Oligometastatic prostate cancer: new horizons for local treatment with the androgen receptor target therapy

Prostate cancer (PC) is notoriously a leading cause of cancer-related death worldwide, representing one of the most frequently diagnosed non-skin cancer among male patients (1). Treatment of PC depends on several factors, including the stage and grade of the cancer, the patient’s overall health, and their preferences. Recent advances in imaging, particularly prostate-specific membrane antigen (PSMA)-positron emission tomography (PET), have played a pivotal role in identifying oligometastatic disease, offering clinicians a clearer picture of metastatic spread and improving patient selection for local treatments.

The role of PSMA-PET staging in oligometastatic PC

The 2017 tumor, node, metastasis (TNM) classification of the Union for International Cancer Control eighth edition for staging of PC should be used (2). The European Association of Nuclear Medicine (EANM) recently proposed a molecular imaging TNM (miTNM) classification, using PSMA-PET/computed tomography (CT) findings (3). PSMA-PET/CT is more sensitive in N staging than magnetic resonance imaging (MRI), abdominal contrast-enhanced CT, or choline PET/CT (4). Studies have shown that targeted imaging of PSMA can alter the management of 12.6–30% of patients (5,6). In a retrospective study performed by Maestroni et al. (7) that analyzes the correspondence between PSMA-PET/CT and final histopathological examination, sensitivity, specificity, positive and negative predictive values of pre-operative Ga-PSMA-PET/CT were 85.7%, 100%, 100% and 97%, respectively. With regard to M-staging, 99mTc bone scan is significantly influenced by prostate-specific antigen (PSA), clinical stage, and International Society of Urological Pathology (ISUP) grade; it should be performed in symptomatic patients, regardless of PSA value, ISUP grade, or clinical stage. According to a meta-analysis (8), diffusion-weighted whole-body and axial MRI is more sensitive than choline PET/CT and bone scan in detecting bone metastases per patient, although choline PET/CT showed greater specificity. PSMA-PET/CT for systemic staging has shown growing evidence and appears to outperform traditional imaging modalities (9). With PSMA-PET, clinicians are able to detect micrometastases that were previously undetectable, enabling earlier intervention with therapies that can potentially eradicate these small metastatic lesions.

Local treatment in oligometastatic PC: technological innovations in radical prostatectomy

Oligometastatic PC is characterized by a limited number of metastases, often fewer than five (10), even though there is no consensus on its definition. In the context of localized (N0M0) PC, management is possible with curative therapies, which can be achieved through surgery (radical prostatectomy with possible pelvic lymph nodes dissection (PLND) or radiotherapy (external beam or brachytherapy). While systemic therapies such as androgen receptor-targeted treatments have revolutionized the management of metastatic PC, the role of local treatment modalities, especially radical prostatectomy, in oligometastatic PC is still evolving and remains an important area of investigation. With technological advancements such as three-dimensional (3D) virtual models, augmented reality (AR), and artificial intelligence (AI), radical prostatectomy is becoming an increasingly powerful tool in the management of oligometastatic PC, offering greater precision, better patient outcomes, and the potential for more personalized treatments. In a non-systematic literature review (11), the employment of 3D virtual models and AR for radical prostatectomy significantly improved the visualization of complex anatomical structures helping in the nerve sparing approach modulation and reducing positive surgical margins. This can be particularly helpful for patients with oligometastatic disease, determining the optimal approach for tumor resection minimizing damage to critical surrounding structures, such as the rectum, bladder, or blood vessels. Similarly, as shown in a review of Castellani et al. (12), the employment of AI in robotic-assisted radical prostatectomy shows improving outcomes concerning prediction of positive surgical margins/extraprostatic extension, biochemical recurrence, patient’s outcomes, improvement of the nerve-sparing surgery using intraoperative superimposition of magnetic resonance images to identify and locate lesions. While radical prostatectomy alone cannot cure oligometastatic PC, it can play a role in controlling the primary disease by means of reducing the tumor burden, reduction in tumor seeding by metastasis-metastasis spread (by both metastatic and primary tumor clones) (13,14), allowing for intermittent systemic therapies with reduced exposure to side effects of systemic agents (15), and also improving local symptoms (16).

PSMA-radio-guided surgery (PSMA-RGS)

PSMA-RGS uses the preoperative application of gamma-emitting PSMA-selective molecules, such as 99mTc-PSMA-I&S or 68Ga-PSMA-11, which radioactively label PSMA-expressing cells. A gamma probe is then used intraoperatively to detect and guide the resection of metastatic or recurrent PC lesions. Maurer et al. in 2019 (17) conducted a prospective trial using 99mTc-PSMA-I&S in patients with biochemical recurrence and oligometastatic nodal disease, reporting a high detection rate of metastatic lymph nodes, leading to improved biochemical response rates post-surgery.

