Consensus on safety management of novel hormonal therapy for advanced prostate cancer

Abstract

Prostate cancer (PCa) is one of the most prevalent malignant tumors in men, accompanied by high incidence and mortality rates. Novel hormonal therapy (NHT) has emerged as the primary treatment for advanced PCa, providing noticeable clinical benefits. However, the diverse range of adverse events (AEs) associated with NHT may influence both treatment efficacy and patients' quality of life. In light of the latest international clinical research evidence and recommendations from domestic and foreign guidelines, this consensus aims to provide a comprehensive overview of the common AEs experienced during NHT for advanced PCa patients. Additionally, it seeks to develop a hierarchical approach to more efficiently manage AEs, presenting valuable insights for clinical medication and adverse reaction management.

Graphical abstract

Keywords

adverse event / novel hormonal therapy / prostate cancer / safety management

1 PART I: UNMET TREATMENT NEEDS

1.1 Epidemiology of prostate cancer

Prostate cancer (PCa) is the most common malignant tumor in the male urogenital system, and it was the second most common cancer type and the fifth leading cause of cancer death among men in 2020[1]. At present, the incidence and mortality rates of PCa continue to rise. In the United States, there were 268 490 new cases of PCa and 34 500 new deaths in 2022[2].

There is a noticeable variation across Asian countries in the incidence and characteristics of diagnosed PCa[3]. The incidence is also remarkably diverse among different Asian countries, along with the highest incidence in Western Asian countries and the lowest incidence in South-Central Asian countries[3]. The mortality/incidence ratio also ranged from less than 10% in Israel to more than 60% in India, Indonesia, Vietnam, and so on[3]. Positive correlations were reported in disease incidence with gross domestic product (GDP) and human development index (HDI)[4]. However, the mortality rate is inversely related to GDP and HDI[4], which can explain the observed difference in mortality/incidence ratio in different countries. In recent years, there has been a noticeable increase in the average annual percentage change (AAPC) of 5 and above in Japan, Korea, China, and Kuwait. Conversely, the AAPC for Israel, the Philippines, and Bahrain has decreased[4]. While the mortality rate of PCa has shown a downward trend in most countries, it is worth noting that both Philippines and Thailand experienced an increase in mortality rate[4].

In addition to the variations in incidence and mortality rates among different Asian countries, it is important to recognize that the presentation of PCa can also differ in these countries. While there is no national screening program for PCa in Asian countries, more developed countries and regions, such as Japan and Chinese Taiwan have reported an increase in the number of PCa patients diagnosed through prostate-specific antigen (PSA) testing, leading to identification of more early-stage PCa patients. However, in other countries (e.g., Malaysia and Jordan), the proportion of patients presented with metastatic disease ranged from 49% to 70%[5]. Nevertheless, even in Singapore, as a highly developed country, approximately 30% of patients are still diagnosed with stage IV disease. Therefore, there is a large proportion of PCa patients requiring the utilization of androgen deprivation therapy (ADT) or other systemic therapies for disease management.

1.2 Changing trend of hormone therapy

PCa is a tumor that depends on androgens for growth, and ADT has become the standard treatment for advanced PCa. ADT can be classified into two categories, including castration therapy and antiandrogenic therapy, based on its mechanism of action and target[6]. Traditional ADT regulates patients' androgen levels by blocking the hypothalamic gonadotropin-releasing hormone pathway or its receptor pathway through surgical or medical castration, while antiandrogens exert antitumor effects by competitively inhibiting testosterone binding to the androgen receptor (AR)[7–11]. With the emergence of resistance to traditional ADT in PCa, novel hormonal therapy (NHT) was introduced. The NHT includes apalutamide[12], enzalutamide[13], darolutamide[14], rezvilutamide[15], and abiraterone[16], etc. The classification and pharmacokinetic characteristics of these therapies are presented in Table 1. The NHT effectively targets multiple steps in the AR signaling pathway. It functions by blocking the translocation of AR from the cytoplasm to the nucleus and inhibiting the transcription of AR binding to DNA[6]. Abiraterone, an androgen synthetic inhibitor, inhibits the development of PCa by blocking androgen synthesis via inhibition of the CYP17 enzyme[17]. To date, NHT has gained approval for multiple stages of PCa. According to the results of the TITAN and SPARTAN clinical studies, apalutamide has demonstrated significant improvements in overall survival (OS) and radiographic progression-free survival among PCa patients. As a result, apalutamide was approved for the treatment of metastatic hormone-sensitive PCa (mHSPC) and nonmetastatic castration-resistant PCa (nmCRPC) patients[18,19]. Table 2 presents other important clinical studies on NHT. The results of these studies have confirmed NHT as the fundamental approach in the management of advanced PCa.

