【2022 ESMO】The latest progress of PSMA in the diagnosis and treatment of prostate cancer

*For medical professionals only

The 2022 European Society for Medical Oncology (ESMO) Annual Meeting was held
in Paris, France from September 9 to 13, 2022 in the form of an online and offline combination.

At this year's ESMO conference, much
attention was paid to the progress of prostate-specific membranous antigen (PSMA) in the diagnosis and treatment of prostate cancer.

Here, this article summarizes the latest diagnostic and treatment progress of PSMA at this conference for the benefit of readers
.

PSMA addresses the difficulties of traditional diagnostic staging

The conference presentation, based on the biological characteristics of PSMA, Ph.
D.
, Principal Investigator, Daniela Oprea Lager, Ph.
D.
, Department of Radiation and Nuclear Medicine, University Medical Center Amsterdam, the Netherlands, describes how PSMA is a promising high-specific target in imaging diagnosis of prostate cancer^[1]:P SMA is a type II transmembrane protein that is expressed 100 to 1000 times more
in prostate cancer cells than in normal cells.

At the same time, only 10% of all primary prostate cancers are PSMA-PET-negative, so imaging evaluation of PSMA can be widely used
.

In addition, PSMA expression is associated with poor prognostic factors, and quantitative assessment can provide prognostic information
.

Figure 1: Biological properties of PSMA

Dr.
Lager went on to present a 2017 review of PSMA that summarized the effectiveness of multiple radiotracers, including 68Ga, 18F, and 177Lu^.
[2]

The biological distribution of different tracers is roughly the same, but the uptake in the liver and spleen varies
.

Dr.
Lager believes that the PSMA tracers most commonly used for PET imaging today are 68Ga and 18F, and then discusses how to select the appropriate population for two different labeled PSMA labels by comparing the half-life, tracer preparation, and image resolution of 68G and 18F markers, so as to make diagnosis and prognostic outcome prediction
.

Figure 2: Specific tumor uptake distribution of 68G and 18F-labeled PSMA ligands

PSMA-PET imaging is well known to be suitable for the first diagnosis and staging of prostate cancer, the re-staging of biochemical recurrence, and the evaluation
of metastatic castration resistance.

Dr.
Lager also focused on the role
of PSMA-PET in the first diagnosis and staging.

The main difficulty faced in the diagnosis and staging of prostate cancer patients is the judgment
of small metastases.

If the patient undergoes bone scanning, only degenerative changes are detected, and CT scans show no evidence of disease metastasis, but PSMA-PET can detect PSMA strong uptake lesions
.

On the other hand, enhanced 68GA-PSMA PET/CT imaging can replace pelvic CT for detecting lymph node metastases
.

In addition, Dr Lager presented the pro-PSMA trial, an Australian multicenter, bi-armed, prospective randomized study whose results support the use of PSMA PET/CT
in the initial diagnosis of high- to medium-risk prostate cancer.

Compared with conventional imaging (CT and bone scan), PSMA PET/CT improved the accuracy of local and distant metastatic disease by 27%, the clinical benefit of changing treatment regimens based on imaging results increased by 13%, and the proportion of positive metastases uncertain decreased by 16%.


At the same time, the radiation exposure of GA-PSMA PET/CT is significantly lower than that of conventional imaging, thereby greatly improving patient safety ^[4].

Figure 3: Pro-PSMA study ^[4].

The 2022 EAU guidelines clearly state that PSMA-PET/CT is more accurate than traditional imaging in staging high-risk localized prostate cancer and that the evidence
on PSMA-PET in diagnosis and staging is updated over time.

It is worth noting that PSMA, in addition to its important application in diagnostic staging and in the treatment of metastatic prostate cancer, also plays a huge role
.

Addition of Lu-PSMA to the latest guidelines is recommended for secondary/third-line therapy at mCRPC: For patients with mCRPC who have previously been treated and progressed, treatment with 177Lu-PSMA-617 is recommended if PSMA uptake is significantly elevated (higher than in the liver) with one or more metastases with a strong level of evidence ^[5].

Table 1: 2022 EAU Guidelines ^[5].

Recent advances in the use of PSMA in the treatment of mCRPC

The VISION study enrolled patients with metastatic hormone-sensitive prostate cancer (mCRPC) and positive PSMA PET/CT to compare the efficacy and safety
of 177Lu-PSMA-617 with standard of care (SoC).

Previous results have shown that treatment with 177Lu-PSMA-617 in combination with SoC prolongs progression-free survival (rPFS) and overall survival (OS), with a 50% decrease in prostate-specific antigen (PSA) levels from baseline than in the SoC group
alone.

This post-mortem analysis was designed to assess the correlation
between the magnitude of the reduction in PSA from baseline levels and clinical outcomes in group 177Lu-PSMA-617.

The PSA decline was divided into four subgroups: no decline, ≤ 50%; 50% to 90% decrease; The decline > 90%, using Cox proportional risk regression to estimate PSA decline versus rPFS and OS risk ratio (HRs
).

The results showed that in the 177Lu-PSMA-617 group, the PSA decline was greater and was associated
with rPFS and OS prolongation.