Similarly, in one multicenter cohort of patients undergoing PSMA-RGS for recurrent disease, biochemical recurrence-free survival was achieved in over 60% of patients at 12 months post-surgery (18).

The DETECT study, using PSMA-RGS in newly diagnosed patients, confirmed the feasibility and safety of this method, identifying nodal metastases intraoperatively with high specificity (19).

Systemic therapies in metastatic PC

In order to control metastatic sites, there is a need for systemic therapies, such as chemotherapy (docetaxel) and androgen receptor-targeted agents (ARTAs), initially approved for the treatment of metastatic castration-resistant PC (mCRPC), and then also used for non-mCRPC and metastatic hormone-sensitive prostate cancer (mHSPC). ARTAs antagonize (competitively inhibit) and block the androgen receptor (AR) much more selectively than bicalutamide by preventing its translocation into the nucleus and thus preventing its binding to DNA, ultimately resulting in a block in cell replication and a reduction in PSA (20). Actually, docetaxel plus androgen deprivation therapy (ADT) should be considered the standard of care in M1 fit patients as the first presentation especially in high volume cases , as noted in STAMPEDE—arm C (21), GETUG (22), and CHAARTED (23) trials.

The CHAARTED (Chemo-hormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) found that patients with high-volume metastatic disease benefited significantly from the addition of chemotherapy (docetaxel) to ADT, showing improved overall survival (OS) compared to those receiving ADT alone. “High-risk” was specifically defined in the study by the presence of extensive disease, characterized by: presence of ≥4 bone lesions or a single visceral metastasis (i.e., metastasis beyond the bones and lymph nodes, such as to the liver or lungs).

The LATITUDE1 study (24) aimed at evaluating the superiority of the association between abiraterone acetate and prednisone in combination with ADT compared to ADT alone. At a median follow-up of 30.4 months, the relative risk of death was 38% lower in patients treated with abiraterone [hazard ratio (HR) 0.62; 95% confidence interval (CI): 0.51–0.76]. All patients included in the study had high-risk disease, defined by: three or more bone lesions, with at least one outside the vertebral column and pelvis, or the presence of visceral metastasis. Similarly, the STAMPEDE trial (arm G) states that abiraterone plus ADT significantly improves oncological outcomes in patients with de novo M1 (21). These studies suggest that high-volume disease is primarily treated with systemic therapy (ADT + AR-targeted therapy ± chemotherapy).

The ENZAMET trial (25) and ARCHES Trial (26) were two multicenter, randomized, double-blind phase III trials that demonstrated the effectiveness of enzalutamide in combination with ADT compared to a placebo plus ADT in men with mHSPC in improving both OS and progression-free survival (PFS). It also showed a significantly improved radiologic PFS (HR: 0.39), a reduced risk of PSA progression, a delay in the start of a new therapy, in time to first symptomatic skeletal event, to castration resistance and pain progression. The first interim analysis of the phase III, randomized, double-blind, placebo-controlled, multinational TITAN study (27) demonstrated improved OS (HR: 0.67) and radiographic PFS (rPFS) (HR: 0.48) with apalutamide added to ongoing ADT in patients with metastatic castration-sensitive PC. ARASENS (28) is a global randomized, double-blind, phase III trial involving 23 countries, that demonstrated an improvement in OS by adding darolutamide to ADT and docetaxel in patients with mHSPC, comparing to standard ADT and chemotherapy alone. A retrospective study of Liu et al. (29) evaluated the efficacy of darolutamide plus ADT in mHSPC, evaluating as primary endpoint PSA reduction and PSA control from two leading medical centers in China, with a median follow-up of 9.3 months, considering that PSA response can predict early treatment response, particularly when delaying time to castration-resistant PC. Median reductions in PSA levels compared to baseline were 84.37%, 91.48%, 94.67% and 99.81% at 2 weeks, 1 month, 3 months and 6 months, respectively, after administration of darolutamide with ADT. The median time to achieve a PSA reduction of 50% or more (PSA50), PSA reduction of 90% or more (PSA90), significant PSA reduction (<0.2 ng/mL) and PSA nadir (PSA <0.02 ng/mL) was 0.97, 1.27, 1.98 and 2.08 months, respectively.

