Hot issues on Chinese expert consensus of prostate cancer management

Abstract

Prostate cancer is one of the most common solid tumors in men, and its incidence continues to rise in China. Several guidelines have been developed and published to facilitate the standardization of diagnosis and treatment of prostate cancer. However, there are still many challenges and issues in clinical practice that lack high‐level evidence. A panel of recognized domestic experts including urologists, medical oncologists, and radiologists was organized and invited to discuss and vote on the key issues of lacking high‐level evidence and unified guideline recommendations questions. Following careful selection and voting processes, 19 questions were identified, leading to the establishment of a consensus based on collective agreement regarding these hot issues. The aim of this consensus is to provide a reference for managing the whole patient journey of prostate cancer for Chinese clinicians.

Keywords

developmental urology / prostate cancer / urologic oncology

1 INTRODUCTION

The incidence of prostate cancer is showing a significant upward trend and gradually evolving into an intractable issue that profoundly impacts the health of the middle‐aged and elderly men in China[1,2]. In 2016, the overall incidence and mortality rates of prostate cancer in China were recorded at 11.05 per 100 000 and 4.75 per 100 000, respectively. According to the 2022 China Cancer Annual Report, it was reported that prostate cancer ranked the 6th in the incidence and the 7th in the mortality of malignant tumors in men in China[3]. It is estimated that by 2030, the number of new cases and deaths of prostate cancer in China will exceed 315 310 and 81 540, respectively[4].

To improve survival outcome and quality of life for patients with prostate cancer, several guidelines have been developed and published internationally and domestically, greatly contributing to and facilitating the standardization of prostate cancer diagnosis and treatment. However, there are still many challenges and issues in clinical practice that lack high‐level evidence. Therefore, a panel consisting of domestic experts including urologists, medical oncologists, and radiologists, was organized to discuss and vote on key issues pertaining to the lack of high‐level evidence and unified guideline recommendations, ultimately aiming to establish a consensus that can serve as a reference for managing the whole patient journey of prostate cancer in China.

2 METHODS

This consensus was established in the presence of 91 member units from the Chinese Urological Doctor Association (CUDA) Oncology Group and the Chinese Prostate Cancer Diagnosis and Treatment Quality Control Group. The writing group consisted of a total of 104 experts from urology, medical oncology, radiation therapy, covering 25 provinces, autonomous regions, or municipalities directly under the central government. These experts were affiliated with various hospitals including 86 tertiary Grade A hospitals, one tertiary Grade B hospital, three secondary Grade A hospitals, and one private hospital. Following a careful selection and voting process, 19 questions were selected and a voting‐based consensus was finally established on these key hot issues.

3 SCREENING

3.1 Based on the current evidence, do you think that prostate‐specific antigen (PSA) screening can reduce prostate cancer‐specific mortality in China?

In the European Randomized Study of Screening for Prostate Cancer (ERSPC), 182 160 men (including 162 389 subjects aged 55–69 years) were randomly assigned to either the PSA screening arm or the control arm. The 16‐year follow‐up results showed that the PSA screening significantly reduced the prostate cancer‐specific mortality by 20% (relative risk [RR]: 0.80, 95% confidence interval [CI]: 0.72−0.89). A subgroup analysis of the Rotterdam cohort (n = 1134) with a 19‐year follow‐up in the ERSPC study showed that the PSA screening reduced the prostate cancer‐specific mortality rate by 54% and the incidence of metastatic disease progression by 52%. These results suggested the positive significance of PSA screening[5]. The Göteborg screening trial in the ERSPC study showed that the cumulative incidence of prostate cancer in the screening group was 12.7% compared to 8.2% in the control arm (hazard ratio [HR]: 1.64, p < 0.0001). After a 14‐year follow‐up, the absolute cumulative risk of prostate cancer death decreased from 0.9% in the control group to 0.5% in the screening group (95% CI: 0.17–0.64)[6].

However, the US Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial indicated that after a median follow‐up of nearly 17 years, the prostate cancer mortality in the intervention group did not significantly decrease compared to the usual care group, with an RR of 0.93 (95% CI: 0.81–1.08; p = 0.38)[7]. An analysis of the PLCO study data revealed the following potential flaws: data contamination, with 77% of the population in the control group also underwent PSA testing during the study; a low biopsy rate of 50% in the screening group; and a low proportion of the high‐risk population, mainly included white individuals but a too low proportion of African Americans and familial patients[8,9].

Van Poppel et al. reanalyzed the data from both the ERSPC and PLCO studies in their study. By removing the confounding factors, they found that PSA screening reduced the risk of prostate cancer death by 25%−31% and 27%−32%, respectively in the two studies. Tsodikov et al. also stated in their study that although the PLCO screening study did not demonstrate a decrease in prostate cancer‐specific mortality, a recent modeling analysis demonstrated that the ERSPC and PLCO studies provided consistent evidence of a reduction in prostate cancer‐specific mortality[9]. Welch and Albertsen analyzed the effect of the introduction of PSA screening on prostate cancer using the SEER database. In the real world, after PSA screening, the reduction in prostate cancer mortality was 37%, higher than the 21% in the ERSPC study, and the reduction in metastatic prostate cancer incidence was 62%, higher than the 47% in the ERSPC study[10]. Catalona mentioned in a study that during the era of PSA screening for prostate cancer, the prostate cancer mortality in the United States decreased by 53%. Concerns about overdiagnosis and overtreatment, along with misunderstandings of clinical study data, have led to recommendations against prostate cancer screening, which subsequently resulted in a return to higher‐risk disease at the time of prostate cancer diagnosis. Therefore, it is necessary to further consider intensive screening for men with high‐risk factors[11].

Data published by Ye et al. showed differences in the speed of improvement in 5‐year survival rates for prostate cancer in different Asian countries: Japan and the Republic of South Korea had an average annual increase of nearly 12%, with 5‐year survival rates reaching nearly 90%; India had an average annual increase of 33.7%, but the 5‐year survival rate was only 44.3%; and China had an average annual increase of 3.7%, with a 5‐year survival rate of 69.2%. The differences in long‐term survival may be related to the coverage of PSA screening, the proportion of patients with advanced disease, and accessibility to new drugs in local regions, suggesting the need to emphasize prostate cancer screening to improve the 5‐year survival rate in the Chinese population[12].

