[2021 EAU] The latest progress of PSMA in the diagnosis and treatment of prostate cancer

*For medical professionals only for reference
.

As the degree of malignancy of the disease increases or recurrence and metastasis occur, the amount of PSMA expressed by PCa cells increases accordingly
.

Studies have shown that the expression of PSMA is closely related to tumor progression and prognosis
.

The 2021 European Urology Annual Conference (EAU) meeting reported the preliminary results of multiple studies related to the diagnosis and treatment of PSMA
.

1.
Related research on PSMA as a predictor Abstract 0836 In patients with PCa recurrence, the Nomo prediction nomogram predicted by 68Ga-PSMA PET results was validated by an external population.
Purpose: In previous studies, the investigator was based on 703 postoperative PSA For the poorly controlled population, the Nomo prediction nomogram was established to predict the positive rate of 68Ga-PSMA-11-PET/CT
.

In this study, the investigator hopes to verify the prediction accuracy, optimal cutoff value and clinical significance of the Nomore line chart in an external multicenter cohort
.

Research methods: retrospectively enrolled 1639 patients with biochemical recurrence (BCR) from 6 centers to evaluate the detection rate of PSMA-PET; use multivariate logistic regression model to evaluate predictive factors; use the coefficients of the original study's Nomoline chart Perform verification (Figure 1)
.

Calculate the quantitative prediction coefficient (PA), evaluate the degree of overestimation or underestimation of the forecast model; analyze the decision curve, and evaluate the net benefit of the nomogram
.

Figure 1 Nomo prediction nomogram and specific coefficient study results: In the verification cohort, the total detection rate of PSMA-PET/CT was 53.
8%, and that of the original population was 51.
2%; in the multivariate analysis, the ISUP classification group (ISUP 5 OR 1.
76), PET/CT PSA (0.
5-0.
99ng/ml OR 3.
64; 1-1.
99 ng/ml OR 6.
27; ≥2ng/ml OR 13.
48), PSADT (6-11.
9 months OR 2.
84; 3-5.
9 months or 9.
12 months); and clinical conditions (group 2 OR 1.
37, group 4 OR 5.
13) are independent predictors of 68Ga-PSMA PET/CT positive results (all p≤0.
02); in the verification cohort, the quantification of Mononomial nomogram The prediction coefficient (PA, Figure 2), similar to the original model, is both 82%; the analysis of the decision curve shows (Figure 3) that using the Monograph, the net clinical benefit increases by 20%
.

Figure 2 In the verification cohort, the quantitative prediction coefficient (PA) of the Monograph is similar to the original data, both of which are 82%
.

Figure 3 The analysis of the decision curve shows that the use of Monograph can increase the net clinical benefit by 20%
.

Research conclusion: The Nomore line chart shows good predictive performance in the externally verified population, and can help clinicians choose the patients who can benefit the most from 68Ga-PSMA PET/CT
.

Abstract 0910 PEDAL Trial Announces Preliminary Results Announcement: A prospective one-arm paired comparison study of multi-parameter MRI and 18F-PSMA-PET/CT on PCa diagnosis and localization capabilities Objective: To explore 18F-DCFPyl by comparing with multi-parameter MRI (mpMRI) -The accuracy of PSMA-PET/CT in detecting prostate lesions
.

Research method: This study is a prospective one-arm paired comparison test, comparing the detection and location of suspicious prostate lesions by mpMRI and 18F-DCFPyl-PSMA-PET/CT
.

Study results: A total of 54 patients with complete imaging test results were included
.

The median age was 66 years, and the median PSA level was 6.
15ng/ml
.

Prostate mpMRI detected 35 lesions (PIRADS 3), while PSMA-PET/CT detected 40 lesions (SUVmax 7.
0)
.

Both mpMRI and PSMA-PET/CT detected 25 lesions, and only PSMA-PET/CT detected 15 lesions
.

Of the 34 men who underwent prostate biopsy, 25 were diagnosed with PCa, and 17 of them (73.
8%) had positive results on both imaging tests
.

In addition, PSMA-PET/CT further found 3 (13%) clinically significant lesions not found by mpMRI, and diagnosed 11 cases of metastatic disease
.

Research results: 18F-DCFPyl PSMA-PET/CT can detect prostate lesions detected by mpMRI, and can identify other clinically significant lesions
.

The high detection rate of PSMA-PET/CT for metastatic lesions reduces the need for patients to undergo secondary pathological staging
.

These early results provide the basis for subsequent trials
.

Abstract 0914 PSMA-PET and multi-parameter magnetic resonance imaging predict the early biochemical progression of PCa patients.
Objective: To analyze the multiple conventional prognostic variables and multiple prognostic variables of limited-stage PCa undergoing robot-assisted laparoscopic radical prostatectomy (RARP).
Parametric magnetic resonance imaging (mpMRI), PSMA-PET imaging and other variables are analyzed to find predictors of early tumor outcome
.