Multimodal treatment and metastasis-directed therapy (MDT)

Recent findings suggest that patients with limited metastatic disease may benefit from a multimodal approach, where local treatment [such as stereotactic body radiotherapy (SBRT) or whole-body radiotherapy] is paired with systemic AR-targeted therapy (e.g., enzalutamide or abiraterone). This strategy aims to eradicate the minimal metastatic burden while preventing further metastasis and reducing the overall disease burden, thereby improving PFS and OS. The STAMPEDE trial (Arm H) (30) showed that in patients with low-volume metastatic disease, adding radiotherapy to the primary tumor significantly improved OS and PFS compared to ADT alone. Similar findings have emerged in the PEACE-1 trial (31), a phase III, randomized, open-label clinical trial that examined how the addition of abiraterone acetate + prednisone (AAP) and/or local prostate radiotherapy affects outcomes when combined with standard-of-care (SOC) therapy in mHSPC (ADT and docetaxel). Radiotherapy (in combination with abiraterone and ADT) improved survival only in patients with low-volume metastatic disease (as per CHAARTED criteria). For patients with high-volume disease, triplet therapy (ADT + docetaxel + abiraterone) is preferred over radiotherapy-based approaches.

These trials suggest that controlling the primary tumor may help delay disease progression, and that low-volume disease (Oligometastatic) may benefit from local radiotherapy to the prostate + MDT + systemic AR-targeted therapy. In oligometastatic cases (≤3–5 metastases), SBRT to metastases has been shown to delay disease progression prolonging PFS and androgen deprivation-free survival, as observed in STOMP (15) and ORIOLE (32) trials, the only two prospective trials of stereotactic ablative radiation versus observation in metachronous oligometastatic castration-sensitive PC.

Lutetium-177-PSMA therapy (Lu-177-PSMA) is an advanced targeted radioligand therapy used primarily for treating mCRPC. Lutetium-177 (¹⁷⁷Lu)-PSMA-617 is a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the surrounding microenvironment. VISION (33) was a phase III trial of targeted radioligand therapy in patients with PC, finding that ¹⁷⁷Lu-PSMA-617 plus standard care significantly prolonged, as compared with standard care, both imaging-based PFS (median, 8.7 vs. 3.4 months; HR for progression or death, 0.40; 99.2% CI: 0.29 to 0.57; P<0.001) and OS (median, 15.3 vs. 11.3 months; HR for death, 0.62; 95% CI: 0.52–0.74; P<0.001) in patients with advanced PSMA-positive mCRPC. Several early-phase trials and retrospective studies suggest potential benefits of Lu-177-PSMA in oligometastatic PC, particularly in patients who have exhausted local treatment options. However, more robust randomized trials are needed to establish its role in standard clinical practice.

For patients with limited metastatic PC, a multimodal approach combining AR-targeted systemic therapy with local treatment (radiation or surgery) has the potential to improve survival, delay progression, and enhance quality of life. Ongoing trials [e.g., PEACE-1 (31), STOPCAP (34), SIMCAP (35)] continue to refine the optimal combination strategies.

Conclusions

Oligometastatic PC, to date, represents a pathologic condition that, if well diagnosed and promptly treated, can lead to excellent results both in terms of quantity and quality of life.

As clinical studies continue to advance our understanding of metastatic PC, the management of oligometastatic disease is poised to undergo a transformative shift. The development of highly sensitive and accurate diagnostic tools has allowed the achievement of excellent results even in the search for the smallest metastatic foci, thus allowing us to undertake targeted therapies from the early stages of oligometastatic disease. First of all, with its ability to detect small, low-volume metastatic lesions, PSMA-PET allows for earlier and more accurate staging, which in turn enables more precise treatment planning. Since the first decades of the 2000s, pharmacological research has significantly expanded our arsenal against PC, regardless of the stage of the disease. The combination of AR-targeted therapies with local treatment modalities offers a promising avenue for improving outcomes in oligometastatic PC patients. The role of radical prostatectomy in oligometastatic PC could be an option in the future, thanks to the integration of cutting-edge technologies like 3D virtual models, AR, AI and PSMA-RGS. These innovations not only enhance the precision and safety of surgery but also pave the way for personalized treatment strategies. The next steps will involve ongoing clinical trials to confirm the optimal combination of local treatments and AR-targeted therapies, ultimately bringing the hope of long-term disease control—and potentially cure—to a subset of patients with oligometastatic PC.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Davide Campobasso, Stefano Puliatti and Stefania Ferretti) for the series “New Evidence and Advances in Surgical Treatment of Prostate Cancer” published in Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-44/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-44/coif). The series “New Evidence and Advances in Surgical Treatment of Prostate Cancer” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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