The consensus vote revealed that nearly 90% of experts concurred that PSA screening can reduce prostate cancer‐specific mortality based on current evidence. Moreover, some experts emphasized the need for the vigorous promotion and widespread adoption of PSA screening among the middle‐aged and elderly men in China. This approach aims to facilitate early diagnosis and treatment, thereby alleviate the disease burden.

3.2 At what age do you recommend starting prostate cancer screening for men (excluding those with BRCA2 mutations or a family history of prostate cancer)?

In 2019, the age‐standardized incidence rates of prostate cancer in China for the age groups of 20−39, 40−59, 60−79, and 80 and above were 0.49/100 000, 7.39/100 000, 100.44/100 000, and 289.91/100 000, respectively. The data showed that the incidence was low for those aged under 40, started to rise for those aged 40−59, and increased rapidly for those aged 60 and over[5]. Studies have shown that the risk of prostate cancer increased with age in China. According to the reports from cancer registries in Beijing, Chongqing, and Zhejiang Province, the incidence of prostate cancer significantly increased after the age of 55−60[13].

After analyzing the Göteborg‐1 study data, Carlsson et al. suggested that PSA screening should start no later than the age of 55. The interrupted time series (ITS) model showed that the younger the age at initial screening, the greater the reduction in prostate cancer mortality. Therefore, to achieve better screening effects, it is recommended to start screening by the age of 55. After the age of 55, the screening effect decreases faster. Between the ages of 55 and 60, the effect decreases in an approximately linear manner; and after the age of 60, the effect decreases significantly. For males diagnosed through the first screening, the tumor invasiveness is higher in those aged 60−64 and is quite balanced between those aged 50−54 and 55−59, suggesting that starting screening after the age of 60 may be too late[14]. Liu et al. recommended the ideal starting age for initial PSA screening was 57.5 years in the Chinese population. The repeat screening should depend on the initial PSA level determined according to age[15,16]. The research data published by Qin et al. showed that PSA screening for prostate cancer should be conducted and repeated for populations in different age groups. Prominent benefits were observed for the age group of 50−65 years: From a societal perspective, the cost‐effectiveness ratios for three age groups (50−65, 65−80, and 50−80 years old) were 2.01, 0.51, and 1.00, respectively. By quantifying the direct and indirect benefits of prostate cancer screening, it was found that the screening could reduce labor losses and bring indirect benefits[17]. Early prostate cancer screening has more medical cost‐effectiveness advantages and higher economic benefits, with greater benefits for patients. PSA‐based prostate cancer screening seems cost‐effective for some high‐risk Chinese males. PSA screening (followed by magnetic resonance imaging and biopsy in case of a positive PSA test) can be recommended for Chinese males aged 50−65, as this method has the lowest risk‐benefit ratio[18].

The CSCO Guidelines for Diagnosis and Treatment of Prostate Cancer recommend starting screening at the age of 50 (aged > 40 for BRCA2 mutation carriers)[19]. The 2021 Chinese Expert Consensus on Prostate Cancer Screening recommended starting screening at the age of 50[20]. The 2022 Chinese Guidelines for Screening and Early Diagnosis and Treatment for Prostate Cancer recommended starting prostate cancer screening at the age of 60 in China[13].

A majority of experts (73%) concurred that PSA screening for prostate cancer should commence at the age of 50 for men without a family history of prostate cancer or BRCA mutations. Furthermore, 17% of experts opined that the recommended starting age for screening should be lowered to 45 years.

4 BIOPSY

4.1 Considering the current research evidence, do you think it is feasible to diagnose suspected prostate cancer patients without a biopsy?

PRIMARY study showed that the combination of 68Ga‐PSMA positron emission tomography (PET)‐CT and multiparametric magnetic resonance imaging (mpMRI) of the prostate improved the negative predictive value (91% vs. 72%) and sensitivity (97% vs. 83%) for detecting clinically significant prostate cancer compared with mpMRI alone, suggesting that the current combined imaging technique had a high sensitivity for the detection of clinically significant cancers[21]. Meissner et al. suggested that biopsy‐free radical prostatectomy (RP) can be explored if mpMRI PI‐RADS score ≥ 4 and PSMA PET/CT score ≥ 4 (based on a 5‐point Likert scale: a score of 4 indicates suspected prostate cancer, and a score of 5 indicates highly suspected prostate cancer). The preliminary study showed that the final pathological diagnosis of malignant tumors was nearly 100% in patients who underwent radical surgery for prostate cancer without prior biopsy by selecting suitable patients, properly utilizing preoperative imaging data such as PSMA PET/CT and mpMRI, and referring to patients' basic information such as PSA[22].

Xing et al. retrospectively analyzed the data of 17 prostate cancer patients who underwent radical surgery without prior biopsy. Results showed that the preoperative PSA in patients was 19 ± 11 μg/L; MRI showed abnormal signals in the peripheral zone in 14 patients, and suggested hyperplasia or inflammation in the remaining three patients; PSMA PET/CT suggested abnormal high‐uptake lesions in all patients, and prostate cancer was highly suspected; DRE showed palpable nodules in only two patients, and three patients were previously tested negative upon biopsy. This study proposed that the accuracy of comprehensive diagnosis of prostate cancer can be significantly improved by combining the imaging techniques (mpMRI, PSMA PET/CT, etc.) with traditional techniques (serum PSA, digital rectal examination, etc.), thereby achieving the goal of avoiding prostate biopsy before surgery[23].

