AR inhibitors like abiraterone be used alone or combined with chemotherapy? The CHAARTED2 study, a prospective phase II open-label randomized trial, enrolled patients with consistent baseline characteristics, with 40.4% presenting with synchronous metastases. Most domestic patients already had metastases at initial diagnosis, needing further improvement.

The study found that cabazitaxel combined with abiraterone significantly extended PFS by five months, improved PSA response, and delayed TTPP in mCRPC patients previously treated with docetaxel compared to abiraterone alone. However, there was no significant difference in OS between groups. Combined treatment had certain toxic side effects, with nearly 80% requiring dose adjustments (including cabazitaxel and abiraterone) after about six cycles. The introduction of dual and triple therapies in mCSPC influenced these results’ widespread application, limiting their clinical use.

Exploratory Analysis of the PSMAfore Study

The PSMAfore study demonstrated that 177Lu-PSMA-617 prolonged rPFS compared to androgen receptor pathway inhibitors (ARPI). This exploratory study analyzed baseline ctDNA characteristics and key prostate cancer drivers in samples with ctDNA scores >0.5% to evaluate the relationship between baseline ctDNA and treatment outcomes. Whole-population analysis showed that higher baseline ctDNA scores correlated with shorter median rPFS, making treatment more challenging. Regardless of baseline ctDNA scores, 177Lu-PSMA-617 significantly extended median rPFS. Patients with PSA and RECIST responses had lower ctDNA scores, and early ctDNA clearance correlated with longer rPFS, confirming ctDNA’s predictive value. Genomic analysis revealed that chromosomal 8q amplification, AR amplification, and TP53 deleterious mutations were associated with shorter rPFS and lower response rates in the 177Lu-PSMA-617 group. Future research should strengthen treatment or adopt multi-faceted approaches for these deleterious mutations and biomarkers to improve rPFS and response rates.

Relative Efficacy of First-Line Treatments for HRR Deficient mCRPC

PARP inhibitors combined with NHT have become a new first-line treatment option for mCRPC. The PROpel study showed that abiraterone plus olaparib achieved a median OS of 42.1 months, and talazoparib plus enzalutamide significantly improved rPFS. However, there is no head-to-head randomized controlled trial comparing these combination strategies, and their relative efficacy remains unknown. This study conducted a matched-adjusted indirect comparison of talazoparib plus enzalutamide versus olaparib plus abiraterone and prednisone/prednisolone for first-line treatment of mCRPC patients with HRR/BRCA mutations.

The indirect comparison showed that for HRR mutant populations, talazoparib plus enzalutamide had numerically superior rPFS and OS compared to olaparib plus abiraterone and prednisone/prednisolone, though results were not statistically significant. For BRCA mutant populations, talazoparib plus enzalutamide had numerically superior rPFS, while olaparib plus abiraterone and prednisone/prednisolone had superior OS, but results were not statistically significant. Differences between these treatment options warrant further exploration.

Dr. Fu Fu Zheng

Chief Physician, Doctoral Supervisor, Postdoctoral Cooperation Supervisor Department of Urology, The First Affiliated Hospital , Sun Yat-sen University Visiting Scholar, Massachusetts General Hospital, Harvard University International Member of the American Urological Association (AUA) Member of the Urogenital Branch of the China International Exchange and Promotion Association for Medical and Healthcare Deputy Group Leader of the Prostate Cancer Group of the Urology Branch of Guangdong Medical Association Member of the Urology Branch of Guangdong Medical Doctor Association Member of the Urogenital Oncology Committee of Guangdong Anti-Cancer Association Standing Committee Member of the Urology Branch of Guangdong Society of Integrated Chinese and Western Medicine Standing Committee Member of the Oncology Branch of the Guangdong Urological Association Executive Editor of the Journal of Urology (Electronic Edition) Reviewer for the Chinese Journal of Experimental Surgery