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 precision 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 the current challenges and directions in prostate cancer treatment, sharing insights into genomics, liquid biopsy, and new targeted therapy explorations presented at the ASCO conference.Research Directions in Prostate Cancer Treatment
In terms of prostate cancer screening and early diagnosis, both domestic and international teams have been actively exploring more accurate and feasible screening methods to achieve better early intervention outcomes. These research directions include:
- Identifying genetic variations associated with tumor development and treatment response through genomics.
- Monitoring and evaluating treatment response using liquid biopsies such as ctDNA and cfDNA.
- Integrating multiple treatment modalities (surgery, radiotherapy, drug therapy, etc.) to enhance treatment efficacy and survival rates.
- Discovering new targets related to the AR signaling pathway and prostate cancer proliferation and survival, and developing targeted therapy strategies.
- Exploring immunotherapy strategies like immune checkpoint inhibitors to enhance the immune system’s response to prostate cancer.
From the perspective of disease progression, surgeons may focus more on locally advanced and biochemical recurrence stages. Various studies (EMBARK, PRESTO, ARASTEP) have explored the efficacy of second-generation antiandrogen drugs and radiotherapy. Currently, salvage radiotherapy is a guideline-recommended treatment for biochemical recurrence patients, but there is no standardized drug therapy regimen. For oligometastatic prostate cancer, local surgical approaches are being explored on the basis of effective systemic therapy. For advanced prostate cancer, studies such as PSMAfore, MANCAN2, and research from The First Affiliated Hospital , Sun Yat-sen University are analyzing the optimal choices for first- and second-line treatments.
Genomics and Precision Medicine
For prostate cancer patients, PSMA-PET plays an essential role in risk assessment, treatment decision-making, prognosis, and follow-up. PSMA-PET is particularly useful in initial staging, risk assessment of biochemical recurrence after surgery or radiotherapy, and recent studies confirm its ability to identify patients who may benefit from 177Lu-PSMA-617 therapy.
The latest update of the 2024 NCCN guidelines (version 3) now clearly recommends NGS genetic testing for metastatic prostate cancer. Relevant genes identified include:
- Homologous recombination repair defect genes such as ATM, BARD1, BRCA1/2, CHEK1/2.
- PI3K/AKT pathway genes including PTEN, AKT1, CDKN2A, PI3CA.
- Tumor suppressor genes like RB1, TP53, PTEN.
- Immunotherapy targets such as MLH1, CDK12, MSI-High.
- AR pathway genes including AR, SPOP.
- Additionally, FGFR2/3 from bladder cancer pathways and EGFR from renal cancer pathways may also appear in prostate cancer.
Which prostate cancer patients should undergo genetic testing to better guide treatment and assess prognosis? Currently, genetic testing is believed to predict the response to AR-targeted therapy. BRCA2 mutations are associated with increased prostate cancer risk and poor prognosis, but these mutations can predict response to PARP inhibitors and platinum-based drugs. Patients with BRCA1/2, CDK12, and PALB2 mutations may be prioritized for PARP inhibitor therapy. SPOP gene mutations are associated with a good response to androgen receptor therapy, while PTEN, RB1, and TP53 mutations are linked to poor AR therapy outcomes. MMR mutations are associated with responses to immune checkpoint inhibitors. The detection results of cfDNA or ctDNA may be influenced by factors such as sample quality, tumor burden, and mutation frequency, requiring further exploration.
Liquid Biopsy Research
Several ctDNA studies were presented at this year’s ASCO. Summarizing these results reveals that baseline ctDNA scores are related to prognosis in the PSMAfore study, and early ctDNA clearance is associated with longer radiographic progression-free survival (rPFS). ctDNA scores can also predict rPFS for 177Lu-PSMA-617 treatment compared to cabazitaxel treatment. ctDNA testing is crucial and can screen most (but not all) patients. Future research should further explore ctDNA through prospective studies to optimize treatment strategies and ultimately improve patient outcomes.
New Targeted Therapy Explorations
JNJ-6420:
ASCO unveiled several exploratory studies on new targets. JNJ-6420 is an innovative radioactive ligand therapy targeting hK2 (encoded by the KLK2 gene), delivering high-energy short-range α-particle emitter 225Ac to prostate cancer cells expressing hK2. The study results indicate that JNJ-6420 can achieve deep and durable remission in mCRPC patients who have previously received ≥1 androgen receptor pathway inhibitor treatment. However, more than half of the patients experienced ≥ grade 3 treatment-related adverse events. Bispecific ADCs can provide more precise treatment and potentially avoid some side effects, warranting further exploration.
ARV-766:
Another study analyzed ARV-766, a novel, potent oral PROTAC androgen receptor degrader. The phase 1/2 dose-escalation study found that ARV-766 was well-tolerated in men with mCRPC who had progressed on prior NHA therapy, with substantial potential clinical activity in patients with AR LBD mutations.
Talazoparib:
Talazoparib, a bispecific T-cell engager immunotherapy, was evaluated for its efficacy in neuroendocrine prostate cancer (NEPC). The study found that talazoparib was well-tolerated, with significant antitumor activity in DLL3-expressing NEPC patients, a type of aggressive prostate cancer with poor prognosis and no standard treatment.
Bipolar Androgen Therapy:
Bipolar androgen therapy is a novel treatment method that rapidly cycles blood testosterone levels above normal (supraphysiologic) and then back to castration levels within a short period. The TRANSFORMER trial’s biomarker analysis confirmed that AR variants in ctDNA could help identify patients who benefit from bipolar androgen therapy.
CDK4/6 Inhibitors:
Previous studies indicated that CDK4/6 plays a key role in maintaining androgen receptor (AR) signaling, uncontrolled proliferation, and hormone resistance. The CYCLONE 2 study showed that while the CDK4/6 inhibitor abemaciclib demonstrated consistent safety with monotherapy, it did not significantly improve rPFS in mCRPC patients, nor did it significantly improve OS in secondary endpoints, requiring further exploration.
Combination Immunotherapy:
For prostate cancer patients, previous single-agent immunotherapy provided limited benefits. However, recent studies have shown that combination immunotherapy exhibits high antitumor activity in mCRPC patients. The NEPTUNES study analyzed the efficacy of different combination immunotherapy strategies in mCRPC patients. The results indicated that inflammatory infiltration could serve as a potential prospective predictive biomarker for analyzing previously treated mCRPC. Although nivolumab 1 mg/kg + ipilimumab 3 mg/kg was more toxic than nivolumab 3 mg/kg + ipilimumab 1 mg/kg, it showed better efficacy.
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