Ma et al. explored the feasibility of biopsy‐free radical resection in patients with highly suspected prostate cancer diagnosed by mpMRI combined with 68Ga‐PSMA PET/CT, and 31 patients who met the following criteria were included in the study: (1) Good general condition, aged ≤ 80 years, with an ECOG score of 0–1; (2) Highly suspected localized prostate cancer suggested by imaging findings (PI‐RADS score ≥ 4 and SUVmax ≥ 4), with no distant lymph node, bone, or organ metastases; and (3) Patients and their family members refused to undergo biopsy and agreed to undergo radical surgery. Results showed that the accuracy of postoperative pathological diagnosis of prostate cancer in patients was 96.8% (30/31), including 86.7% (26/30) patients diagnosed with clinically significant cancer, and the remaining one patient diagnosed with high‐grade prostatic intraepithelial neoplasia. Patients were divided into a low SUVmax group (SUVmax < 10) and a high SUVmax group (SUVmax ≥ 10) by the maximum standard uptake value (SUVmax) on 68Ga‐PSMA PET/CT. Subgroup analysis of all confirmed patients showed that the ISUP grade in the high SUVmax group was higher than that in the low SUVmax group (p = 0.003), and there was no significant difference in the positive surgical margin rate, invasion of seminal vesicle, and postoperative staging. Among the 26 patients with clinical significant prostate cance (CsPCa), 10 (38.5%) had a PI‐RADS score of 4 and 16 (61.5%) had a score of 5. In the CsPCa group and non‐CsPCa group, the median prostate volume was 34.3 mL and 73.0 mL, respectively (p = 0.006), and the median PSAD was 0.70 ng/mL² and 0.13 ng/mL², respectively (p = 0.001); the number of patients who had a PI‐RADS score of 5 (p = 0.018) was 16 and 0, respectively; and the median SUVmax was 14.3 and 6.1, respectively (p = 0.001), with statistically significant differences. Based on the study, it was considered that biopsy‐free RP was safe in patients with highly suspected localized prostate cancer suggested by comprehensive diagnosis findings and an attempt to perform biopsy‐free RP can be made after adequate communication[24]. Xu et al. presented at the 2023 EAU Conference, an open‐label, single‐arm clinical study of preoperative biopsy‐free radical resection in patients with highly suspected prostate cancer. Fifty‐nine patients with suspected prostate cancer (SUVmax ≥ 4 on PSMA PET/CT or PI‐RADS ≥ 4 on mpMRI) were included in this study and successfully underwent biopsy‐free RP. The final pathological findings showed that 58 patients (98.3%) had pathologically confirmed prostate cancer, among these 52 patients (88.1%) were diagnosed with clinically significant cancer and one patient was diagnosed with high‐grade prostatic intraepithelial neoplasia (HGPIN)[25].

The biopsy‐free strategy means that it is impossible to clearly evaluate the patient's staging and grading before treatment, and this strategy cannot be served as the pathological basis for other treatment methods (such as lymph node dissection, radiotherapy, or endocrine therapy). Thus there remains great controversy in this field[26].

In this consensus vote, 74% of the experts opined that biopsy‐free treatment could be considered solely for elderly patients with high suspicion of PSA, definitive imaging diagnosis, and multiple underlying diseases, following comprehensive patient communication and informed consent. In addition, 25% of experts did not recommend biopsy‐free treatment.

5 LOCALIZED AND LOCALLY ADVANCED

5.1 For high‐risk localized prostate cancer patients who are planning to perform RP, do you support extended lymph node dissection (ePLND) when PSMA PET/CT shows no evidence of metastasis (N0M0)?

A total of 302 high‐risk patients with limited‐stage prostate cancer who were expected to receive curative therapy were included in the randomized controlled study proPSMA to evaluate the accuracy of PSMA PET/CT versus conventional imaging (CT, bone scan) for prostate cancer metastases[27]. This study demonstrated that, compared to conventional imaging techniques, PSMA PET/CT improved accuracy by 27%, with higher sensitivity and specificity for metastases. The proportion of patients whose treatment regimen changed was high among patients who underwent PSMA PET/CT. However, this study lacked long‐term survival data. A total of 764 moderate to high‐risk prostate cancer patients who underwent PSMA PET/CT were included in a study in 2022. Among these, 277 patients underwent radical surgery and pelvic lymph node dissection after examination, and 240 patients completed follow‐up[28]. Results showed that preoperative PSMA‐positive patients had significantly lower biochemical recurrence‐free survival (BCR‐FS) compared with preoperative PSMA‐negative patients. Staging by PSMA PET was predictive for BCR‐FS after RP. Patients with extraprostatic diseases detected by preoperative PSMA PET scans had a high risk of biochemical recurrence. Among them, there was no statistical difference in BCR‐FS between the postoperative lymph node positive/PSMA negative group and the lymph node negative/PSMA positive group. A systematic review concluded that the sensitivity of PSMA PET for regional primary lymph node staging varied greatly across studies (23%−100%), and the sensitivity based on statistical analysis was about 60%. Therefore, there is still a lack of evidence from large‐scale clinical studies on whether regional lymph node staging by PSMA PET can provide guidance on subsequent treatment decisions for limited‐stage prostate cancer.

Considering that traditional imaging methods were often used for disease staging in previous clinical studies, it remains unclear whether PSMA PET will interfere with the conclusions of previous clinical studies or even affect the final results of the study; the consistency across different contrast agents has not been fully demonstrated; further research is needed to demonstrate the reasonable application of PSMA PET/CT in prostate cancer.

Among patients with high‐risk localized prostate cancer scheduled for RP, 56% of experts would not opt for ePLND in the absence of metastases detected by PSMA PET/CT.

5.2 Do you think it is necessary to provide an adjuvant ADT for patients with negative lymph nodes in postoperative pathology but with other high‐risk factors (PSA > 20 ng/mL, Gleason score [GS]> 7, clinical stage ≥ cT2c)?

Adjuvant therapy refers to the adjuvant use of ADT or radiotherapy after radical resection of prostate cancer, with the aim of eliminating residual lesions and residual positive lymph nodes in the tumor bed and small metastases in other sites after surgery, so as to improve long‐term survival.

A model for predicting biochemical recurrence after radical surgery for prostate cancer included 2518 patients with pT2‐T3N0 prostate cancer[29]. Results showed that preoperative PSA, GS, extraprostatic extension, seminal vesicle involvement, positive margins, and absence of adjuvant treatment were all independent risk factors for biochemical recurrence after radical surgery. A study involving 400 Chinese patients with high‐risk localized prostate cancer indicated that preoperative PSA > 20 ng/mL and clinical stage ≥ T2c were significantly associated with positive surgical margins following RP[30].

