Highlights of Prostate Cancer Research at the 2024 EAU Congress

Highlights of Prostate Cancer Research at the 2024 EAU Congress

The 2024 European Association of Urology (EAU) Congress was successfully held in April. As one of the world’s largest and most influential urology congresses, the EAU showcased groundbreaking research, new guidelines, and the latest developments in urology from around the world.

Prostate cancer (PCa), one of the most common malignant urological tumors in men, has always been a hot topic of discussion at the congress, highlighting several recent advances in the diagnosis and treatment of prostate cancer.

Highlight 1: Challenging Guidelines, Relaxing the Serum PSA Baseline for Low-Risk Prostate Cancer to 1.5 ng/ml

The ERSPC Rotterdam study results show that early screening for prostate cancer (compared to a control group not screened) can reduce the relative risk of prostate cancer mortality by 27% (P < 0.05). So, which populations should undergo enhanced prostate cancer screening? And which populations are considered low-risk for developing prostate cancer? What is the serum PSA level for low-risk individuals at the age of 45? Currently, the EAU guidelines define individuals with a serum PSA level below 1 ng/ml at the age of 45 as low-risk, requiring a PSA retest after 8 years. At this year’s EAU Congress, Professor Albers from the University of Duesseldorf in Germany presented the results of the PROBASE study, challenging this notion.

PROBASE is a population-based randomized trial that recruited 46,495 45-year-old German men and compared the screening results for developing prostate cancer (PCa) starting at age 45 and 5 years later. Based on PSA levels, men were classified into risk groups with different screening intervals: low-risk (<1.5 ng/ml, screened every 5 years), medium-risk (1.5-2.99 ng/ml, screened every 2 years), and high-risk (>3 ng/ml, immediate biopsy recommended). The results showed that among individuals with baseline PSA levels below 0.5 ng/ml, 0-1 ng/ml, and 0-1.5 ng/ml, the number of individuals developing prostate cancer 5 years later was 0 cases (0%), 2 cases (0.02%), and 7 cases (0.04%), respectively. Most of the patients who developed prostate cancer were staged as having clinically insignificant PCa. Based on this, Professor Albers believes that a baseline serum PSA level below 1.5 ng/ml at age 45 can be defined as low-risk for prostate cancer, with a reevaluation recommended after 5 years.

Expert Commentary:

In recent years, the incidence of prostate cancer has been increasing year by year worldwide. Therefore, early screening and diagnosis of prostate cancer can effectively improve patient survival rates. At the same time, defining and selecting low-risk populations for prostate cancer is equally important to reduce unnecessary repeat examinations and minimize waste of medical resources. The results of the PROBASE study from Germany clearly indicate that a baseline serum PSA level below 1.5 ng/ml in 45-year-old men is considered low-risk for prostate cancer, with no need for repeat serum PSA testing within 5 years. This finding challenges the current EAU guideline’s mention of the 1 ng/ml level, providing important guidance for clinical screening work and reducing unnecessary blood tests for more individuals. However, it is regrettable that the study mainly focused on the age of the population and did not consider the impact of carrying gene mutations (such as BRCA2 gene mutations) on the study results. Furthermore, there is still a lack of reports on large-scale, long-term studies in the country. We look forward to more results from cohort studies in the future.

Highlight 2: Biparametric MRI Replaces Multiparametric MRI as the Preferred Imaging Method for Prostate Cancer Diagnosis

In 2018, Professor Kasivisvanathan published an article in the New England Journal of Medicine titled “MRI-Targeted or Standard Biopsy for Prostate-Care Diagnosis.” The results of this study changed the previous application mode of MRI mainly for the staging of PCa after diagnosis, bringing forward its application to before biopsy, for screening patients for the need for biopsy and guiding targeted biopsy based on imaging results. Since then, multiparametric MRI (mpMRI) technology, including DWI and DCE sequences, has been clearly recommended by domestic and international guidelines for the diagnosis of initial PCa, and prostate-targeted combined with systematic biopsy based on mpMRI has also become the preferred biopsy method recommended by guidelines. However, some scholars believe that the DCE sequence has limited additional value for the diagnosis of PCa, so it is considered that biparametric MRI (bpMRI) containing only T2WI and DWI can be used for the routine diagnosis of PCa. So, is there a similar diagnostic efficiency between bpMRI and mpMRI for the diagnosis of PCa?