Research method: A total of 500 patients who underwent RARP and expanded pelvic lymph node dissection (ePLND) were included in the study.
The outcome indicator was the occurrence of biochemical progress (PSA≥0.
2 ng/ml)
.

Cox regression analysis was used to evaluate predictors of biochemical progress, including initial PSA, pathological biopsy grading group (GG), mpMRI T staging, and PSMA-PET imaging lymph node status (miN0 vs.
miN1)
.

Study results: The median total follow-up time was 12.
8 months (IQR 6.
6-22.
3)
.

As shown in Figure 4, the initial PSA value, biopsy GG, mpMRI T staging and PSMA-PET imaging of lymph node status (miN0 vs.
miN1) are independent predictors of disease biochemical progress, as shown in Figure 4
.

Figure 4 Cox regression analysis.
In addition, the number of pelvic lymph node metastases of PSMA-PET is significantly related to biochemical progress: 1 pelvic lymph node metastasis vs.
no metastasis, OR=2.
60, 95%CI 1.
57-4.
31, p<0.
001; PSMA- In PET, there were 2 or more pelvic lymph node metastases vs.
no metastases, OR=4.
61, 95%CI 2.
84-7.
48, p<0.
001
.

Research conclusions: The initial PSA value, biopsy GG≥4, mpMRI showed ≥rT3 disease and PSMA-PET miN1 are predictors of early biochemical progression after RARP
.

In addition, the number of pelvic lymph node metastasis stages PSMA-PET is related to biochemical progress
.

Early identification of patients with high risk of postoperative biochemical progression can provide more basis for patients' follow-up treatment
.

Abstract 1175 A long-term validation study of the effect of PSMA-PET on MFS in a rescue radiotherapy cohort.
Purpose: Previous studies have shown that in the population with biochemical progression after radical RP, patients with negative PSMA-PET have a significantly higher response rate to rescue radiotherapy.
PSMA-PET positive patients
.

However, we have not seen more long-term follow-up results, such as long-term metastasis-free survival (MFS)
.

Research method: Retrospectively enrolled patients with limited-stage PCa who received salvage radiotherapy after indirect RP from 2012 to 2018
.

According to the results of the PSMA-PET test, the patients were divided into three groups: PSMA positive, PSMA negative, and no PSMA test
.

According to the clinical symptoms and the status of receiving ADT treatment, the propensity score is based on 4:1
.

Univariate Kaplan-Meier was used to analyze the 6-year MFS, and the Cox proportional hazard model was used to calculate the correlation between PSMA-PET and MFS
.

All tests are two-sided, and the significance level is p<0.
05
.

Research results: A total of 1784 patients were enrolled and grouped according to the PSMA-PET test.
The specific RP biochemical recurrence time, PSA, ADT treatment, etc.
are shown in Table 1: Table 1 The basic conditions of patients in the multivariate Cox regression analysis, Compared with “no PSMA PET”, “negative” and “positive” PSMA-PET are independently associated with worse MFS (PSMA-PET negative: HR 2.
38, CI 1.
12-5.
04, p=0.
02; PSMA-PET positive: HR 24.
55, CI 15.
60-38.
63, p<0.
0001)
.

Research conclusion: After adjusting for clinical characteristics, different treatment methods and other factors, the PSMA-PET results still have a high predictive effect on MFS
.

Abstract 1203 The regional lymph node metastasis of PSMA-PET is related to BCR-free and treatment-free survival after radical prostatectomy (RP).
Objective: To investigate the effects of PSMA-PET on BCR and auxiliary before RP and pelvic lymph node dissection (PLND) Or the impact of salvage treatment time
.

Research method: Collected PCa patients (64 cases of intermediate risk, 166 cases of high risk) who received 68Ga-PSMA-11 PET test and subsequently treated with RP and PLND during 2013-2017, and observed the BCR-free time and treatment-free survival
.

Research results: A total of 230 patients were enrolled, of which 4 (6.
2%) intermediate-risk patients and 47 (28.
3%) high-risk patients had extraprostatic PSMA-PET positive lesions; 66 patients (28.
7%) had positive lymph node histopathology ( pN1)
.

With a median follow-up of 30.
2 months, 50.
4% (n=116) of the patients had BCR, and 46.
5% (n=107) of the patients received adjuvant or salvage treatment
.

The histopathological test results and PSMA-PET test results are shown in Table 2.
Compared with the lymph node histopathological test, PSMA-PET has a sensitivity of 48.
5%, a specificity of 95.
7%, a positive prediction rate of 82.
1%, and a negative prediction.
The rate is 82.
2%
.