According to 51% of experts, adjuvant ADT is deemed necessary for patients with negative lymph nodes after RP, provided they exhibit other high‐risk factors (PSA > 20 ng/mL, or GS > 7, or clinical stage ≥ cT2c) prior to the RP.

5.3 Do you think it is necessary to provide an adjuvant ADT for patients with negative lymph nodes in postoperative pathology but with other adverse clinical/pathological factors (PSA > 0.1 ng/mL, or positive margins)?

As issue 5.2 just mentioned, the presence of positive surgical margins and the administration of postoperative adjuvant therapy were identified as independent factors influencing postoperative biochemical recurrence. Furthermore, multiple studies have demonstrated that persistent PSA following RP is correlated with more advanced disease (such as positive surgical margins, pathologic stage ≥ T3a, positive nodal involvement, and/or pathologic ISUP grade group > 3) and unfavorable prognosis[31–33].

A majority of experts (82%) concurred that adjuvant ADT was indispensable for patients exhibiting negative lymph nodes but presenting other unfavorable postoperative clinical/pathological factors, such as PSA > 0.1 ng/mL or positive surgical margins.

5.4 How about the duration of adjuvant ADT you usually recommend for the high‐risk localized patients?

Regarding the comparison between early salvage radiotherapy (sRT) and adjuvant radiotherapy, interim results reported from three RCT studies (RADICALS‐RT study, RAVES study, and GETUG‐AFU‐17 study), with follow‐up duration ranging from 4.9 to 6.25 years, showed no statistically significant difference in the disease progression‐free survival rate between early ART and adjuvant radiotherapy. Additionally, early sRT contributed to a significant reduction in the incidence of Grade ≥ 2 adverse reactions to advanced radiotherapy[34–38]. The NRG0534/SPPORT study[39], with a median follow‐up of 8.2 years, also showed the benefit of adding ADT to adjuvant radiotherapy (RT) in prostate cancer after prostatectomy. However, the aforementioned studies included patients with low preoperative PSA level (median 7.4−8.0 ng/mL), and a relatively small proportion of patients with seminal vesicle involvement (15%–20%) and GS 8–10 (10%−18%).

Results from four prospective clinical studies (SWOG 8794, EORTC 22911, ARO 96‐02, and FinnProstate Group)[40–43] showed that immediate adjuvant radiotherapy after the recovery of urinary control significantly improved the disease progression‐free survival rate and overall survival (OS) rate in patients with pathological features such as positive surgical margins, pT3‐4, and lymph node metastases after RP. Tilki et al.'s study[44] (enrolled 26 118 patients) demonstrated that adjuvant compared with early sRT was associated with a significantly lower all‐cause mortality (ACM) risk among men with adverse pathology at RP (pT3‐4, GS 8–10) when men with pN1 prostate cancer were excluded.

The SWOG 9921 study included 961 patients with a PSA nadir of ≤ 0.2 ng/mL after RP and bearing ≥ 1 high‐risk characteristics (GS ≥ 8, preoperative PSA ≥ 15 ng/mL, T3b, T4 or N1, GS = 7 and preoperative PSA ≥ 10 ng/mL or positive surgical margins) to receive complete androgen blockade (CAB) adjuvant endocrine therapy for two years. Results showed that 5‐year overall survival (OS) and BCR‐FS were 96% and 92.5%, respectively, at a median follow‐up of 4.4 years (estimated 5‐year OS for only 71%); the 2‐year adjuvant CAB group had a 10‐year DFS of 72% and 10‐year OS of 87% at a median follow‐up of 11.2 years (estimated 10‐year OS for only 50%). Subgroup analysis showed that patients with GS = 7/positive surgical margins or PSA > 10 had a 10‐year OS rate of 90%, while patients with GS ≥ 8 or T3b had a 10‐year OS rate of 87%[45]. Results from a study including 105 patients with pT3N0 prostate cancer who received long‐term ADT after RP showed that, with long‐term adjuvant ADT (≥ 5 years), the 10‐year BCR‐FS rate was 88.3%, clinical recurrence‐free survival rate was 93.0%, prostate cancer‐specific survival rate was 96.3%, and OS rate was 85.7%[46].

However, due to factors such as limited patients' acceptance, accessibility, and popularity, the clinical utilization rate of adjuvant radiotherapy remains low in China. In conclusion, a total of 73% of experts agreed on the need for a duration of adjuvant ADT longer than 12 months.

6 BIOCHEMICAL RECURRENCE

6.1 For patients with PSA recurrence after radical treatment, in which of the PSA range do you recommend an imaging examination?

The definition of PSA recurrence after radical treatment is currently not standardized across different guidelines. According to the NCCN prostate cancer guideline[47], PSA recurrence after RP is defined as a subsequent detectable PSA that increases on two or more determinations or when it increases to > 0.1 ng/mL. PSA recurrence after RT is defined as: (1) PSA increase by 2 ng/mL or more above the nadir PSA recurrence after EBRT with or without hormone therapy; and (2) PSA has been confirmed to be increasing after RT even if the increase above nadir is not yet 2 ng/mL, especially in candidates for secondary local therapy who are young and healthy. According to the EAU prostate cancer guideline, a PSA level > 0.4 ng/mL and increasing is considered the optimal threshold for predicting further metastases after RP. However, with access to ultra‐sensitive PSA testing, a rising PSA much below this level will be a cause for concern for patients. After primary RT, with or without short‐term hormonal manipulation, the RTOG‐ASTRO Phoenix Consensus Conference definition of PSA failure (with an accuracy of > 80% for clinical failure) is any PSA increase > 2 ng/mL higher than the PSA nadir value, regardless of the serum concentration of the nadir[48].

Studies suggested that the positive rates in prostate cancer patients with PSA ranges of 0−0.19, 0.2−0.49, 0.5−0.99, 1−1.99, and > 2 ng/mL after RP were 33%, 46%, 57%, 82%, and 97%, respectively, according to PSMA‐PET/CT findings[49–54]. PSMA PET/CT is more sensitive than choline PET/CT, particularly when PSA levels are < 1 ng/mL[54–56]. A prospective study of 272 patients who experienced BCR after radical therapy showed that 68Ga‐PSMA PET/CT could be used to provide guidance on subsequent treatment decisions (such as local treatment versus systemic treatment) when PSA values were low (0.2−1 ng/mL)[54].