In the “Game Changing” session of this year’s EAU Congress, Professor Kasivisvanathan, a pioneer in PCa diagnosis and screening, presented the preliminary results of the latest PRIME study. PRIME is a prospective, international, multicenter clinical trial aimed at evaluating whether bpMRI is non-inferior to mpMRI in diagnosing clinically significant PCa. Its main study endpoint is the proportion of patients detected with clinically significant PCa (Gleason score ≥3+4 or Gleason grade ≥2). The study included 490 patients, and the results showed that there was no significant difference between bpMRI and mpMRI in diagnosing clinically significant PCa (P = 0.5). At the same time, there was no significant difference between bpMRI and mpMRI in terms of the specificity and sensitivity of diagnosing overall PCa (P = 0.5 and 0.48, respectively). More importantly, the study did not find an increase in the proportion of patients in the bpMRI group undergoing biopsy due to unclear imaging. Therefore, Professor Kasivisvanathan believes that biparametric MRI should replace multiparametric MRI as the preferred imaging method for the diagnosis of prostate cancer.

Expert Commentary:

Early diagnosis of PCa is of great significance for improving the prognosis of the disease. In recent years, MRI technology has rapidly developed and has become an important imaging tool for PCa diagnosis. mpMRI is currently the preferred imaging method for PCa diagnosis and staging, playing a leading role in guiding biopsy and treatment, while bpMRI, due to the absence of adverse reactions caused by contrast agents, relatively lower cost, and shorter acquisition time, has been proposed for the routine diagnosis of PCa. The choice between the two has always been the focus of academic discussion. The publication of the PRIME clinical trial results clearly indicates that bpMRI is non-inferior to mpMRI in diagnosing PCa. Therefore, bpMRI is expected to replace multiparametric MRI as the preferred imaging method for the diagnosis of prostate cancer. Another conclusion worth noting is that the quality of MRI imaging is particularly important for result interpretation. In addition to using a 3.0T magnetic resonance, the patient’s cooperation and the operation of the radiologist during the examination will also affect the final MRI imaging quality. At the same time, the PRIME study also found that the DCE parameters could detect 6.3% of lesions that could not be detected by bpMRI, suggesting that some patients could still benefit from mpMRI, which may be related to the vascular enrichment of certain lesions, which can be better evaluated when using contrast agents. Therefore, although the PRIME trial suggests that the overall PCa diagnostic accuracy of bpMRI is similar to that of mpMRI, whether the diagnostic performance of bpMRI is similar to that of mpMRI in PCa subgroups (e.g., diagnosed with PI-RADS3 score) still needs further study.

Highlight 3: Expanding Pelvic Lymph Node Dissection Significantly Reduces the Risk of Postoperative Distant Metastasis in Prostate Cancer Patients

Pelvic lymph node dissection (PLND) is an important step in radical prostatectomy (RP) and is the gold standard for determining lymph node metastasis. Extended pelvic lymph node dissection (EPLND) provides more accurate lymph node staging than limited pelvic lymph node dissection (LPLND) and better guides subsequent treatment. However, whether EPLND has an advantage over LPLND in terms of patient survival has been controversial.

In 2021, Professor Touijer published the results of a clinical randomized controlled trial titled “Limited versus Extended Pelvic Lymph Node Dissection for Prostate Cancer: A Randomized Clinical Trial.” The study included 1440 patients and showed no significant difference in postoperative biochemical recurrence (BCR) between the EPLND and LPLND groups. At this year’s EAU Congress, Professor Touijer updated the follow-up results. The average 4.2-year follow-up results showed that there was still no significant difference in postoperative biochemical recurrence (BCR) between the EPLND and LPLND groups. However, the probability of postoperative distant metastasis was significantly lower in the EPLND group (P < 0.001). Further research showed that patients with postoperative pathological N1 could benefit from extended lymph node dissection. The difference in the probability of distant metastasis was not statistically correlated with postoperative BCR, whether salvage treatment was received, or the number of lymph nodes cleared during dissection, suggesting that it may be related to the location of lymph node metastasis. Based on this, Professor Touijer believes that radical prostatectomy should be performed with EPLND.