1.3 Overview of NHT-induced AEs

There is a significant difference in the incidence of associated adverse events (AEs) among different NHT regimens. AEs induced by AR inhibitors, such as apalutamide and enzalutamide, are primarily associated with reduced androgen levels, resulting in symptoms, such as fatigue, fracture, and fall[18,19]. Abiraterone acts as an inhibitor of CYP17 enzyme, which can lead to the development of metabolism-related AEs, including hypokalemia, hypertension, and edema[26–30]. The consensus is to identify AEs during NHT or early clinical studies by considering several criteria. These criteria include AEs with an incidence rate of 10% or higher, AEs that are of special interest in clinical research, and AEs that have a significant impact on patients' quality of life (QoL). Further details are presented in Table 3. According to the type of AEs, they can be categorized into symptomatic AEs, which include central nervous system (CNS)-related AEs, skin AEs, cardiovascular AEs, fatigue, edema, fractures, and so on, and laboratory abnormality-related AEs, which encompass hematological AEs, liver and kidney dysfunction, glucose metabolism disorder, and so on. The probability of experiencing AEs during NHT in PCa patients is noticeable, and improper management easily affects antitumor efficacy and patients' QoL. Therefore, systematic consensus on AE management is vital to guide the clinical application of NHT.

1.4 AEs during NHT affect therapeutic efficacy and patients' QoL

Although NHT is highly effective for PCa, the incidence of AEs during clinical treatment still significantly impacts patients' QoL and therapeutic efficacy. In real-world studies, 46% of patients experienced AEs of any grade during NHT, and 38% of patients experienced CNS-related AEs. Any AEs and CNS-related AEs increased the risk of discontinuing NHT by 48% and 38%, respectively[40]. The SPARTAN study revealed that 33% of patients discontinued NHT due to AEs, while the PROSPER study reported a discontinuation rate of 9.4% due to AEs. These findings emphasize the negative influence of reduced therapy compliance on patients' OS[19,21,41]. In addition, AEs, such as fatigue, pain, and fracture that may be experienced during apalutamide treatment have a significant impact on patients' QoL. It has been reported that 96% of patients developed pain of varying degrees during the first year of NHT, in turn affecting their mood, sleep, and daily activities[42]. Abiraterone treatment significantly increases the risk of hospitalization due to liver injury, atrial fibrillation, and other AEs[43]. The incidence of NHT-related AEs is high, and severe events may result in treatment discontinuation and patients' hospitalization, thereby influencing the safety and effectiveness of NHT. At present, there is a lack of consensus on the systematic management of AEs, hindering clinicians from selecting safe and effective NHT based on each patient's condition.

Therefore, this consensus will systematically review NHT-related AEs based on the results of key clinical trials of both currently marketed and ongoing NHT, as well as domestic and international guidelines. Regarding the prevention and management of complications and patient care during NHT, this consensus aims to provide comprehensive recommendations for the prevention and treatment of NHT-related AEs. These recommendations may assist clinical doctors and patients in better managing AEs that occur during NHT, thereby enhancing patients' treatment compliance and medication safety. Moreover, they may improve patients' survival and QoL. Ultimately, this consensus may contribute to the development of safe and effective NHT strategies for PCa patients.

2 PART II: MANAGEMENT STRATEGY

2.1 Symptomatic AEs

NHT-related AEs can be divided into five grades according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0[44], as shown in Table 4.

The primary concern in NHT-related AEs is the occurrence of both symptomatic AEs and laboratory abnormality-related AEs. These symptomatic AEs primarily involve CNS-related complications (e.g., seizures, convulsions, cognitive/memory impairment, etc.), skin-related AEs (e.g., rash, pruritus, etc.), and cardiovascular AEs, such as hypertension, ischemic heart disease (IHD), heart failure (HF), and so on. Notably, AEs are mainly drug-related and can be effectively managed by dose reduction, discontinuation of administration, or supportive care. The criteria used to select AEs in this consensus are as follows: AEs that have an incidence rate of 10% or higher, or those that are of particular interest in the trial, or those that have a significant impact on patients' QoL.

2.1.1 CNS-related AEs

Incidence and mechanism of CNS-related AEs

CNS-related AEs include seizure and cognitive impairment. Table 5 summarizes the rates for all grades of CNS-related AEs based on findings from the landmark studies, in which the incidence of seizure ranges from 0.2% to 1.0%, and the incidence of cognitive impairment ranges from 0.4% to 5.0%. Notably, NHT can penetrate the blood–brain barrier to inhibit γ-aminobutyric acid-chloride channels, affect CNS, lower seizure threshold, and it can also cause seizure by inhibiting GABA_A receptors, leading to off-target effects[45,46]. In addition to seizure, cognitive impairment is also a common CNS-related AE during NHT. NHT suppresses androgen levels in patients, which in turn affects normal hippocampal function and leads to cognitive impairment[47].

Grading and management of CNS-related AEs

CNS-related AEs can be graded based on CTCAE (version 5.0), and they are presented in Supporting Information: Table 1[44]. Patients who are at high risk should be identified before NHT. This includes cases with a history of anticonvulsant usage, brain injury, epilepsy, or any relevant diseases. The management of NHT-induced seizure includes two aspects. First, the seizure grade should be assessed. For grade 1–2 seizures, lamotrigine is recommended, while levetiracetam and topiramate are recommended for grade ≥3 new-onset seizures[48]. When monitoring levels of drugs in the bloodstream, it is advisable to slowly raise the dosage of antiseizure medications in order to sustain a reduced effective amount[49]. Second, lifestyle interventions, such as smoking cessation, alcohol withdrawal, and adopting a bland diet, have also been found effective in reducing the incidence of seizures. Grade 1 cognitive impairment induced by NHT is mild and it does not require intervention, while cognitive impairment at grade 2 or above requires professional care and medication, including CNS stimulants (e.g., methylphenidate) and memory impairment drugs (e.g., donepezil)[50]. Appropriate vitamin and mineral supplementation during NHT may assist in preserving cognitive function[51]. Although the probability of CNS-related AEs induced by NHT is low, it is prone to induce CNS-related lesions. The utilization of NHT should be immediately terminated in the event of a seizure, and patients' conditions should be continuously monitored throughout subsequent treatment[13].