At the same time, a study of 314 patients who experienced BCR after radical therapy with a median PSA level of 0.83 ng/mL showed positive result upon 68Ga‐PSMA PET/CT scans in 197 patients (67%)[57]. In addition, since it took 7−8 years for patients with biochemical recurrence to progress to clinical metastases, the positive rate upon bone scan/pelvic CT in asymptomatic patients was very low[58]. The FORMULA‐509 study released at the ASCO GU Conference in 2023 included the efficacy and safety evaluation of 345 patients with increased PSA levels after radical surgery (≥ 0.1 ng/mL) and one or more high‐risk factors (GS 8−10, PSA > 0.5, pT3/4, pN1 or radiographic N1, PSA doubling time < 10 months, negative surgical margins, not decreased PSA ongoing, enlarged local/regional lesions, decipher high‐risk) who received salvage therapy combined with endocrine therapy, and the results suggested that patients benefited more significantly when PSA levels were > 0.5 ng/mL.

Based on the results of the above clinical studies, 47% of experts believe that imaging should be performed at “0.2 ng/mL ≤ PSA < 0.5 ng/mL,” 19% of experts believe that imaging should be performed at 0.5 ng/mL ≤ PSA < 1 ng/mL, and 21% of experts believe that imaging should be performed at “PSA > 1 ng/mL.”

6.2 For patients undergoing RP with only PSA recurrence, which of the salvage therapy do you usually recommend?

Based on current research evidence, salvage therapy is initiated at varying levels of PSA in different studies. In a retrospective study of 2460 patients who underwent sRT following radical surgery, the 5‐year BCR‐FS rate was 71% for those with a pre‐sRT PSA level of 0.01−0.2 ng/mL, 63% for those with a pre‐sRT PSA level of 0.21−0.5 ng/mL, 54% for those with a pre‐sRT PSA level of 0.51−1.0 ng/mL, 43% for those with a pre‐sRT PSA level of 1.01−2.0 ng/mL, and 37% for those with a pre‐PSA level of > 2.0 ng/mL, respectively (p < 0.001)[59]. The RAVES and RADICAL studies evaluated patients who underwent sRT following RP with median PSA levels of 0.1−0.2 ng/mL. Results from both studies showed a 5‐year BCR‐FS rate of 88%. Furthermore, a retrospective study involving 106 patients, four revealed that the distant metastases rates at 5 years and 10 years were 7% versus 14% and 13% versus 25%, respectively (p < 0.001), when using a PSA cut‐off ≤ 0.5 ng/mL versus > 0.5 ng/mL before sRT following RP; the rates of disease‐specific mortality at 5 years and 10 years were 1% versus 4% and 6% versus 13%, respectively (p < 0.001); the rates of OS were 94% versus 92% at 5 years and 83% versus 73% at 10 years (p > 0.05)[60–62].

However, according to the NCCN Prostate Cancer guideline, trials indicating noninferiority of early RT compared with adjuvant RT after RP have used a PSA threshold of 0.1 ng/mL or 0.2 ng/mL to trigger treatment. Imaging and treatment at lower PSA levels may be appropriate in patients at high risk for progression based on pretreatment risk factors, pathologic parameters, timing of recurrence, and GC score, among other factors.

Regarding the selection of salvage treatment, diverse studies have reported varying therapeutic options. A retrospective analysis of 635 patients who were followed up after RP and experienced biochemical and/or local recurrence and did not receive salvage therapy (n = 397) or received salvage RT only (n = 160) within 2 years after biochemical recurrence showed that salvage RT was associated with a three‐fold increase in prostate cancer‐specific survival compared to patients who did not receive salvage RT (p < 0.001)[63]. RTOG 9601 study showed that 2‐year endocrine therapy with bicalutamide 150 mg added to sRT prolonged disease‐specific survival and OS[64,65]. The GETUG‐AFU16 study showed that 6‐month endocrine therapy with LHRH analogs added to sRT significantly increased patients' 10‐year BCR‐FS and metastasis‐free survival rates. In the McGill 0913 study, postoperative salvage RT combined with a 2‐year LHRHa yielded a notable benefit in the 5‐year PFS for high‐risk prostate cancer patients, while RT + 2‐year leuprorelin resulted in a 5‐year PFS rate of 78.0%[66]. However, according to the NRG0534 trial[39] adhering to RADICALS‐defined criteria for early versus delayed salvage, at least half of the patients were classified as late‐saving cases (median PSA ranging from 0.3 ng/mL to 0.4 ng/mL). This trial revealed that incorporating short‐term ADT alongside RT targeting the prostatic bed did not yield improvements in DMFS. The study conducted by Boorjian et al. suggested that high‐risk patients with a high International Society for Urological Pathology (ISUP) grade and a short PSA‐DT (usually less than 6 months), especially those with a longer life expectancy, benefited most from (early) ADT[67].

Drawing upon the aforementioned research evidence, for patients with PSA recurrence after radical treatment, 47% of experts chose sRT combined with endocrine therapy and 32% chose salvage endocrine therapy. Further evidence is still needed on the optimal timing and duration of adding endocrine therapy to adjuvant radiotherapy or early sRT. In the meantime, clinical experts should be mindful of the need to engage with patients about the potential benefits and risks of endocrine therapy to ensure an informed decision‐making process.

7 METASTATIC CASTRATION SENSITIVE PROSTATE CANCER (mCSPC)

7.1 For low‐volume mCSPC patients, which kind of treatment do you prefer to combine with ADT?

Phase III studies such as TITAN, ARCHES, and ENZAMET also demonstrated that ADT combined with novel endocrine therapies such as apalutamide and enzalutamide led to significant improvements in survival in metastatic hormone‐sensitive prostate cancer (mHSPC) patients with no convincing evidence of differences between low‐volume and high‐volume subgroups[68–70].

