Best of 2024 in Prostate Cancer and Prostatic diseases

The year 2024 has been transformative for prostate cancer (PCa) and prostatic diseases, marked by advancements in basic science, diagnostic tools and novel therapeutic options.

The exact pathophysiology of PCa and benign prostatic hyperplasia (BPH) remains unknown. However, several studies suggest that inflammation plays a pivotal role in the pathogenesis of both conditions [1,2,3,4]. Notably, molecular pathways involving inflammation and autophagy have emerged as potential therapeutic targets for PCa and BPH, attracting considerable attention in recent years [5, 6]. Despite promising findings, no drugs directly targeting these mechanisms have been approved yet, but the journey is underway Table 1.

PCa diagnosis continues to face challenges of over-detection and overtreatment. Recently, advances in Artificial Intelligence (AI) powered risk calculators, refined biopsy strategies, and prostate-specific membrane antigen (PSMA) positron emission tomography-computed tomography (PET-CT) scan have improved diagnostic and staging accuracy [7, 8]. However, the best diagnostic and staging pathway has yet to be defined.

In terms of treatment, the body of literature on focal therapy is slowly increasing and several studies are defining its exact role in the management of PCa [9]. However, most of the available evidence is of low quality, as the majority of studies are single-center, non-comparative, retrospective in design, and exhibit heterogeneity in definitions, approaches, follow-up strategies, outcomes, and duration of follow-up [10]. As for the time being, the guidelines still consider the approach investigational and recommend its use in clinical trials or prospective registries.

In more advanced stages of the disease, such as biochemical recurrence (BCR), the introduction of next-generation imaging (NGI) and novel treatment modalities has significantly transformed patient management. Overall, the treatment of patients with BCR in the castration-sensitive non-metastatic setting remains a matter of debate, particularly regarding the patients who may benefit from an early treatment [11]. In this context, several studies suggest a role for PSA doubling time (PSADT) in stratifying patients.

Finally, technological innovation remains a key driver of progress. Recently, the developments of AI, particularly in natural language models (NLP), have expanded its applications in managing patient and clinicians’ information [12]. On the other side, several new robotic platforms have been developed over the recent years with the goal of improving outcomes and reducing morbidity [13].

The introduction of minimally invasive techniques (MISTs) has dramatically changed the management of lower urinary tract symptoms (LUTS) and BPH patients [14,15,16,17]. MISTs represent a new possibility to manage these patients, particularly in those patients wanting to preserve their sexual function [18]. However, despite initial enthusiasm, ongoing research should identify target patients for the different available techniques.

In 2024 hundreds of manuscripts were evaluated by our editorial team. In this commentary, we present the best articles selected to highlight the hot topics of this year for “Prostate cancer and prostatic diseases

Autophagy, a conserved evolutionary process that maintains cellular homeostasis under stress, has been implicated in the development of prostatic diseases. In their review, Lemos et al. evaluated the autophagy pathway in PCa, BPH and prostatitis. Their findings suggest that dysregulated autophagy may contribute to prostatic inflammation, potentially leading to BPH or PCa [19,20,21]. Preclinical studies on drugs such as sirolimus and everolimus (mTOR inhibitors) have shown promise in modulating autophagy, however their outcomes remain suboptimal [19, 22]. Conversely, medications like statins and metformin, which activate autophagy, have shown potential for PCa and BPH prevention, although evidence remains inconclusive [19, 23, 24]. Notwithstanding these promising results, several questions remain unanswered, particularly regarding the upstream mechanisms by which autophagy is deregulated in prostatic diseases. Finally, toxicity of autophagy-targeting drugs significantly limits their clinical use. Future research should focus on targeting the inflammatory pathway and translating these findings from bench to bedside.

Risk calculators (RC) for PCa, strongly endorsed by clinical guidelines, are valuable tools for reducing overdiagnosis and identifying significant cancers [25,26,27]. Denijs et al. identified 96 unique risk calculators (45 externally validated) for the diagnosis of clinically significant PCa (different definitions were used). The median area under the curve (AUC) of externally validated RCs ranged from 0.63 to 0.93, with 0.75 to 0.93 for clinical models including MRI, and 0.69 to 0.85 for blood biomarkers [28]. Despite their promise, these tools remain underused for several reasons including the lack of adaptive performance, usability and generalizability. Clinicians should exercise caution in selecting the appropriate RC and the possible role of AI in improving these limitations should be better investigated.

