Editor’s Note: Comprehensive and accurate assessment of prostate cancer metastasis and diagnosis is crucial for adjusting treatment plans and evaluating prognosis. With continuous advancements in diagnostic and therapeutic technologies, novel approaches such as radionuclide therapies are gaining increasing attention. Recently published findings on PSMA-targeted therapies have introduced new options for prostate cancer patients at various stages. From November 14 to 17, 2024, the 2024 Chinese Conference on Integrated Oncology (CCHIO), hosted by the Chinese Anti-Cancer Association, was held in Xi’an. After the event, Oncology Frontier invited Dr. Shaoli Song from Fudan University Shanghai Cancer Center to share her insights on the characteristics and latest developments of PSMA-targeted diagnostic and therapeutic strategies, as well as her outlook for the future.

Oncology Frontier: What are the characteristics of PSMA-targeted nuclear imaging techniques, and why are they widely used in prostate cancer management?

Dr. Shaoli Song: Prostate-specific membrane antigen (PSMA), also known as folate hydrolase I or glutamate carboxypeptidase II, is a type II transmembrane protein composed of 750 amino acids. Its primary function is hydrolyzing peptides in prostatic fluid, generating glutamate as part of the cell surface peptidase composition to ensure cell survival and promote proliferation. In prostate cancer, PSMA expression is 100–1000 times higher than in normal tissue. Studies have confirmed a direct correlation between PSMA expression and Gleason scores, as well as a positive association with aggressiveness. PSMA expression is particularly elevated in metastatic and castration-resistant prostate cancer (CRPC).

PSMA-targeted nuclear imaging techniques, such as PSMA PET/CT and PET/MR, are becoming increasingly valuable in the comprehensive management of prostate cancer diagnosis and treatment. Several international and domestic guidelines and consensus documents recommend PSMA PET imaging for early staging of prostate cancer, assessing intermediate- and high-risk cases, detecting biochemical recurrence, and evaluating therapeutic efficacy. With the approval of 177Lu-PSMA-617 in several countries and its application under priority review domestically, approval in China is anticipated by mid-2025. PSMA PET imaging will play a critical role in patient selection for radioligand therapy.

Oncology Frontier: Recent international conferences have unveiled research findings on 177Lu-PSMA therapy for mHSPC. What is the significance of these findings for improving outcomes in metastatic prostate cancer?

Dr. Shaoli Song: The results of the UpFrontPSMA study, presented at this year’s ESMO conference and simultaneously published in Lancet Oncology, marked a significant breakthrough. This study is the first randomized trial to demonstrate the benefits of 177Lu-PSMA-617 in mHSPC patients. The research compared sequential therapy with 177Lu-PSMA-617 and docetaxel versus docetaxel monotherapy in mHSPC patients. Results showed that the sequential therapy group achieved a significantly higher undetectable PSA rate at 48 weeks compared to the monotherapy group (41% vs. 16%, P=0.002). Additionally, the median PSA progression-free survival (PSA-PFS) was extended (30 months vs. 21 months, P=0.002), along with a longer median time to castration-resistant progression (20 months vs. 16 months, P=0.033).

This represents a groundbreaking advancement in the treatment of mHSPC. Furthermore, global phase III studies are currently underway, with Vice President Dingwei Ye and I serving as Lead PIs for the domestic studies. Based on outcomes observed at our hospital, most patients experienced disease alleviation and symptom improvement.

Oncology Frontier: From your clinical experience, what is the value of radionuclide therapies such as 177Lu and 225Ac for mCRPC patients?

Dr. Shaoli Song: Both 177Lu and 225Ac radionuclide therapies have shown promise in the management of mCRPC. 177Lu primarily emits beta radiation, which has moderate energy and a suitable action radius. In contrast, 225Ac emits alpha radiation with high energy but a shorter action radius. Sequential therapy studies combining these two therapies have yielded promising clinical results. The combination approach, often referred to as the “long spear and short cannon” strategy, is expected to deliver even greater benefits to patients.

In current clinical practice, 177Lu is more established. Data from the global phase III VISION study demonstrated that 177Lu-PSMA-617 combined with the best standard of care significantly improved overall survival (OS) and radiographic progression-free survival (rPFS) in PSMA-positive metastatic CRPC patients compared to standard care alone. OS was extended by four months, reducing the risk of death by 38% (HR: 0.62, 95% CI: 0.52–0.74). rPFS was extended by 5.3 months, reducing the risk of radiographic progression or death by 60% (HR: 0.40, 99.2% CI: 0.29–0.57).

In chemotherapy-naïve mCRPC patients, 177Lu-PSMA-617 also significantly extended rPFS compared to alternative endocrine therapy, doubling the median duration (12.02 months vs. 5.59 months, HR=0.43, 95% CI: 0.33–0.54) and reducing the risk of radiographic progression or death by 57%. Secondary endpoints showed that PSA50 response rates were more than twice as high in the treatment group (57.6% vs. 20.4%), and objective response rates (ORR) were over three times higher (50.7% vs. 14.9%). These findings offer new hope for mCRPC patients and significantly boost clinical confidence.

To my knowledge, there are currently no large-scale global multicenter studies on 225Ac-labeled PSMA. However, I anticipate that domestic research will soon align with international efforts, and we look forward to seeing the results.

Oncology Frontier: What further explorations will you and your team pursue regarding PSMA?

Dr. Shaoli Song: Our team is currently exploring 99mTc-PSMA SPECT/CT imaging, 18F-PSMA imaging, and 177Lu-PSMA therapies. In the future, we may also conduct expansion studies combining 177Lu-PSMA with novel endocrine therapies.

About Dr. Shaoli Song

Dr. Shaoli Song is the Director of the Department of Nuclear Medicine at Fudan University Shanghai Cancer Center and the Department of Nuclear Medicine at Shanghai Proton and Heavy Ion Hospital. She also serves as the Director of the Department of Nuclear Medicine at the Fujian/Xiamen campuses of Fudan University Shanghai Cancer Center and the Director of the Shanghai Molecular Imaging Probe Engineering Technology Research Center.

She is recognized as a Leading Talent in Shanghai, an Outstanding Technical Leader in Shanghai, and has been honored as Shanghai’s Most Beautiful Female Doctor. Professor Song is the Deputy Leader of the Tumor Imaging Group of the 12th Committee of the Nuclear Medicine Branch of the Chinese Medical Association, an Executive Director of the 10th Council of the Nuclear Medicine Physicians Branch of the Chinese Nuclear Society, and a Member of the Nuclear Medicine Physicians Branch of the Chinese Medical Doctor Association.

Additionally, she is the Chair of the Tumor Nuclear Medicine Committee of the Shanghai Anti-Cancer Association, Chair of the Experimental Nuclear Medicine and Radiopharmacy Committee of the Shanghai Nuclear Society, and Vice Chair of the 10th Nuclear Medicine Branch of the Shanghai Medical Association. Professor Song is an editorial board member for Nuclear Medicine and Molecular Imaging and Chinese Journal of Cancer, as well as Deputy Editor of Oncologic Imaging.

She has led six projects funded by the National Natural Science Foundation of China, published more than 116 papers in SCI-indexed journals, holds 15 patents, and has successfully commercialized five patents.