Regarding RT to the primary tumor, the STAMPEDE trial showed the addition of prostate RT for patients with low tumor burden improved 3‐year OS (HR: 0.68, 95% CI: 0.52–0.90; p = 0.007; 3‐year survival 73% with control versus 81% with radiotherapy) while no evidence of a treatment effect in patients with a high metastatic burden (HR: 1.07, 95% CI: 0.90–1.28; p = 0.420)[71]. Although the PEACE‐1 trial didn't show OS benefit with addition of RT (p = 0.81), it did show the RT prevention effect on severe urinary symptoms[72].

Based on the results of the above clinical studies, 53% of experts prefer ADT combined with NHA for low‐volume mCSPC patients, while 21% of experts would like to choose ADT with RT to the primary tumor.

7.2 For high‐volume mCSPC patients, which kind of treatment do you prefer to combine with ADT?

In the STAMPEDE trial, a phase III study, the addition of abiraterone plus prednisoneto ADT in mHSPC patients demonstrated OS benefits[73]. STAMPEDE was a heterogeneous mix of patients with high‐risk, non‐metastatic, node‐positive, or M1 disease. A post‐hoc analysis from STAMPEDE showed the same benefit whatever the risk or the volume category[74].

The CHAARTED study included 790 patients with mHSPC who were randomized to receive either combination therapy (ADT + docetaxel) or ADT alone. Results showed a significant increase in median OS by 13.6 months in the combination therapy group versus the ADT group (57.6 months vs. 44 months). Subgroup analyses revealed that the addition of chemotherapy to ADT led to an increase in median OS by 17.0 months in mHSPC patients with high tumor burden compared with ADT alone (49.2 months vs. 32.2 months, p < 0.01) while no significant OS benefit was observed in patients with low tumor burden in the combination therapy group[75]. Additionally, more recently, two large Phase III studies (PEACE‐1 and ARASENS) have now shown an OS benefit by adding an ARPI to ADT and docetaxel.

The PEACE‐1 study was a randomized, open‐label, phase III clinical trial with a 2 × 2 factorial design conducted to evaluate the efficacy and safety of the SoC consisting of ADT ± docetaxel, in combination with abiraterone and prednisone ± radiotherapy. The study demonstrated that the triple regimen was effective in prolonging OS (p = 0.03) and radiographic progression‐free survival (rPFS) (p < 0.0001). Analyses conducted in patients stratified by tumor burden showed that mHSPC patients with low tumor burden had no benefit from this triplet regimen (p = 0.66), whereas mHSPC patients with high tumor burden had a more pronounced benefit, with the median OS increasing from 3.5 years to 5.1 years (HR: 0.72, p = 0.019)[76]. The study ARASENS included 1306 patients with mHSPC who were randomized at 1:1 ratio to receive either darolutamide in combination with ADT plus docetaxel or placebo in combination with ADT plus docetaxel. The study demonstrated that the triple therapy regimen consisting of ADT, darolutamide, and docetaxel reduced the risk of mortality by 32.5% compared with placebo group. Subgroup analyses revealed a substantial reduction in the risk of mortality by 29.3% in patients with newly diagnosed mHSPC who constituted a considerable proportion of the patient population in China, following treatment with the triple regimen[77]. The updated data presented at ASCO GU in 2023 indicated that the intensive treatment regimen exhibited a tendency to prolong OS in patients with high tumor burden (HR: 0.69), high‐risk patients (HR: 0.71), and low‐risk patients (HR: 0.62). However, for patients with low tumor burden, despite a HR for OS of 0.68, the upper limit of the 95% CI was 1.13, suggesting that patients with low tumor burden may not derive benefits from the intensive treatment[78].

In conclusion, 65% of experts prefer ADT combined with NHA for high‐volume mCSPC patients, while 30% of experts would like to choose ADT combined with NHA and chemotherapy.

8 CASTRATION‐RESISTANT PROSTATE CANCER (CRPC)

8.1 For nonmetastatic castration‐resistant prostate cancer (nmCRPC) patients, when traditional imaging results show no evidence of metastasis, would you choose to perform further PSMA PET/CT examination?

In the studies ARAMIS, PROSPER, and SPARTAN, the criteria for evaluating metastases relied on conventional imaging examinations such as bone scans, CT scans, or MRIs[79–81]. Patients who tested negative for all three imaging examinations were defined as patients with nmCRPC. However, with the advancement in imaging detection methods in recent years, more accurate approaches have emerged.

A retrospective analysis of PSMA PET in 200 patients with high‐risk nmCRPC evaluated by conventional imaging showed that 98% of patients were positive for PSMA PET and patients with pelvic diseases and distant metastases accounted for 44% and 55%, respectively[82].

Another study prospectively included 37 patients who had a PSA progression (≤ 2 ng/mL) and high‐risk (PSA doubling time ≤ 10 months) nmCRPC by conventional imaging. All patients underwent both 68Ga‐PSMA and 18F‐FDG PET/CT examinations. The findings indicated distant metastases were detected in 41% of patients by 18F‐FDG PET/CT and in 57% of patients by 68Ga‐PSMA PET/CT[83].

PSMA PET/CT is helpful in detecting metastases; however, it remains unclear whether the utilization of PSMA PET/CT in this setting will lead to improved outcomes[84]. If PSMA PET/CT is employed for detection, the possibility that a substantial proportion of patients may actually have metastases should be considered.

Approximately 75% of experts opt for additional PSMA PET/CT when traditional imaging results indicate no metastasis in nmCRPC patients.

8.2 For newly diagnosed mCRPC patients who were previously treated with ADT combined with NHA for mCSPC, what do you think is the preferred treatment at this stage?

Studies showed durations of second‐line treatment ranged from 13 weeks to 3 months when using abiraterone followed by enzalutamide, with PSA50 response rates ranging from 3% to 8%[85,86]. Studies conducted by Schrader et al. and Schmid et al. showed that durations of second‐line treatment ranged from 2.8 months to 4.9 months when enzalutamide was used sequentially after abiraterone, with a PSA50 response rate of approximately 20%. These studies suggested patient received limited benefit from the sequential use of the NHAs[87,88].