2.1.2 Skin-related AEs

Incidence and mechanism of skin-related AEs

Rash is a common skin-related AE, and Table 6 summarizes the rates for all grades of skin-related AEs based on findings from the landmark studies, in which the incidence of rash ranges from 2.6% to 29.2%. The mechanism of rash primarily involves humoral immune-mediated type IV hypersensitivity, encompassing the reaction of secondary metabolites of apalutamide with cysteine. This reaction leads to the generation of thiazolidine products that trigger immune reactions, ultimately resulting in the development of rash[52,53]. In addition to allergy-mediated AEs, there may also be skin-related AEs that are mediated by nonallergic mechanisms, such as drug-related AEs and dysbacteriosis[54]. The skin-related AEs induced by NHT are mostly mild, while neglecting or handling them improperly may exacerbate skin reactions, leading to the interruption and discontinuation of NHT, which in turn affects the antitumor efficacy. Therefore, it is essential to manage the skin-related AEs appropriately[54].

Grading and management of skin-related AEs

From a clinical vantage point, rashes can be classified into two primary categories: ordinary drug-induced rashes and severe drug-induced rashes. The clinical presentations of the common rash exhibit a broad spectrum and can be organized into various subtypes, encompassing measles-, scarlet fever-, and urticaria-like presentations. Severe rash refers to the following four types: Stevens–Johnson syndrome/toxic epidermal necrolysis, drug reactions with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, and exfoliative dermatitis/erythroderma. These can be diagnosed and classified based on morphological manifestations, histopathological examination, and systemic reactions[55,56].

Grading and management of common rash.

A common rash typically presents with localized pruritus, redness, and other symptoms that are limited to the surface of the skin, without any accompanying systemic manifestations[56]. It can be graded based on the extent of body surface area (BSA) involvement and clinical manifestations. Figure 1 presents further details related to grading criteria and corresponding treatment approaches[18,57].

Research has shown that in patients who develop a rash and require to hold NHT, the NHT can be resumed at a reduced dose when the rash recovers to grade 1 or below. However, if the patient develops a rash that requires a dose reduction for the second time, NHT should be immediately discontinued[18]. Healthcare professionals should educate patients about rash before undergoing NHT, enabling them to understand potential skin-related AEs during NHT. Measures, such as moisturizers and sunscreens, are taken to prevent and minimize the influences of skin-related AEs on cancer therapy, thereby improving patients' QoL.

Identification and management of severe rash.

Severe rash involves the skin and is accompanied by systemic reactions, such as cough, fever, myalgia, and so on. It can be categorized based on the following criteria: (1) signs: fever, or heart rate >120/min; (2) skin abnormalities: mucosal involvement (periocular, oral, perineal), skin pain, desquamation, blister-like; (3) important abnormalities in laboratory indicators: white blood cells, eosinophils, increased lymphocytes, serum urea nitrogen level >10 mmol/L, serum glucose level >14 mmol/L, serum bicarbonate level <20 mmol/L, alanine aminotransferase (ALT) level > 100 U/L or other organ damage[55]. Patients displaying a severe rash require prompt evaluation of its intensity and immediate referral to a dermatologist. If deemed essential, administration of intravenous glucocorticoids or intravenous human immunoglobulin should be initiated. Additionally, in cases where it is warranted, the implementation of plasma exchange can be considered as a means to eliminate residual drugs and inflammatory agents from the body. If patients' conditions are unstable and multiple organ damage occurs, it is necessary to cooperate with multidisciplinary consultation for diagnosis and treatment[55].

Management principles for rash

The management pathway for rash is illustrated in Figure 2. The overarching principles for managing rash are outlined below:

Before NHT, patients should be educated on preventive measures, including avoiding allergens, using gentle cleansers, moisturizers, and sunscreen for skincare, as well as preventing excessive heat during bathing. Patients should also be educated to report and seek timely medical attention from urologists or dermatologists if they experience rash, pruritus, or other symptoms during NHT.

At the time of prescription, it is important to identify patients who are at a high risk of developing skin rash and provide prolonged follow-up. High-risk characteristics include a history of allergies, illnesses (e.g., autoimmune diseases, dermatitis, diabetes, and thyroid dysfunction), and lifestyle factors, such as smoking and alcohol consumption. High-risk patients should receive an additional 1-month follow-up after NHT, including assessment of body signs, skin, and mucosa, as well as blood and organ function tests.

If patients develop a rash during NHT, it is important to promptly identify those patients with severe rash and refer them to clinics for treatment. Treatment for common rash should be based on the affected BSA and symptoms. Patients who have temporarily held NHT should be reassessed after a period of 2 weeks. In case of improving the rash to grade 1 or returning to baseline, NHT can be resumed with a reduced dose. However, in case of no improvement in the rash, it is advisable to consult with a dermatologist[57].