The introduction of multiparametric magnetic resonance imaging (mpMRI) has completely changed PCa management over the past decades, significantly reducing unnecessary biopsies and improving the accuracy clinically. significant (csPCa) detection. However, the management of patients with a negative biopsy and a positive MRI is still a matter of debate. It is not clear, whether these findings depend on a false-positive MRI interpretation or missed lesions during biopsy rather than a true disease-negative state. Zattoni et al. focused on a retrospective cohort of 694 patients with these characteristics with a median follow-up of 28 months (13–51) [29]. According to their results, 27% and 19% of these patients were diagnosed with PCa and csPCa respectively. A follow-up strategy, with mpMRIs and prostate biopsy based on clinical and radiological triggers, was associated with a lower risk of PCa and csPCa diagnosis during the follow-up period. Furthermore, several clinical and radiological covariates during the initial biopsy (including patients age, prostate volume, PI-RADS score at the first MRI, presence of atypical small acinar proliferation at the initial biopsy, number of Target (>3 fusion cores) or systematic biopsy (>12 cores)) were identified as predictors of PCa diagnosis on second biopsy. Despite its retrospective nature and its limitations, the present study identifies some predictors to improve the management of patients with a negative prostate biopsy and a positive MRI to avoid missing clinically significant cancers. A better standardization of imaging modalities and biopsy techniques, combined with the integration of patient characteristics and genetic testing into the PCa diagnostic process, could further reduce discrepancies in the near future.

Current guidelines recommend staging high-risk PCa using NGI techniques, particularly the PSMA PET-CT scan. However, its role in intermediate risk PCa is still questionable. Hagens et al. revisit the appropriateness of PSMA PET/CT in the unfavorable intermediate-risk PCa and validated the Prostate Cancer Network the Netherlands (PCNN) subclassification. Specifically, the PCNN subclassification defines low metastatic potential as a radiological tumor stage T1-2 and ≤50% positive prostate biopsies, moderate metastatic potential as a radiological tumor stage T1-2 and >50% and ≤75% positive prostate biopsies, and high metastatic potential as a radiological tumor stage ≥T3 and >75% positive prostate biopsies. Overall, the authors enrolled 182 patients with intermediate risk PCa recording metastasis in 23/185 (12.4%) men. The incidence of metastatic disease presents an incremental pattern across the distinct PCNN subgroups: 4.5% (4/89) for low metastatic potential, 13.3% (2/15) for moderate, and 20.0% (12/60) for high. So far; omitting NGI screening in patients with low metastatic potential could reduce the PSMA PET/CT scan burden by 48% [30]. Their findings reaffirm the staging role of PSMA PET/CT in unfavorable intermediate-risk PCa, highlighting the importance of patient stratification to optimize innovative diagnostic opportunities while ensuring no treatment opportunities are missed.

In the past years, previous studies have evaluated the role of PSADT in patients with BCR after radical prostatectomy. Overall, PSADT (<3 months) is associated with worse outcomes and most of the patients receive delayed androgen deprivation therapy (ADT) at metastasis, with few patients receiving early ADT (prior to metastasis).Freedland et al. [31]. examined a contemporary real-world cohort of patients with non-metastatic, castration-sensitive PCa and a BCR after definitive treatment to assess the impact of PSADT on oncological outcomes. Patients were divided into two cohorts: patients with rapid PSADT (≤9 months) and less rapid PSADT (>9 to ≤15 months). Median follow-up was 49 months; 502/781 (64%) had rapid PSADT and 279/781 (36%) had less rapid PSADT. A rapid PSADT was associated with statistically significant worse outcomes, including shorter time to first systemic antineoplastic therapy (median 11.4 vs. 28.3 months, HR: 2.17 [1.83–2.57]), metastasis-free survival (MFS) (76.1 vs. 106.3 months, HR: 1.73 [1.33–2.24]), and overall survival (OS) (120.5 vs. 140.5 months, HR: 1.76 [1.22–2.54]) compared to a slower PSADT. These results further support the prognostic role of PSADT, regardless of whether patients receive early or delayed ADT and the need of an early intervention in patients with a rapid PSADT following BCR. The possibility to manage patients with a BCR using the new androgen receptor signaling inhibitors open new insights on the importance to better identify and stratify these patients. Moreover, PSADT may help identifying patients who can benefit from an early treatment. The role of PSMA PET/CT scan for an early detection of local and distant metastasis in patients with BCR should be also evaluated and integrated with clinical data and PSA values in future studies.