PROfound study included 387 patients with mCRPC and HRR mutations who experienced progression after prior treatment with abiraterone/enzalutamide. These patients were categorized into Cohort A (BRCA1/2 or ATM mutations) and Cohort B (mutations in BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L). The objective of the study was to compare the efficacy of olaparib versus the physician's choice of novel endocrine therapy (enzalutamide or abiraterone) in these cohorts. Results revealed that olaparib significantly improved rPFS in both Cohort A and Cohort A + B (Cohort A: 7.4 months vs. 3.6 months, HR: 0.34, p < 0.001; Cohort A + B: 5.8 months vs. 3.9 months, HR: 0.59, p < 0.001). Olaparib also improved OS (OS) in Cohort A (19.1 months vs. 14.7 months, HR: 0.69, p = 0.02) and Cohort A + B (17.3 months vs. 14.0 months, HR: 0.79). Improvements were also observed in other study indicators　510, such as objective response rate, time to pain progression, and patient‐reported survival treatment scores, in patients treated with olaparib. Patients with BRCA mutations in the olaparib group had a significantly greater benefit in terms of rPFS (9.79 months vs. 2.96 months, HR: 0.22, 95% CI: 0.15–0.32) and OS (20.1 months vs. 14.4 months, HR: 0.63, 95% CI: 0.42–0.95) compared with those in the NHA treatment group[89,90].

For patients who had previously received ADT combined with NHA in mHSPC and progressed to the mCRPC, 45% of experts advocated genetic testing at this stage was very important. PARP inhibitors such as Olaparib should be administered if a patient has BRCA mutations. Additionally, 23% of experts would opt for chemotherapy, while 22% would recommend switching to another NHAs.

8.3 For newly diagnosed mCRPC patients who were previously treated with ADT combined with chemotherapy for mCSPC, what do you think is the preferred treatment at this stage?

The PRESIDE study explored the survival benefit and safety of enzalutamide combined with docetaxel in patients with mCRPC following enzalutamide treatment. The study showed that PFS was significantly better in patients receiving enzalutamide plus chemotherapy in the second phase compared with those receiving chemotherapy alone (9.5 months vs. 8.3 months; HR: 0.72; 95% CI: 0.53–0.96; p = 0.027)[91]. This finding not only provided new insights into the combination of docetaxel with sequential original endocrine therapy following the failure of novel endocrine therapy, but also suggested that switching to another NHA may still be effective if the original NHA was not used sequentially. However, further clinical data is required to support this. The COU‐AA‐301 study included patients who experienced progression after prior docetaxel treatment, and these patients were randomly assigned to receive either abiraterone or placebo. Results showed that the OS was 15.8 months versus 11.2 months in the abiraterone and placebo groups, respectively (p < 0.0001, HR: 0.74, 95% CI: 0.64–0.86), suggesting that ADT + NHA was an effective treatment method[92,93].

The study CARD evaluated the efficacy of cabazitaxel as a third‐line treatment in patients with mCRPC. Results showed that cabazitaxel significantly improved rPFS (8.0 months vs. 3.7 months, p < 0.001) and OS (13.6 months vs. 11.0 months, p = 0.008) compared with abiraterone/enzalutamide in patients with mCRPC. Cabazitaxel also demonstrated improvements in pain symptoms, time to pain progression (NE vs. 8.5 months), and time to symptomatic skeletal events (NE vs. 16.7 months). Although this study primarily verified the efficacy of cabazitaxel in the mCRPC stage, it may be used as reference when sequential treatment following docetaxel is provided[94].

The PROpel study compared the efficacy of olaparib (300 mg Bid) combined with abiraterone (1000 mg QD) versus abiraterone alone (1000 mg QD) in 796 patients with mCRPC in the first‐line setting who did not receive abiraterone previously and were not genetically screened. Twenty‐two percent of the patients included in this study received docetaxel during the mHSPC stage. Results showed that the combination of olaparib and abiraterone significantly prolonged rPFS compared with abiraterone alone (24.8 months vs. 16.6 months, HR: 0.66, p < 0.0001). These findings suggested that olaparib combined with abiraterone can be considered as one of the options for disease progression following docetaxel treatment[95].

For patients who had previously received ADT combined with chemotherapy in mHSPC and progressed to the mCRPC, 84% of experts advocated the prioritization of NHAs as the treatment option.

8.4 For mCRPC patients, when do you recommend performing the genetic testing if necessary?

Based on the above evidence, 71% of experts agreed that genetic testing should be performed at the time of diagnosis for mCRPC patients.

9 BONE PROTECTION AND BONE HEALTH

9.1 At what disease stage do you think it is necessary to start monitoring bone health, including regular bone mineral density (BMD) testing and bone protectants as needed?

When the diagnosis of prostate cancer is established, more than 70% of patients with advanced prostate cancer had bone metastases and skeletal‐related events (SREs) caused by bone metabolic disorders. A study showed that 41.9% of prostate cancer patients had SREs within 2 years after the diagnosis of bone metastases[96]. Early diagnosis can help prevent and treat SREs in a timely manner and reduce or delay the adverse effects of SREs on patients. Newly diagnosed prostate cancer patients with Gleason score ≥ 8 or clinical stage ≥ T3 can also be considered as the group with high‐risk bone metastases. In addition, when evaluating bone metastases in prostate cancer, medical history, symptoms, signs, and imaging examinations should also be taken into account, and biopsies can be performed in cases with doubtful clinical diagnosis.

At the beginning of endocrine therapy and after a period of endocrine therapy, ADT can cause rapid and significant reduction in circulating androgens and estrogens, disrupt bone remodeling balance, stimulate osteoclast activity, reduce osteoclast apoptosis, and increase osteoblast apoptosis, all of which will lead to net bone loss[97]. Another prospective study found that bone density loss was fastest in the first year of ADT (5%–10% loss of bone density), which was greater than the normal age‐related bone loss (0.5%–1.0% per year) and menopause‐related bone loss[98,99]. Therefore, all men who begin or continue to receive long‐term ADT should follow lifestyle advice on bone health[100].

When certain clinical symptoms occur, the majority of prostate cancer patients with bone metastases have no obvious symptoms in the early stage, and some patients may seek medical treatment due to bone pain, pathological fracture, or limb movement disorder after disease progression[101]. The presence of bone metastases should be suspected when a patient has (1) bone pain or fracture; (2) symptoms of spinal cord or nerve compression; (3) blood alkaline phosphatase increased; (4) hypercalcemia.