2.1.3 Cardiovascular AEs

Incidence and mechanism of cardiovascular AEs

The cardiovascular AEs induced by NHT are predominantly characterized by hypertension. Table 7 summarizes the rates for all grades of cardiovascular AEs based on findings from the landmark studies, in which the incidence of hypertension ranges from 6.4% to 24.8%, the incidence of IHD ranges from 1.7% to 4.0%, and the incidence of HF ranges from 1.9% to 2.6%. NHT affects the follicle-stimulating hormone level, thereby increasing the risk of cardiovascular complications. Abiraterone, through the inhibition of CYP17 enzyme, leads to elevated levels of mineralocorticoids, resulting in conditions, such as hypertension[58–61].

Grading and management of cardiovascular AEs

The most common AEs caused by NHT are related to the cardiovascular system, with hypertension being the most prevalent. Hypertension can be graded based on CTCAE (version 5.0) and they are presented in Supporting Information: Table 2[44].

The first-line treatment for hypertension should include angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and other related medications. High-risk patients should initiate treatment at grade 1 hypertension, while those with normal risk can commence treatment at grade 2 hypertension, in order to reach a target blood pressure of <130/89mmHg[62,63]. The selection of antihypertensive medications should be based on individual patient risk factors. For instance, patients with proteinuria are eligible for receiving angiotensin receptor blockers, while diuretics should be avoided[64]. In addition, caution should be exercised when patients receive nondihydropyridine calcium channel blockers, as they may interact with P-glycoprotein and CYP3A4 enzymes[65]. In addition, decreasing salt intake and moderating coffee consumption can contribute to lowering the likelihood of developing hypertension[63].

Cardiovascular AEs frequently occur in elderly patients; therefore, it is advisable to establish a multidisciplinary cardiac oncology treatment team before NHT to optimize individualized drug administration. Continued monitoring of hypertension and cardiovascular AEs in target organs is also recommended[63].

2.1.4 Fatigue

Incidence and mechanism of fatigue

Fatigue is the most common symptom among cancer patients. Table 8 summarizes the rates for all grades of fatigue based on findings from the landmarks studies, and incidence of fatigue ranges from 10.0% to 39.0%[66]. The underlying mechanism of fatigue induced by NHT is associated with mitochondrial dysfunction. NHT may lead to a decrease in red blood cell count and the development of anemia in patients, thereby increasing the incidence of fatigue[67–69].

Grading and management of fatigue

Cancer-related fatigue (CRF) is mainly overlooked by healthcare professionals and patients due to inadequate assessment. It is recommended to conduct CRF assessment during the initial visit of cancer patients, and CRF can be graded based on CTCAE (version 5.0) and are presented in Supporting Information: Table 3[44,70].

The consensus recommends the use of visual analog scale (VAS) score or numerical rating scale (NRS) score for preliminary assessment of patients to determine the degree of fatigue[71]. For patients with VAS/NRS scores < 4 points, nonpharmacological treatment can be implemented, including low-to-moderate intensity exercises, such as walking and yoga, as well as providing psychosocial interventions (e.g., emotional support and stress management). For patients with VAS/NRS scores ≥4 points, pharmacological treatment can be added to top of nonpharmacological treatment, including the utilization of psychostimulants (e.g., methylphenidate) and herbal treatments (e.g., Astragalus polysaccharide injection and ginseng)[72]. In addition to acupuncture, massage, and aromatherapy, patients should prioritize getting enough sleep and improving their nutrition management to effectively alleviate fatigue.

During treatment, it is important to manage CRF and promptly monitor and address CRF, in order to minimize its impact on treatment efficacy and patients' QoL[71].

2.1.5 Edema

Incidence and mechanism of edema

Edema induced by NHT includes generalized and peripheral edema. Table 9 summarizes the rates for all grades of edema based on findings from the landmark studies, in which the incidence of edema ranges from 11.0% to 27.0%. The high occurrence of edema in PCa patients treated with abiraterone is mainly caused by the inhibition of the CYP17 enzyme by abiraterone. This inhibition causes an elevation in adrenocorticotropic hormone levels, which in turn leads to an excess of mineralocorticoids. This results in the retention of water and sodium, leading to the development of generalized or peripheral edema in patients[73,74].

Grading and management of edema

The incidence of edema is relatively high during NHT. It is recommended to measure patients' limb circumference before treatment, as it can help assess the symptoms of edema[75]. Edema can be graded based on CTCAE (version 50), and they are presented in Supporting Information: Table 4[44].

For mild edema (grades 1 and 2), lifestyle modifications, such as wearing compression stockings, receiving local massage, or engaging in stretching exercises are recommended. If edema persists and worsens, treatment with diuretics and adjustment of the dose of NHT may be necessary. Once the edema resolves, NHT can be resumed at a reduced dose. It is important for patients experiencing edema to reduce their physical activity, avoid fatigue, wear comfortable clothes, and control their intake of sodium and water[76]. NHT-induced edema is often generalized and commonly accompanied by facial or limb swelling, which is different from renal or malnutrition-related edema[76]. During NHT, it is necessary to continuously monitor limb edema. When there is a 5%–10% change in limb circumference, continuous monitoring is advised. If there is a perimeter change exceeding 10%, immediate initiation of compression therapy is recommended. It is also important to follow-up on any changes in patients' limbs[76].