Focal therapy is still considered an investigational approach for effectively managing PCa patients, aiming to reduce complications related to urinary and sexual function often associated with surgery or radiotherapy. Overall, high intensity focal ultrasound (HIFU) remains one of the mostly investigated modalities for focal therapy.

Shoji et al. evaluated, in their multi-centered study, oncological and functional outcomes of patients undergoing HIFU with intraoperative prostate compression in order to reduce the vascular flows in intraprostatic plexus and minimize the heat sink effect [32]. Overall, 240 patients with low-intermediate or high risk PCa were treated. No major complications were recorded but 24% of patients experienced erectile dysfunction after treatment. In their long follow-up study, the biochemical and the pathological failure-free survival rates after a single treatment were 92.2% and 93.7% for the low; 89.7% and 91.6% for the intermediate and 85.4% and 86.6% for the high-risk group. No significant differences in terms of radical or systematic treatment free rates were observed in the three groups (94–96%). A small number of patients also presented a csPCa on a six-months re-biopsy. Although the study presents important limitations such as the single center design and the small medium prostate size (30 grams), their encouraging results confirm the possible role of HIFU to manage localized PCa. Further studies should evaluate possible indication, patients ‘selection or how to define outcomes and manage possible recurrence. To address all these questions a collection on PCa focal therapy is ongoing and will be published soon in our Journal.

Chat Generative Pre-trained Transformer (ChatGPT), an internet-based large language model (LLM) chatbot application, was made publicly available few years ago [33,34,35,36]. In particular, the ability of these interactive chatbot to answer to common questions has been deeply evaluated in several medical areas with controversial results. Particularly, the risk of false or inaccurate medical information provided can determine significant risk for patients ‘care. Hershenhouse et al. evaluated the accuracy, readability and understandability of GPT 3.5 responses to nine PCa patient questions from both the urologist and patient perspectives. Questions were identified through google trends [37]. GPT-generated output was deemed correct by 71.7% to 94.3% of raters (36 urologists, 17 urology residents) across the nine different scenarios. GPT-generated simplified layperson summaries of this output was rated as accurate in 8 of 9 (88.9%) scenarios and sufficient for a patient to make a decision in 8 of 9 (88.9%) scenarios. Although the answers were deemed correct, the technology is not designed to deliver patients information due to the low readability and understandability of the answers. Overall, the present study highlights the possible application of the new chatbots in urology. However, the technology is still imperfect, and it is not completely accurate and fully reliable for patient education. Overcoming these limitations, might further extend their routine use for the management of PCa patients.