Forty‐three percent of experts believed that the bone health of prostate cancer patients should be prioritized upon diagnosis, while 28% of experts suggest early attention to this aspect during hormonal therapy. Additionally, 21% of experts recommend incorporating bone health measures after a certain period (e.g., 1 year) of hormonal therapy.

9.2 For mCRPC patients with confirmed bone metastases, do you think it is necessary to provide routine bone therapy?

A Phase III study evaluating denosumab versus placebo in patients receiving ADT indicated a 6.7% increase in BMD and a 1.5% risk of fracture in patients treated with denosumab at 24 months (3.9% in the placebo group)[102]. Based on this study, the NCCN Guidelines also pointed out that denosumab was already approved by the FDA for the treatment of bone loss and fracture in the course of ADT and as prophylactic treatment to prevent the occurrence of SREs in patients with bone metastases. It is also recommended that denosumab (60 mg every 6 months), zoledronic acid (ZA) (administered intravenously in a dose of 5 mg each time) or alendronate (70 mg pre‐os [PO] per week) should be used as drug therapy when there is absolute risk of fracture.

No treatment should be provided/analgesic treatment should be provided only for patients with bone pain: Since the pathogenesis of bone metastases is mainly osteogenic or osteolytic changes caused by prostate cancer cells in the circulatory system[103], active treatment of the primary disease is an important prerequisite for the management of bone metastases and bone‐related diseases. Previous studies showed that ZA failed to delay disease progression, prolong OS, and improve patients' quality of life; results from the ALLIANCE study evaluating the efficacy of ZA in mHSPC patients showed that ZA failed to prolong the time to first occurrence of SREs[104]. Wirth et al. also evaluated the efficacy of ZA in patients with high‐risk localized prostate cancer who met one of three criteria (PSA ≥ 20 ng/mL, lymph node positive, or GS of 8–10). After a median follow‐up of 4.8 years, 14.7% of patients in the ZA group had bone metastases, while the incidence of bone metastases in the control group was only 13.2% (p = 0.65), and the study results indicated that ZA administered once every 3 months did not reduce the incidence of bone metastases in patients with high‐risk localized prostate cancer[105]. However, a Phase III clinical trial comparing the efficacy of denosumab and ZA in bone metastases in CRPC patients showed that the median time to first occurrence of SREs was 20.7 months in the denosumab group and 17.1 months in the ZA group (HR: 0.82). Further subgroup analyses showed that denosumab significantly reduced the risk of first symptomatic SREs as well as the risk of first and subsequent symptomatic SREs compared with ZA[106]. Analgesic drugs are one of the main treatment methods to relieve the pain caused by bone metastases in prostate cancer. According to the principles of the WHO three‐step analgesic ladder for cancer pain management, different doses of analgesic drugs should be selected according to the pain intensity of patients. Numeric rating scale (NRS) should be used: for mild pain (NRS score ≤ 3 points), nonsteroidal anti‐inflammatory drugs (NSAIDs) could be used, and low‐dose opioids could be considered if NSAIDs are contraindicated; for moderate pain (3 points < NRS score < 7 points), either weak opioids or low‐dose strong opioids may be used, and a combination of NSAIDs and adjuvant analgesics (sedatives, anticonvulsants, antidepressants, etc.) may be used; for severe pain (NRS score ≥ 7 points), strong opioids are preferred, and a combination of non‐steroidal anti‐inflammatory analgesics and auxiliary analgesics can be considered. However, the use of bone‐modifying drugs such as denosumab or bisphosphonates in patients with bone metastases can effectively delay the aggravation of pain and reduce the usage rate of opioids[107].

For patients with definite bone metastases in mCRPC, it is recommended by 60% of experts that denosumab or bisphosphonates should be administered as a routine treatment. In addition, 35% of experts suggested that should only provide bone‐protectant preventive measures after evaluating the existing fracture risk in patients.

10 FOLLOW‐UP

10.1 For patients receiving radical treatment, what is the usual follow‐up frequency you recommend?

Ideally, the PSA should be reduced to an undetectable level 4–8 weeks after RP, and the PSA threshold of 0.1–0.2 ng/mL was used in most studies. If PSA levels cannot be reduced to below 0.1–0.2 ng/mL, possible causes such as local residual tumor, presence of tumor metastases in the preoperative setting and residual benign prostate tissue should be considered, and patients should be re‐evaluated and an appropriate treatment regimen should be selected.

• EAU Guidelines (2023 version): Once every 6 months within the first 3 years and once every year thereafter.

• NCCN Guidelines (2024 version): Once every 6–12 months within the first 5 years and once every year thereafter; for high‐risk patients, the follow‐up can be conducted once every 3 months.

• CSCO Prostate Cancer Guidelines (2023 version): Once every 3–6 months.

• Chinese Guidelines for Diagnosis and Treatment of Urology and Andrology Diseases (2023 version): Once every 3 months within the first year, once every 6 months in the second and third years, and once every year after 3 years.

For patients who had undergone curative treatment, 47% of experts recommended a follow‐up every 3 months. There were 32% of experts suggested a follow‐up once every 3 months during the first year and then once every 6 months if the disease remains stable.

10.2 For patients with advanced disease, what is the usual follow‐up frequency you recommend?

The overall prognosis was poor in patients with advanced prostate cancer, and the frequency of follow‐up should be individualized according to the patient's condition. According to the study SWOG9346, patients were divided into three different prognostic groups based on PSA levels after 7 months of endocrine therapy: ① PSA < 0.2 ng/mL with the median survival of 75 months; ② PSA > 0.2 ng/mL and < 4 ng/mL with the median survival of 44 months; ③ PSA > 4 ng/mL with the median survival of 13 months. Data from a China real‐world study showed that the follow‐up frequency was nearly every 3 months[108].

• EAU Guidelines (2023 version): At least once every 3–6 months.

• NCCN Guidelines (2024 version): Once every 3–6 months.

• CSCO Prostate Cancer Guidelines (2023 version): Once every 3–6 months.

For patients with advanced prostate cancer, 58% of experts recommended follow‐up every 3 months, while 31% of experts suggested monthly follow‐up.

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