2.1.6 Bone-related AEs

Incidence and mechanism of bone-related AEs

NHT significantly increases the risk of patients' bone-related AEs, including bone pain, fracture, fall, and osteoporosis[77]. Table 10 summarizes the rates for all grades of bone-related AEs based on findings from the landmark studies. Incidence of bone pain ranges from 6.5% to 20.0%, incidence of fracture ranges from 3.7% to 15.6%, and incidence of fall ranges from 4.2% to 11.7%. Bone pain is associated with the metastasis of PCa. Once bone metastasis forms, tumor cell growth causes progressive bone damage, in which the inflammatory cells recruited to the metastatic lesions release various inflammatory mediators, such as endothelin, kinins, and interleukin-6, and pain is generated by the activation of sensory nerve endings innervated by the nervous system[78,79]. The mechanism by which NHT causes osteoporosis, fall, and fracture may be related to the reduction of serum testosterone level, which accelerates bone turnover leading to bone loss and microstructural damage. This increases the risk of fall and fracture in patients and affects treatment efficacy and patients' QoL[80].

Grading and management of bone-related AEs

Bone-related AEs can be graded based on CTCAE (version 5.0), and they are presented in Supporting Information: Table 5[44]. Due to the high risk of bone-related AEs during NHT, high-risk patients should be identified before treatment, and skeletal-related parameters should be closely monitored during treatment[81]. Management of osteoporosis can be divided into nonmedical and medical management strategies[82,83]: (1) nonmedical management strategies are summarized as follows: first, ensuring sufficient calcium intake through diet and supplements (≥1200 mg daily) and supplementing with vitamin D3 (800–2000 U daily), especially for patients receiving bisphosphonates and denosumab; second, maintaining healthy lifestyle habits, including reasonable sun exposure, quitting smoking, and limiting alcohol consumption; finally, maintain exercising. (2) Medical management strategies are summarized as follows: first, supplementation with bone-targeting agents, denosumab, and bisphosphonates has shown to improve bone mineral density and reduce the incidence of osteoporosis when bone mineral density (BMD) t-score is <−2.5 (denosumab: 60 mg every 6 months; alendronate: 10 mg daily orally or 70 mg orally weekly); second, BMD testing is performed at least every 2 years to monitor bone health and prevent the risk of fracture. When the fracture is grades 1 and 2, no treatment or fixation may be required; when the fracture is ≥grade 3, surgical treatment should be immediately conducted. Multiple factor-induced bone pain exists during NHT and is managed accordingly for different pain mechanisms to achieve optimal bone pain relief. Nonsteroidal anti-inflammatory drugs, such as paracetamol and aspirin, can be selected for mild pain (grade 1); weak opioids, such as codeine, can be added to nonsteroidal anti-inflammatory drugs for moderate pain (grade 2); and oral morphine can be utilized for severe pain (grade 3). Radiotherapy and bone-targeting agents may also be applied to relieve bone pain[84,85].

Bone-related AEs have a significant impact on patients' QoL and treatment adherence. Therefore, it is crucial to regularly follow-up patients during treatment to promptly evaluate the effectiveness of the drug, assess any AEs, and ensure treatment compliance[86].

2.1.7 Urinary retention

Incidence and mechanism of urinary retention

Patients are prone to acute urinary retention (AUR) disease. Table 11 summarizes the rates for all grades of urinary retention based on findings from the landmark studies, and the incidence of urinary retention ranges from 2.0% to 3.5%. AUR is caused by processes linked to lower levels of androgens, which have shown to control urinary function in men. It is noteworthy that NHT can potentially induce bladder outlet obstruction, consequently leading to AUR[87]. Consensus is urgently required to manage NHT-related lower urinary tract symptoms and reduce the risk of AUR in patients.

Grading and management of urinary retention

Urinary retention can be graded based on CTCAE (version 50), and they are presented in Supporting Information: Table 6[44]. Patients experiencing AUR are diagnosed based on postvoid ultrasound results, indicating an elevated residual urine volume. Specifically, a residual urine volume equal to or greater than 50 mL is considered abnormal[88]. For patients with mild urinary retention (grade 1), urethral catheterization and medication treatment are unnecessary. Rectal stimulation with suppositories can be used to stimulate bladder contraction and promote urination. For moderate-to-severe urinary retention (grades 2 and 3), urethral catheterization is the preferred option. Alternatively, suprapubic bladder puncture and trial catheter removal can be considered. Combination treatment with an α-1 adrenergic receptor blocker (e.g., doxazosin) can increase the success rate[89,90]. Surgical intervention is necessary for patients experiencing grade 4 or higher severe urinary retention, in order to effectively prevent the long-term recurrence of AUR[89]. In addition to the aforementioned treatments, nonpharmacological interventions, such as bladder training, intermittent self-catheterization, and pelvic floor rehabilitation can also be employed to alleviate AUR symptoms[88]. Simultaneously, collaborative assessment of AUR symptoms is conducted by departments, such as Rehabilitation Medicine and Traditional Chinese Medicine, in order to implement targeted treatments.

2.2 Laboratory abnormalities

Laboratory abnormality-related AEs mainly include hematological AEs, metabolism-related AEs, and hepatic and renal-related AEs. The impact of laboratory abnormality-related AEs may be overlooked as mild abnormalities are mainly unrelated to symptoms. However, some abnormalities may worsen and lead to symptoms that affect patients' QoL. Therefore, timely identification and intervention for laboratory abnormal-related AEs are urgently needed.

