Editor's Note: Prostate cancer is one of the most common malignant tumors in the male urinary system, with over 110,000 new cases diagnosed annually in China. The bones are the primary site of metastasis for prostate cancer, leading to bone-related events (BREs) such as pathological fractures, spinal cord compression, and bone pain, which significantly impact patients' quality of life and long-term prognosis. Studies have shown that 60%-75% of prostate cancer patients with bone metastases experience severe bone pain at diagnosis, causing substantial disruption to their daily lives. Bone-related events, represented by bone pain, accompany the entire course of disease progression in prostate cancer bone metastasis patients, imposing a heavy economic burden on patients, families, and society. Urology Frontier has invited Dr. Shun Zhang from Medical School of Nanjing University Affiliated Nanjing Drum Tower Hospital to share insights on this topic.01
Urology Frontier:What are the key characteristics of prostate cancer patients with bone metastases? Could you share some typical cases from your clinical practice and their treatment strategies?
Dr. Shun Zhang:In clinical practice, I recall a case of an elderly patient with advanced prostate cancer who had multiple bone metastases and liver metastasis, with a Gleason score of 9. The patient presented with symptoms of spinal cord compression, causing sensory and motor issues in the right lower limb before hospitalization. Later, the patient experienced severe pain in the lower back, sacrum, and hip, which was not relieved by tramadol. We administered ADT (androgen deprivation therapy) combined with enzalutamide and denosumab. After six cycles of treatment, the patient’s PSA levels significantly decreased, pain was notably reduced, and follow-up bone scans showed reduced radiotracer uptake in the right shoulder joint. The patient tolerated the treatment well, with alkaline phosphatase and calcium levels remaining within the normal range, indicating stabilization of the disease. The patient continues to receive regular treatment under this regimen.
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Urology Frontier:How can we optimize the standardized management of prostate cancer bone metastases throughout the course of the disease?
Dr. Shun Zhang:With the introduction of new drugs, the survival period of clinically diagnosed prostate cancer patients has gradually extended. The average duration of ADT usage has exceeded five years and may be even longer. However, prolonged ADT leads to increased risk of fractures due to decreased bone mass and density, which significantly affects patients’ survival and quality of life. The 2010 Canadian Guidelines for Osteoporosis Diagnosis and Management indicate that patients at moderate risk of fracture (10%-20% risk of fracture within 10 years) who are receiving ADT should undergo bone protection therapy.
For patients with metastatic castration-resistant prostate cancer (mCRPC), bone metastasis treatment has become an integral part of comprehensive prostate cancer management, in addition to systemic anti-tumor therapy. A post-hoc analysis based on the COU-AA-302 study, published in European Urology in 2015, aimed to evaluate the impact of bone-targeted therapy (BTT) on chemotherapy-naïve mCRPC patients treated with abiraterone. The results showed that combining BTT significantly improved overall survival (OS) compared to patients who did not receive BTT (HR 0.75; P=0.01). It also significantly extended the time to ECOG performance status deterioration (HR 0.75; P<0.01) and the time to opioid use for cancer pain (HR 0.80; P=0.036).
Regarding the choice of bone-protective agents, commonly used drugs include denosumab and bisphosphonates. In a Phase III randomized controlled trial comparing denosumab and zoledronic acid in the treatment of mCRPC, denosumab significantly delayed the time to first skeletal-related event (20.7 months vs. 17.1 months, HR 0.82 [95% CI 0.71-0.95], P=0.008). Additionally, for patients who experienced skeletal-related events during bisphosphonate therapy, switching to denosumab significantly reduced the risk of subsequent skeletal-related events (HR 0.47 [95% CI 0.25-0.88], P=0.019). Denosumab is currently recommended as the first-line bone protection treatment in international guidelines.
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Urology Frontier:Do you believe that bone protection therapy is necessary for mHSPC patients with bone metastases?
Dr. Shun Zhang:In China, the proportion of newly diagnosed mHSPC patients is about 30%, with a five-year survival rate of just over 60%, significantly lower than that in developed countries. The mHSPC stage is a critical treatment window for delaying disease progression to metastatic castration-resistant prostate cancer. It deserves sufficient attention, and the adverse effects and economic burden caused by new combination therapies should also be closely monitored during patient follow-up. Currently, clinical assessments of disease progression primarily focus on changes in patient symptoms and PSA monitoring. It is recommended that asymptomatic patients and those with clinical improvement have their PSA levels monitored every 3-6 months, with appropriate imaging evaluations every six months. Prostate cancer patients undergoing endocrine therapy experience a 2%-3% annual decrease in bone density. For patients with bone metastases, it is crucial to improve survival through tumor treatment while ensuring a good quality of life.
A post-hoc analysis of the LATITUDE study involving 1,199 high-risk mHSPC patients indicated that patients who received bone protection agents had a longer time to skeletal-related events (SERs) compared to those who did not, regardless of whether they were in the abiraterone acetate plus prednisone group (difference of 7.8 months [95% CI, 4.2-11.3]) or the ADT group (difference of 9.3 months [95% CI, 5.2-13.3]).
Additionally, the long-term results of the STAMPEDE study also demonstrated that BMA (bone-modifying agent) therapy significantly reduced the fracture rate in M1-HSPC patients compared to those who did not receive BMA therapy (4.55% vs. 12.9%, P<0.0001). BMA therapy significantly reduced the fracture risk in M1-HSPC patients (HR=0.36 [95% CI, 0.22-0.57], P<0.0005). In contrast, it did not reduce the fracture risk in M0-HSPC patients (HR=0.67 [95% CI, 0.32-1.39], P=0.28). These findings further confirm the therapeutic benefits of BMA therapy in the mHSPC population.
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Urology Frontier:What insights do you have on managing bone protection-related adverse reactions?
Dr. Shun Zhang:Hypocalcemia and osteonecrosis of the jaw (ONJ) are among the most clinically concerning adverse reactions associated with bone protection agents. Hypocalcemia is a predictable adverse reaction because bone protection agents inhibit osteoclast function, directly lowering blood calcium levels. Therefore, it is essential to ensure that patients receive routine calcium supplementation before treatment to maintain normal blood calcium levels. Throughout the course of treatment, it is also necessary to monitor alkaline phosphatase levels and keep them as low as possible to prevent excessive calcium depletion.
Although the incidence of osteonecrosis of the jaw is only about 1%, it can cause significant clinical challenges. Most cases of osteonecrosis of the jaw can be avoided with proper management. Current evidence suggests that oral infections and invasive procedures are major risk factors for ONJ. Therefore, regular oral health assessments, maintaining good oral hygiene, routine dental check-ups and care, and prompt treatment of oral conditions before and during bone protection therapy can help reduce the risk of ONJ.
Dr. Shun Zhang
Associate Chief Physician, Doctor of Medicine Department of Urology, Medical School of Nanjing University Affiliated Nanjing Drum Tower Hospital Member of the Translational Collaboration Group, Chinese Medical Doctor Association Urology Physician Branch Youth Member, Chinese Society of Gerontology and Geriatrics Specializes in chemotherapy, immunotherapy, targeted therapy, and comprehensive management of urinary system tumors Responsible for over 40 clinical trials in urology Well-versed in the latest developments in various international cutting-edge drugs