Table 2 The histopathological results of the patient’s lymph node test and PSMA-PET test results pN1 and PSMA-PET LN-positive patients have the worst benefits for BCR-free survival and treatment-free survival (1.
7 months, 2.
6 months), pN1 and Patients with negative PSMA PET LN followed (7.
5 months, 8.
9 months), and patients with no evidence of lymph node metastasis on histology and PSMA-PET (both 36 months) were the best (36 months), Figure 5
.

Figure 5 The results of a stratified survival analysis based on the results of PSMA-PET and lymph node histopathology.
A has no BCR survival period and B has no treatment survival period
.

Research conclusions: Although receiving complete PLND, patients with positive lymph nodes on PSMA-PET before RP still need early BCR and adjuvant/save treatment
.

Therefore, the results of the PSMA-PET test are helpful for patient consultation, stricter follow-up planning, and planning of new/adjuvant treatment options
.

Abstract 1204 Preoperative PSMA-PET/CT detection can be used as a predictor of early BCR.
Research purposes: in patients with suspected lymph node metastasis (LN) after RP combined with pelvic lymph node dissection (ePLND), to analyze the persistence of PSMA-PET/CT for PSA (BCP) and the predictive value of early BCR
.

Research method: Include patients who received 68Ga/18F-PSMA PET/CT before surgery, followed by RP and ePLND, who were newly diagnosed with moderate or high-risk PCa
.

BCP is defined as serum PSA level ≥0.
1 ng/ml 6-20 weeks after surgery
.

Early BCR is defined as follow-up within 12 months after surgery, PSA is continuously measurable (>0.
2 ng/ml)
.

According to the patient's LN status on PSMA-PET/CT, the patients were divided into PSMA- or PSMA+, and the lymph node histological status (pN) determined by ePLND was stratified
.

Research results: 1058 consecutive patients who received RP were enrolled, and 213 of them met the inclusion criteria
.

There was no statistical difference between the PSMA-negative group and the PSMA-positive group in age, preoperative PSA level, T stage, ISUP grade, surgical margin or lymph node metastasis
.

The median number of LN removed was 20 (IQR 15-26)
.

The results of PSMA-PET/CT and the histological results of ePLND are shown in Table 3.

.

The sensitivity of PSMA detection is 29%, the specificity is 83%, the positive prediction rate is 33%, and the negative prediction rate reaches 80%
.

Compared with histopathological detection of lymph nodes, the accuracy of PSMA reaches 71%
.

Table 3 The histopathological results of lymph node detection and PSMA-PET test results of patients.
Among the patients with complete data, 12% of patients (26/211) developed BCP, and 21% of patients (23/110) developed early BCR
.

The incidence of BCP and BCR in patients subdivided according to PSMA-PET and pN status is shown in Figure 6 (without multivariate correction)
.

Compared with the PSMA-PET -/pN1 group, the risks of BCP and BCR in the PSMA-PET +/pN1 group were significantly increased (p=0.
004; p<0.
001)
.

Figure 6 The occurrence of BCP and BCR after PCa radical operation.
The conclusion of the study: Among the patients with negative PSMA-PET, 20% of the lymph node histological test results are still positive
.

Therefore, patients with preoperative PSMA-PET/CT negative still need to consider ePLND; patients with preoperative PSMA-PET/CT positive and pN1 confirmed compared with PSMA-PET/CT negative patients, the risk of BCP and early BCR is significantly increased
.

2.
Related research on PSMA radionuclide therapy Abstract 1205 177 Lu-PSMA-I&T (LuPSMA) radionuclide feasibility study in neoadjuvant treatment of high-risk PCa Purpose: To evaluate neoadjuvant LuPSMA combined with RP through an open-label single-arm clinical trial With PLND, the safety of the treatment of HRPCa and the short-term prognosis of the tumor
.

Research method: HRPCa patients planned to receive 68Ga-PSMA PET/CT examination were continuously enrolled and received two 7.
4 GBq LuPSMA treatments 6 and 8 weeks before RP combined with PLND
.

Record the side effects of LuPSMA and related surgical indicators, and record the final surgical pathological results and postoperative biochemical reactions
.

All patients completed valid health-related quality of life questionnaires during baseline and postoperative follow-up
.

Research results: A total of 7 patients received two LuPSMA treatments, of which 6 patients have already received surgery
.

The median age was 66 years (IQR: 60, 68), and the median baseline PSA was 11.
4 ng/dL (IQR: 7.
6, 27)
.

There are 4 cases in group 4 of Gleason classification, and 3 cases in group 5 of Gleason classification
.

The only adverse event reported during LuPSMA treatment was fatigue in one patient (14%)
.

Two of the 6 patients had periprostatic adhesions during the operation, and there were no intraoperative complications
.