Table 2: Risk regression analysis of PSA and rPFS and OS in the 177Lu-PSMA-617 group

Study conclusions: The magnitude of the reduction in PSA levels in patients with mCRPC was important
for the prediction of clinical outcomes during treatment with 177Lu-PSMA-617 plus SoC.

The RRU study retrospectively analyzed data from 133 patients with mCRPC at the German Nuclear Medical Center from 2021 to 2022 to evaluate the efficacy and safety
of different treatment regimens - Ra-Lu (223 radium-chemotherapy-177 lutetium) and Ct-Ra-Lu (chemotherapy-223 radium-177 lutetium).

The results showed that in the baseline analysis, the proportion of ECOG scores of 0, 1 and 2 before the treatment of 177Lu-PSMA was 0%, 62% and 38%, respectively.
The median PSA was 285.
5 ng/ml; The median alkaline phosphatase (ALP) is 146.
0 U/L
.

56% of patients received ≥ 4 medications (71% for Abitron, 70% for Nzarumine, 74% for Docetaxel and 23% for Cabatarace).


71% of patients have received 6 223Ra injections
.

All patients have bone metastases; Visceral metastases
are present in 27% of patients.

73% of patients received 1-4 cycles of 177Lu-PSMA, and 23% of patients received a treatment cycle of ≥5
.

The table lists the specific safety data
.

The study showed that the overall patient PSA50 response rate during the treatment period of 177Lu-PSMA was 42%; Ra-Ct-Lu group was 46%; The Ct-Ra-Lu group was 36%.


The overall patient response rate to ALP50 was 9%; The Ra-Ct-Lu group and the Ct-Ra-Lu group were both 6%.


OS patients as a whole were 13.
2 months (95% CI 10.
5-15.
6 months); Ra-Ct-Lu group was 12 months (95% CI 8.
8-14.
6 months); The Ct-Ra-Lu group was 14 months (95% CI 9.
4-16.
9 months
).

Table 4: Statistics of adverse events

Figure 4: PSA50 and ALP50 response rate analysis for different treatment sequences

Figure 5: OS analysis of different treatment sequences

Conclusions: Real-world studies have verified the safety and efficacy of 177Lu-PSMA after treatment with 223 radium and chemotherapy, and the order of 223Ra and chemotherapy does not change the safety and OS results
of 177Lu-PSMA.

The study included a total of 79 mCRPC patients who had received 177Lu-PSMA radioligand therapy (RLT) between 2016 and 2021, with a median age of 82 years, and the study evaluated PSA response rate, PFS, OS outcomes, and safety signals
.

Patients who have received androgen-targeted therapy (ARAT) and paclitaxel-based chemotherapy or are not eligible for chemotherapy may be included, and all patients have high PSMA expression
.

Patients had received an average of 2 mCRPC treatment regimens before, and 50 patients (63.
3%) had not received chemotherapy before 177Lu-PSMA treatment; Forty patients (17.
7%) had visceral metastases
.

The results showed that 38 patients (48.
1%) had a 50% decrease in PSA; PSA decreased 90% to 25 cases (31.
6%)
.

Compared with patients who had received chemotherapy, patients who had not received chemotherapy had a higher PSA response rate (50% reduction in PSA), 55.
1% vs.
44.
0%.


The overall median PFS and OS were 9.
5 and 16.
5 months,
respectively.

Patients who had not received chemotherapy had significantly longer median PFS and OS than those who had received chemotherapy (PFS: 11.
3 months versus 6.
4 months, p<0.
01; OS: 20.
4 versus 14.
0 months, p<0.
01).

In terms of safety, grade 3 trial-related adverse effects (TRAE) occurred as follows: 4 cases (5%) of anemia, 3 cases (4% of cases) thrombocytopenia, and 6 cases (8%) of chronic renal impairment
.

No non-hematological safety events
above grade 3 were observed.

The most common side effects are dry mouth, fatigue and loss of appetite, which is grade
1-2.

Figure 7: Survival data analysis of patients who initially received chemotherapy versus those who received chemotherapy (a.
PSA-PFS； b.
Clinical PFS; c.
OS)

Study conclusions: The efficacy and safety of 177Lu-PSMA radioligand therapy in elderly patients with mCRPC are comparable
to those previously reported.

Patients who did not receive chemotherapy responded better to treatment and benefited for a longer
period of time than those who had received chemotherapy.

Expert reviews

PSMA detection is very important in the clinical staging of prostate cancer, and also has high predictive value
for the efficacy of different treatment options and the prognosis of disease progression.

The reason why PSMA can be an ideal target for prostate cancer diagnosis and treatment is that PSMA is specifically highly expressed
in prostate cancer cells.

Some studies have shown that the expression of PSMA in prostate cancer cells is positively correlated with elevated tumor grades
.

In addition, the use of PSMA-PET can perform more accurate clinical staging and post-biochemical recurrence in patients with high-risk prostate cancer, and PSMA can be found to be expressed
in different types of prostate cancer.

At the same time, PSMA can initiate the endocytosis reaction, thereby increasing the aggregation of radiotracers inside the cell, improving imaging or efficacy
.