2.2.1 Hematological AEs

Incidence and mechanism of hematological AEs

Hematological AEs are relatively common after undergoing NHT. Table 12 summarizes the rates for all grades of hematological AEs based on findings from the landmark studies. Most AEs are typically mild in nature and do not necessitate any adjustments to the dosage. The incidence of anemia ranges from 1.0% to 70.0%, while the incidence of leukopenia ranges from 27.0% to 47.0%. Neutropenia rate ranges from 0.9% to 33.7%, whereas febrile neutropenia is infrequent, ranging from 7.0% to 7.8%. The incidence of thrombocytopenia is 1.0%–6.0%. A decrease in androgen level induced by NHT has been proposed as a potential mechanism for hematological AEs, as androgens play a crucial role in stimulating erythropoiesis. Consequently, NHT may result in anemia, although there are limited reports on the impact of NHT on platelets[91,92].

Grading and management of hematological AEs

Hematological AEs can be graded based on CTCAE (ver. 5.0), and they are presented in Supporting Information: Table 7[44]. Most of the mild hematological AEs do not require any treatment. It is recommended to assess the baseline blood cell count level of the patient before starting NHT. For patients with anemia at baseline, further examination is recommended to determine the cause of anemia. Some patients may have anemia of chronic disease, while others may have iron-deficiency anemia. Investigations on iron metabolism are recommended for patients with iron-deficiency anemia. Iron preparations are recommended for patients with hemoglobin (Hb) ≤ 11 g/dL and laboratory test results are suggestive of iron deficiency. In addition, patients with a deficiency of vitamin B12 and folic acid should receive appropriate nutritional supplements[93]. For patients with Hb < 7 g/dL and/or severe anemia symptoms who require immediate improvement of Hb level and symptoms, red blood cell infusion is recommended[93]. The role of erythropoietin-stimulating agents (ESAs) in patients with anemia secondary to cancer treatment remains controversial. ESAs may be considered for patients with Hb < 10 g/dL with anemia symptoms, or Hb < 8 g/dL without anemia symptoms. However, the majority of anemias experienced during NHT are typically not severe[93].

Grade 1–2 neutropenia does not necessitate any unique care except for regular follow-up. On the other hand, grade 3–4 neutropenia and febrile neutropenia are very infrequent with NHT. Granulocyte colony-stimulating factor therapy is seldom recommended during this treatment[94,95].

2.2.2 Metabolism-related AEs

Incidence and mechanism of metabolism-related AEs

Weight gain is a significant metabolic alteration induced by NHT. Table 13 summarizes the rates for all grades of metabolism-related AEs based on findings from the landmark studies. The incidence of hypertriglyceridemia ranges from 17.0% to 67.0%, the incidence of hypercholesterolemia ranges from 19.0% to 76.0%, and the incidence of hyperglycemia ranges from 2.8% to 70.0%. Various metabolic pathways are excessively activated in PCa cells, leading to the progression of PCa[96]. Patients undergoing ADT may experience a reduction in steroid biosynthesis, ketone body production, and fatty acid metabolism[97]. Metabolism-related AEs may lead to a broad spectrum of medical concerns, increasing the risk of emergency visits and hospitalizations, and they may remarkably affect patients' QoL[98].

Grading and management of metabolism-related AEs

Metabolism-related AEs can be graded based on CTCAE (ver. 5.0), and they are presented in Supporting Information: Table 8[44]. The management of metabolism-related AEs includes the following items: (1) physical examination of patients, including assessment of weight, waist circumference, and body mass index (BMI), as well as performing laboratory tests to measure blood pressure, fasting glucose level, and lipids; (2) screening for diabetes mellitus; (3) metabolic assessments should be conducted every 6–12 months during the treatment period; (4) patients should follow a diet and exercise protocol, which should involve consuming a diet rich in fruits, vegetables, fish, seafood, and other nutritional food products, as well as engaging in aerobic exercises (e.g., swimming and ball sports)[82,99].

2.2.3 Hepatorenal-related AEs

Incidence and mechanism of hepatorenal-related AEs

Drug-induced liver injury is primarily characterized by increased levels of serum transaminases, alkaline phosphatase, and total bilirubin. Table 14 summarizes the rates for all grades of hepatorenal-related AEs based on findings from the landmark studies. Incidence rates of hepatorenal-related AEs with the increase of AST, ALT, and bilirubin are in the ranges of 2.6%–37.0%, 2.8%–42.0%, and 2.0%–16.0%, respectively. Renal AEs were infrequent and proteinuria was only reported in the study with rezvilutamide, the incidence rate in the phase I/II clinical trial was 13.7%, while it was 8.0% in the phase III clinical trial[25,100]. The mechanisms underlying liver injury induced by NHT may involve direct hepatotoxicity, idiosyncratic hepatotoxicity, and indirect hepatotoxic effects of the drug[101,102]. NHT hinders the relaxing effect of testosterone on renal vessels and disrupts glomerular function, leading to renal injury[103,104].