Expert Commentary:

Lymph node metastasis is the most common way for prostate cancer to spread. Some patients undergoing radical prostatectomy are relatively late staged, with a high degree of malignancy (high Gleason score) and a high risk of pelvic lymph node metastasis. Therefore, it is necessary to perform lymph node dissection in some patients. From the perspective of Professor Touijer’s study, patients with postoperative pathological lymph node metastasis can benefit from EPLND, which means that it is particularly important to accurately determine whether patients have lymph node metastasis before surgery. Currently, the risk of lymph node metastasis in prostate cancer patients can be predicted by various models, and the widely used one is the nomogram prediction model established by Briganti et al., which calculates the risk of lymph node metastasis based on variables such as biopsy Gleason score, positive biopsy needle number, preoperative PSA, and clinical stage. New imaging techniques such as PSMA PET-CT should also be included in the examination methods to assess whether prostate cancer patients need to undergo extended lymph node dissection, reducing the risk of unnecessary lymph node dissection complications.

Another important clinical issue raised by this study is why, in the absence of a significant difference in postoperative BCR between the two groups, EPLND can reduce the risk of postoperative distant metastasis in patients? This may be related to the heterogeneity of metastatic lesions in the prostate, the presence of dormant tumor cells in lymph nodes, and other factors. It is hoped that with the conduct of more combined clinical and basic experiments in the future, this question can be answered.

Highlight 4: PARP Inhibitor Combination Therapy Becomes the First-Line Precision Treatment for mCRPC

Poly ADP-ribose polymerase (PARP) inhibitors have become a recommended first-line treatment option for mMRPC in guidelines, possibly being the most exciting and talked-about report in prostate cancer at this year’s EAU Congress. The PROpel study showed that the overall survival (OS) in the combination therapy group, HRm cohort, and BRCA1/2m cohort was improved. The TALAPRO-2 study results showed that compared to placebo plus enzalutamide, talazoparib combined with enzalutamide significantly improved radiographic progression-free survival (rPFS) (HR=0.45; 95%CI: 0.33-0.61; P < 0.0001, NR vs 13.8 months). The OS HR was 0.69 (95%CI: 0.46-1.03; P=0.07). In the BRCA1/BRCA2 mutation and non-BRCA1/BRCA2 mutation subgroups, the OS HR was 0.61 (95% CI: 0.31-1.23; P=0.16) and 0.66 (95% CI: 0.40-1.10; P=0.11), respectively. The MAGNITUDE study found that in the HRR gene mutation cohort, the combined group of patients showed a significant improvement in radiographic progression-free survival (rPFS), with a 27% reduction in the risk of disease progression or death (HR=0.73; p=0.022). This improvement was most pronounced in patients with BRCA1/2 gene mutations. Based on the above studies, the latest EAU guidelines have included PARP inhibitor combination therapy as a first-line treatment option for mCRPC (strong recommendation).

Expert Commentary:

Since the approval of the first PARP inhibitor in 2014, the concept of “synthetic lethality” has become popular in the field of oncology. In just a few years, six PARP inhibitors have been approved globally, harvesting indications for breast cancer, pancreatic cancer, and ovarian cancer. This year’s EAU Congress also strongly recommends including PARP inhibitor combination therapy as a first-line treatment option for mCRPC. However, we should objectively and rationally assess the treatment value of PARP inhibitor combination therapy in mCRPC.

1. The optimal indications for PARP inhibitor combination therapy are still unclear: From the results of the PROpel, TALAPRO-2, and MAGNITUDE studies and their meta-analyses, it is clear and significant that PARP inhibitor combination therapy is effective in patients with BRCA2 mutations, while there is a lack of significant differences in efficacy in other homologous recombination repair gene (HRR) mutations (such as BRCA1, ATM, and CDK12). The benefit observed in the HRRm cohort may be due to statistical bias towards including patients with BRCA2 mutations. Therefore, more data are needed for non-BRCA2 HRR mutation patients.

2. The PROpel, TALAPRO-2, and MAGNITUDE studies all used radiographic progression-free survival (rPFS) as the primary clinical endpoint. Since the three studies did not adopt a crossover design experimental plan, whether rPFS can ultimately be translated into overall survival (OS) benefits still needs further follow-up.

3. The side effects of PARP inhibitors should not be underestimated: In the PROpel study, 45% of patients in the combination therapy group paused treatment due to side effects, 20% of patients paused treatment, and 13% of patients discontinued treatment. In the TALAPRO-2 study, the rate of grade 3-4 adverse reactions in the talazoparib plus enzalutamide group was 75%, significantly higher than the 45% in the control group. Horizontally, due to the potential increased risk of death, under FDA review, the approval of PARP inhibitors for the treatment of third-line and higher ovarian cancer was withdrawn in 2022. Therefore, the safety of PARP inhibitor combination therapy needs further verification.