Therefore, when the biopsy results are not ideal or the clinical diagnosis is not very certain, the use of PSMA-PET can provide more accurate tumor localization and grading information, and also avoid complications
such as local bleeding or infection caused by unnecessary biopsy sampling.

Results published in the VISION Phase III study show that 177Lu-PSMA-617 in combination with standard therapy prolongs rPFS and OS in patients with mCRPC with positive expression of PSMA, so 177Lu-PSMA-617, as a second- and third-line treatment for mCRPC, has been recommended
by the 2022 EAU guidelines.

In addition, multiple studies published at the conference, revealing the correlation between PSMA-targeted therapeutic endpoints, such as rPFS and OS, and PSA decline, help to find more effective alternative endpoints for clinical studies of PSMA drug therapy trials
.

As research progressed, it was found that PSMA expression levels (SUVmax) were closely related to the PSA50 response rate and OS after treatment ^[10], so PSMA-PET could also be used to accurately screen suitable patients for targeted therapy
.

In addition, for the post-line treatment of advanced mCRPC, it is also important
to look for PSMA treatment opportunities.

One study exploring the efficacy and safety of 177Lu-PSMA in the treatment and post-chemotherapy of 223 radium isotope showed that the order of isotope therapy versus chemotherapy did not alter the OS and safety of
177Lu-PSMA therapy.

With the development of multiple clinical trials of PSMA drugs, more safety information from longer follow-up times has also been reflected
in the benefits of using these drugs in elderly patients.

Among the ≥80-year-old patients who have previously received ARAT treatment and chemotherapy, 177Lu-PSMA treatment has good efficacy and safety, and the efficacy is better for patients who have not received chemotherapy than for patients who have received chemotherapy, and the benefit time is longer
.

In general, in the era of precision treatment of advanced mCRPC, the diagnosis and treatment of PSMA can play a greater advantage, suggesting that the treatment mode of multiple disciplines such as urology, medical oncology and nuclear medicine (MMT) should be strengthened
.

At present, more and more large hospitals in China are gradually incorporating PSMA-PET into routine examination items, but for further expanding its scope of application, reducing testing costs, accurately selecting patients, avoiding overdiagnosis, etc.
It is also a matter of great concern to clinical experts, and it is still necessary for scholars in China to conduct more in-depth research and exploration
.

Professor Zheng Fufu

Department of Urology, First Affiliated Hospital of Sun Yat-sen University

Chief physician, Ph.
D.
, doctoral supervisor, postdoctoral co-supervisor

He is a member of the Genitourinary Branch of the China Association for the Promotion of International Healthcare Communication

International member of the American Society of Urology (AUA).

Deputy Leader of the Prostate Group of the Urology Branch of the Guangdong Medical Association

He is a member of the Urology Branch of Guangdong Medical Doctor Association

He is a member of the Urology Branch of Guangdong Association of Integrative Traditional Chinese and Western Medicine

Visiting Scholar, Massachusetts General Hospital, Harvard University

Reviewer of Chinese Journal of Experimental Surgery

[1].
T Maurer et.
al.
Current use of PSMA-PET in prostate cancer management.
Nat Rev Urol.
2016 Apr; 13(4):226-35.

[2].
M.
Eiber et.
al.
J Nucl Med.
Prostate-Specific Membrane Antigen Ligands for Imaging and Therapy.
2017 Sep; 58(Suppl 2):67S-76S.

[3].
Afshar-Oromieh et.
al.
The Rise of PSMA Ligands for Diagnosis and Therapy of Prostate Cancer.
J Nucl Med.
2016 Oct; 57(Suppl 3):79S-89S.

[4].
Hofman et.
al.
Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study.
Lancet.
2020 Apr 11; 395(10231):1208-1216.

[5].
EAU guideline 2022

[6].
A.
J.
Armstrong, et al.
Association between prostate-specific antigen decline and clinical outcomes in patients with metastatic castration resistant prostate cancer in the VISION trial.
2022 ESMO.
Abstract 1372P.

[7].
K.
Rahbar, et al.
Lutetium-177-prostate-specific membrane antigen therapy (177Lu-PSMA) in patients (Pts) with prior radium-223 (223Ra): Safety and effectiveness outcomes.
2022 ESMO.
Abstract 1392P.

[7].
R.
L.
Tauber, et al.
Treatment efficacy and safety of 177Lu-PSMA radioligand therapy in octogenarians with metastatic castration-resistant prostate cancer.
2022 ESMO.
Abstract 1414P.

[8].
Hofman MS, Emmett L, Sandhu S, et al.
[(177)Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): A randomized, open-label, phase 2 trial.
Lancet.
2021 Feb 27; 397(10276):797-804.

[9].
Gafita A, Fendler WP, Hui W, et al.
Efficacy and Safety of 177Lu-labeled Prostate-Specific Membrane Antigen Radionuclide Treatment in patients with diffuse bone marrow involvement: A multicenter retrospective study.
Eur Urol.
2020 Aug; 78(2):148-154.

*This article is for the sole purpose of providing scientific information to medical professionals and does not represent the views of this platform