Grading and management of hepatorenal-related AEs

Hepatorenal-related AEs can be graded based on CTCAE (ver. 5.0), and they are presented in Supporting Information: Table 9[44]. The management of liver injury induced by NHT is summarized as follows: (1) the risk of disease progression after discontinuation and exacerbation of liver injury from continued medication should be carefully considered; (2) if the patient meets the criteria for discontinuation, the medication causing liver injury should be promptly discontinued to avoid the re-administration of suspected or similar drugs (the following criteria for discontinuation are outlined: (1) serum ALT or AST >8× upper limit of normal (ULN) value; (2) ALT or AST >5× ULN value for 2 weeks; (3) ALT or AST >3× ULN value, and total bilirubin >2ULN or international normalized ratio >1.5; (4) ALT or AST >3× ULN value, with fatigue and gastrointestinal symptoms gradually aggravated, and/or eosinophilia (> 5%); (3) selecting appropriate drug treatment (e.g., magnesium isoglycyrrhizinate, silymarin, etc.) based on the clinical type of drug-induced liver injury[101]; (4) if liver injury-related AEs improve to grade 1 or return to the pre-existing grade before the administration of NHT, the NHT can be resumed at either the original dose or a reduced dose; (5) in case of occurrence of grade ≥3 AEs or intolerable AEs when the dose is reduced, the treatment should be permanently discontinued[14,15].

Dose adjustments for the administration of NHT in patients with hepatic and renal dysfunction are variable and are outlined in Table 15.

2.3 Other AEs and special patient management

Other AEs associated with NHT include hot flushes, nausea, and vomiting. The selection criteria for these AEs are based on their high incidence or significant impact on patients' QoL during ADT and NHT.

2.3.1 Hot flushes

Incidence and mechanism of hot flushes

The duration of NHT is positively correlated with the incidence of hot flushes[105]. Table 16 summarizes the rates for hot flushes based on findings from the landmarks studies. The incidence of hot flushes ranges from 5.2% to 27.1%. Studies have demonstrated that the development of hot flushes is attributed to the elevated central norepinephrine level. This mechanism may be the result of decreased estrogen level, reduced endorphin activity, and diminished inhibition of norepinephrine, leading to the increased norepinephrine level and stimulation of gonadotropin-releasing hormone (GnRH) neurons. Furthermore, the diminished direct inhibition of GnRH by endorphin contributes to the elevation of GnRH release. These changes in GnRH activity affect adjacent thermoregulatory neurons, resulting in alterations to the body's temperature setpoint and ultimately inducing hot flushes[106,107].

Grading and management of hot flushes

Hot flushes significantly impact patients' QoL and medication compliance. To effectively address hot flush symptoms, appropriate measures can be implemented, such as lifestyle and pharmacological interventions. Lifestyle interventions may involve wearing loose, breathable clothing, utilizing physical cooling methods, and practicing yoga to alleviate hot flush symptoms[108]. For patients experiencing milder hot flushes, lifestyle interventions are recommended as a first-line approach to alleviate associated symptoms. In cases where lifestyle interventions fail to improve hot flushes, drug interventions can be considered. These include the use of selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors, anticonvulsants, and antihypertensive drugs. These medications have shown to effectively reduce the incidence and severity of hot flushes[109]. Venlafaxine, an SSRI drug, is commonly prescribed to alleviate symptoms associated with hot flushes. However, it is important to note that venlafaxine is mainly linked with gastrointestinal reactions, including decreased appetite, nausea, and constipation. Therefore, caution should be exercised when using venlafaxine to treat hot flushes in patients who have gastrointestinal AEs[110]. Another SSRI, paroxetine, has also demonstrated its ability to treat hot flushes and significantly reduce the incidence of hot flushes[109]. In addition to drug intervention, acupuncture and moxibustion have also a certain effect on hot flushes, and numerous studies have shown that acupuncture and moxibustion reduced the incidence and severity of hot flushes, while the effect was weakened over time[108]. During the follow-up period, it is important for the patient to consult with doctor in order to select the most appropriate medication for the treatment of hot flushes. Additionally, any changes in the patient's body temperature should be closely monitored, and it is essential to promptly inform doctor of any physical discomfort or concerns.

2.3.2 Gastrointestinal AEs

Incidence and mechanism of gastrointestinal AEs

Nausea and vomiting are common gastrointestinal AEs, and Table 17 summarizes the rates for nausea and vomiting based on findings from the landmark studies. The incidence of hot flushes ranges from 5.2% to 30.0%. Nausea and vomiting are multistep reflex processes that are mainly regulated by the vomiting center, and their mechanisms mainly include peripheral and central pathways: (1) peripheral pathways: antineoplastic drugs stimulate chromaffin cells in the gastrointestinal mucosa to release 5-hydroxytryptamine 3 (5-HT3), which is induced by binding to the 5-HT3 receptor and typically manifests as acute vomiting; (2) central pathways: they are induced by substance P through binding to neurokinin 1 receptors located in the vomiting center and mainly manifests as delayed vomiting[111].