Robotic surgery has completely changed PCa surgical management in the last 20 years. Since the introduction of the Da Vinci robot, several other platforms have been introduced into the market with competitive results. Recently the new Da Vinci Single port platform is available and seem to be an innovative approach to further reduce surgery invasiveness in PCa and BPH management. Franco et al. performed a comprehensive systematic review and meta-analysis on the current knowledge on the current evidence on single port robot-assisted radical prostatectomy (SP-RARP) and SP robot-assisted simple prostatectomy (SP-RASP) procedures [38]. A total of 21 studies investigating 1400 patients were included in the systematic review, 18 were related to SP-RARP while 3 to SP-RASP. Only 8 comparative studies were eligible for meta-analysis to compare SP vs multi-port (MP). Similar outcomes were observed for SP-RARP and MP-RARP in terms of operative time, catheterization time, pain score, complications rate, continence and potency rates, positive surgical margin, and BCR rates. Length of hospital stay was shorter in the SP group after sensitivity analysis (WMD − 0.58, 95% IC − 1.17 to −0.9, p<0.05) when compared to MP group. A lower positive surgical margins rate in the SP extraperitoneal technique compared to MP-RARP (WMD 0.55, 95%CI 0.35–0.87, p = 0.01) was also recorded. Regarding simple prostatectomy, SP approach required a significantly shorter hospital stay (17 vs. 33 h, p < 0.01), less use of opioids (12% vs. 42%, p < 0.01), and a shorter catheterization time compared to MP-RASP (6 vs.9 days, p < 0.01). No differences in post-operative outcomes were reported (symptoms or flow). The present study suggests the SP platform may reduce surgical invasiveness and hospitalization, paving the way for a day-case management of PCa and BPH. However, stronger evidence is needed to understand the real role of the SP platform in the current robotic armamentarium and to identify it routine applicability in different settings and patients.

MISTs are emerging options in managing BPH patients and they represent a possible alternative to medical treatment or to endoscopic prostatectomy in patients who want to preserve their sexual function. Lambertini et al. have the merit of analyzing very precisely the perioperative and long-term complications after MISTs—including Aquablation, water vapor energy ablation (Rezūm), Transperineal laser ablation of the prostate (TPLA), implantation of a prostatic urethral lift (PUL) and temporary implantable nitinol device (iTIND)—in BPH patients [39]. According to their results, the different MISTs have different safety profiles. Particularly, Aquablation presented a higher major complications rate of 14% (IQR 6–22), mostly in patients with prostates <70 ml; PUL showed a higher early postoperative acute urinary retention rate (10.9%, IQR 9.2–12.3%), while 1.4% of patients treated with iTIND experienced major perioperative complications. Urinary tract infections were mostly reported in series assessing TPLA and Rezūm. Although this systematic review is characterized by heterogeneity in terms of study design, as several studies lack a comparison with standard of care options it represents a comprehensive analysis of all the possible complications reported with the available MISTs. These data are important in counseling patients regarding the different options now available to manage their symptoms and to preserve sexual function. Tailored treatment should be based on patient’s characteristics and perspectives. However, patients undergoing MISTs should be informed about their efficacy and safety, while also understanding that these procedures are not entirely free of complication risks.

The Optilume BPH Catheter System represents a novel addition to the MIST armamentarium. Kaplan S et al. presented the 2 year results of the PINNACLE study, evaluating the durable symptom relief and safety with the Optilume BPH Catheter System vs a sham procedure [40]. Of the 100 participants randomized to receive Optilume BPH, data from 77 participants are available at 2-years follow-up. Particularly, 67.5% (56/83 CI 56.3%, 77.4%) of participants in the Optilume BPH arm were symptomatic responders as defined by ≥30% improvement in international prostatic symptoms score (IPSS) without medical or surgical retreatment. IPSS significantly improved from 23.4 ± 5.5 to 11.0 ± 7.0 and Qmax improved from 8.9 ± 2.2 to 19.0 ± 16.3. No device and/or treatment related serious adverse events or changes in sexual function were reported. These results postulate Optilume BPH catheter system as a new possible MISTs to manage BPH patients. The lack of comparative studies with other MISTS or with standard endoscopic treatments is a strong limitation to possible identify the best patients for the best treatment. Long term results, retreatment rates, availability and costs are also unresolved issues in the real life MITSs practice.

Management of PCa and prostatic disease are challenging but several innovations have been recently introduced and/or are under investigation. A continuous innovation in imaging technologies will reduce the number of unnecessary biopsies and the diagnosis of insignificant PCa; AI may further help to improve the current risk calculators and may deliver a better education to our patients. Urology practice has been always linked to technological improvement and the continuous development of new options for focal therapy, for robotic platforms and for BPH minimally invasive treatments is a proof of this innovation. However, we have not to forget how many innovative treatments have been introduced into the market with excellent results but then they have been abandoned after few years of practice. Year after year we have to challenge in clinical trials and in real life practice all these innovations with the final goal to settle down their indication and improve our patient’s quality of life.