The median length of operation and the median estimated blood loss were 240 minutes (IQR 200, 260) and 250 ml (IQR 200, 350), respectively
.

The only adverse event after surgery was fever in 1 patient (14%)
.

The average length of hospital stay was 3 days (IQR 2, 4)
.

Four of the six final surgical specimens showed treatment-related histological changes
.

The surgical margins of 2 patients were positive
.

Biochemical reactions were observed in all patients, and the postoperative median PSA was 0.
01 ng/dL (IQR 0.
01, 0.
07)
.

The number of urine pads required in 6 patients within 3 months after operation was ≤1
.

Research conclusions: Preliminary research results show that two LuPSMA combined with RP therapy in HRPCa patients has good safety
.

Although longer follow-up is required, LuPSMA treatment does not seem to affect the recovery of urinary control
.

Experts comment that PSMA is a type II transmembrane protein whose expression in PCa cells is 100 to 1000 times that of normal cells
.

Studies have shown that the expression of PSMA in cancer cells increases with the tumor grade
.

PSMA is composed of two groups inside and outside the cell.
The external group can be connected to ligands with different functions, and the internal group contains functional factors for endocytosis, which can increase the accumulation of radiotracers inside the cell
.

These characteristics make PSMA a biological target with great development potential
.

Whether it is PSMA-related imaging tests or the development of small molecule radiopharmaceuticals (PSMA inhibitors), more and more researchers are paying attention
.

The EAU conference reported a number of new developments in the diagnosis and treatment of PSMA in PCa
.

In limited/late-stage patients, whether it is compared with the results of biopsy histopathology, or in the PEDAL test with multi-parameter MRI, the PSMA-PET test shows higher sensitivity and specificity, and The ability to identify clinically significant changes other than mpMRI detection provides strong evidence support for the role of PSMA-PET detection in clarifying the clinical staging of patients
.

The predictive value of PSMA-PET in the efficacy of treatment options and disease prognosis has also been fully discussed
.

The location and number of lymph node metastases of PSMA-PET are closely related to the occurrence of biochemical progression after radical PCa resection, expanded lymph node dissection, the formulation of salvage radiotherapy regimens, and the long-term benefits of MFS
.

The PSMA-PET test results have a high predictive value for the survival and prognosis of patients, which is helpful for patient consultation and development of stricter follow-up plans
.

However, PSMA-PET has not yet become a routine inspection item in China, with poor accessibility and expensive inspection costs
.

What kind of patients need more PSMA-PET testing, and how to avoid over-diagnosis has also become a problem of great concern to clinical experts
.

The research team from Italy established the Nomo prediction nomogram to predict the positive rate of PSMA-PET testing.
This prediction model was validated in an external multi-center cohort
.

Through intuitive visual nomograms, it helps clinicians choose the patients who can benefit the most from 68Ga-PSMA PET/CT
.

The Nomore line chart provides a certain selection basis for PSMA-PET detection, but it still needs to be verified in the Chinese population
.

In addition to its application in diagnosis, PSMA-related targeted therapy has also received extensive attention
.

In this year’s ASCO-GU and ASCO meetings, a number of PSMA-related radioligand therapy (RLT) clinical studies were successively announced, especially the VISION study of 177Lu-PSMA-617, which has entered phase III studies, bringing benefits to mCRPC patients More possibilities for survival
.

In this EAU conference, the researchers analyzed the benefits of another PSMA-related nuclide therapy LuPSMA in HRPCa neoadjuvant therapy.
The preliminary results showed that LuPSMA is very safe and does not affect the recovery of postoperative urinary control.
, Provides safety evidence for RLT in early patient research
.

Based on the inherent advantages of the structure of PSMA, radionuclide-labeled small molecule PSMA ligands show great potential in the diagnosis and treatment of PCa
.

More and more clinical studies support PSMA-PET detection as a predictor of patients' early clinical outcome
.

However, the published studies are mostly single-center or retrospective, with small sample sizes and lack of higher-level evidence support; the nuclear treatment plan based on PSMA is still in the exploratory stage
.

How to transform the prognostic analysis results of the PSMA-PET test to the clinic, how to select the population with the greatest benefit from the test, and form a test and treatment plan suitable for the Chinese population, still need more exploration and verification
.

Expert profile Professor Ding Guoqing, deputy secretary of the Party Committee of the Run Run Run Run Department Hospital, Zhejiang University School of Medicine, deputy director of the Department of Urology, PhD, chief physician, member of the Standing Committee of the Urology Branch of the Zhejiang Medical Association, and deputy leader of the Minimally Invasive Group, Zhejiang Medical Association Urogenital Tumor Deputy Chairman of the Special Committee Member of the Minimally Invasive Surgery Committee of the Zhejiang Medical Association Used to provide scientific information to medical professionals and does not represent the views of this platform