Grading and management of gastrointestinal AEs

According to the incidence of acute vomiting caused by antitumor drugs, domestic guidelines classified the risk of emesis caused by these drugs into four levels: high-risk (> 90%), moderate-risk (30%–90%), low-risk (10%–30%), and mild-risk (< 10%). In contrast, the risk of emesis induced by NHT was categorized as less than low[112]. Severity of nausea and vomiting can be categorized into five grades based on CTCAE, as shown in Supporting Information: Table 10. Before primary NHT, a comprehensive assessment of patients' medical history (including nausea and vomiting, alcohol consumption, anxiety, dizziness, etc.) and specific medical conditions (e.g., intestinal obstruction, vestibular dysfunction, brain metastasis, electrolyte imbalances, etc.) should be conducted. Enhanced monitoring and prevention strategies should be implemented for high-risk patients. Regarding gastrointestinal AEs during NHT, if grade 1 AE occurs that does not require drug intervention, lifestyle interventions, such as eating smaller and lighter meals, can be employed[113]. For grade 2 AEs, monotherapy with lifestyle interventions can be considered. This includes 5-HT3 receptor antagonists (e.g., ondansetron and granisetron), dopamine receptor antagonists (e.g., metoclopramide), and phenothiazines (e.g., prochlorperazine and promethazine)[112]. For grade ≥3 AEs, despite the utilization of standard antiemetic treatment, patients who continue to experience refractory nausea and vomiting are advised to consider another medication with a different mechanism of action, while also ensuring adequate hydration and electrolyte balance[112].

2.3.3 Special patient management

Notably, 60% of patients are middle-aged and elderly individuals who mainly require multiple drug treatments due to accompanying complications, such as hypertension and diabetes. This can lead to a high risk of drug–drug interactions (DDIs)[114]. Therefore, special attention should be paid to drug selection.

For patients with concomitant hypertension, caution should be exercised in the selection of medications, such as abiraterone and enzalutamide due to their potential risk for hypertension. Both abiraterone and enzalutamide are potent inducers of the CYP3A4 enzyme, which may lead to inactivation and reduced plasma concentrations of antihypertensive drugs, thereby affecting the treatment of hypertension. Therefore, for patients with concomitant hypertension, the dosage of NHT should be appropriately adjusted according to patients' conditions. If grade 3 hypertension occurs, NHT should be discontinued immediately and treatment with captopril or losartan should be initiated. NHT can be resumed when hypertension symptoms regress to grade 1 or baseline[16]. Patients with concomitant hyperlipidemia and diabetes should use caution when taking medications, such as abiraterone, as these drugs can disrupt lipid and glucose metabolism and exacerbate related symptoms. Additionally, abiraterone is an inducer of the CYP2C8 enzyme, which can decrease the blood concentrations of drugs metabolized by CYP2C8, such as pioglitazone and rosiglitazone, leading to inactivation and affecting the therapeutic efficacy for patients with hyperlipidemia and diabetes[12,16]. For PCa patients concomitant with other diseases, NHT with a low probability of cardiovascular AEs and minimal drug interactions can be selected to ensure medication safety[14].

Special patients should be managed during NHT, and their medical history should be obtained before prescribing. A multidisciplinary team (MDT) centered around oncology and cardiology experts should be formed to optimize cardiovascular treatments[63]. Evaluation should be conducted during NHT for patients who are coadministering substrates of CYP3A4, CYP2C8, CYP2C19, or UGT1A1 to determine the occurrence of DDIs and adjust medication dosages accordingly. Plasma concentration monitoring is also necessary for cardiovascular drugs with a narrow therapeutic window to optimize cardiovascular risk management in specific patients[12,14–16]. Patients should undergo regular follow-up after NHT, including assessment of treatment efficacy and drug-related AEs. Evaluation of treatment efficacy should be based on routine hematological examinations, tumor markers, and imaging studies. Monitoring of drug-related AEs should include regular assessment of vital signs, complete blood cell count, and other relevant tests.

2.4 Concluding remarks and future prospects

With the publication of an increasing number of clinical research data over the past decade, the combination of ADT and NHT has become the cornerstone of treatment for men with advanced PCa. However, AEs that occur during treatment may impair patients' QoL and compromise treatment efficacy[18,22,23,31]. The current management strategies for NHT-induced AEs have still certain limitations. Two areas can be further strengthened in the future. First, it is suggested to establish an MDT team to optimize individualized diagnosis and treatment for patients. During NHT, eligible institutions should implement PCa-related MDTs to develop management plans for potential AEs. This includes early identification of high-risk patients, specifying treatment plans for different grades of AEs, and formulating appropriate treatment strategies to improve patients' survival, prognosis, and QoL[115]. Second, further exploration should be conducted on interventional strategies for region-specific AEs, targeting optimization of interventions for NHT-induced AEs. Localized interventional approaches for AEs, such as traditional Chinese medicine decoctions for bone pain, acupuncture for alleviating CRF, and the use of Traditional Chinese Medicine combined with moxibustion for treating hot flashes, should be applied[116–118].

During the specified period of this consensus, some unresolved issues that have not reached a consensus have been identified. These are summarized as follows: (1) PCa patients are mainly elderly, and further exploration is needed to optimize pretreatment patient education and improve timely self-reporting of AEs; (2) when interrupting NHT due to AEs, the duration of interruption and the criteria for resuming NHT need more clinical studies or experience to determine whether patients who are receiving reduced-dose treatment due to AEs can safely resume the full-dose treatment; (3) with the diversified treatment options for advanced PCa and the increasing popularity of novel targeted therapies, a wide range of treatment regimens also cause new challenges in the management of AEs. Further research is essential to more effectively manage AEs in clinical practice.

This consensus concerning NHT safety management incorporates the wisdom of experts from multiple countries and regions in Asia-Pacific, providing a strong reference for clinicians in managing advanced PCa patients and maintaining their health-related QoL. We look forward to seeing the consensus to better serve clinicians and benefit more patients.

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