New hormonal agents and integrated strategies for non-metastatic, hormone-sensitive prostate carcinoma: the orphan setting?—a narrative review

Introduction

Prostate carcinoma (PCa) is the second leading cause of cancer-related death worldwide, and its incidence is expected to rise sharply, with the 1.4 million newly diagnosed cases of 2021 projected to double by 2040 (1,2). The vast majority of PCa patients are diagnosed when the disease is still confined to the prostate, has just extended beyond the prostatic capsule, or to loco-regional lymph nodes. Optimal management at this stage is crucial to achieving the highest cure rates (3). Alterations of the androgen receptor (AR) pathway, which physiologically is involved in prostate cell development and function, are commonly responsible for PCa initiation (4,5). Along these, aberrations in DNA damage repair mechanisms, or PI3K-AKT-mTOR signalling, are likely to co-occur (6,7).

The introduction of new generation AR pathway inhibitors (ARPIs), which include abiraterone acetate, apalutamide, enzalutamide, and darolutamide, has changed the treatment paradigm of advanced PCa (8-15). On this basis, several ongoing trials are testing ARPI + androgen deprivation therapy (ADT) with radiotherapy (RT) or surgery in the early stages of disease—aiming at longer relapse-free survival (RFS) rates and quality of life (QoL) preservation. Nevertheless, it remains debatable whether intensifying treatment for the non-metastatic setting could replicate the results reported for the advanced disease.

To shed light on this topic, we review the most promising of these clinical trials, including those employing novel drugs acting alongside AR pathway, and those studying ARPIs for the treatment of patients experiencing a biochemical relapse with no signs of extra-prostatic spread on conventional imaging. We present this article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-25-35/rc).

Methods

MEDLINE and PubMed databases were searched for trials or study reports encompassing the treatment of localised/locally advanced PCa, and for which the protocol included the use of second-generation ARPIs. The search criteria included the following terms: “prostate”, “cancer”, “localised”, “locally advanced”, “androgen receptor”, “darolutamide”, “abiraterone”, “enzalutamide”, “apalutamide”, “docetaxel”, “cabazitaxel”, “radiotherapy”, and “prostatectomy”. Articles published prior to 2010 and case reports were excluded. Additionally, reports from scientific conferences, including the American Society of Clinical Oncology (ASCO), ASCO Genito-Urinary Cancer Symposium (ASCO-GU), and European Society of Medical Oncology (ESMO), were screened for relevant evidence (Table 1).

Defining non-metastatic disease

The prostate serves as an accessory exocrine gland, and its secretion forms part of the semen. Its function depends on the stimulation via the male hormone testosterone and its precursors dehydroepiandrosterone (DHEA), androstenediol, and androstenedione (16). Its extraperitoneal location places it tightly connected to the blood and lymphatic vessels of the pelvis, explaining the typical pattern of metastatic spread—with pelvic nodes being a frequent site of metastasis and one of the most important risk factors for disease relapse (17,18). Localised and locally advanced PCa aggressiveness has originally been evaluated based on the Gleason scoring, a pathology-based assessment of tumour differentiation; scores range from 2 to 10, calculated as the sum of the two most prevalent histological patterns, rated from 1 (well differentiated) to 5 (very poorly differentiated or anaplastic carcinoma). To improve standardisation and decision-making, the International Society of Urological Pathology (ISUP) subsequently revised the Gleason scoring system by excluding patterns 1 and 2 and introducing a prognostic grade group classification (ranging from 1 to 5), with each group corresponding to specific Gleason score combinations (19,20). Histological, biochemical, and staging parameters are now integrated into widely used risk stratification systems.

Among these, D’Amico’s risk classification stratifies localised PCa patients into low, intermediate, or high-risk of biochemical recurrence on the basis of the clinical TNM staging, a biopsy-derived Gleason score (bGS), and the preoperative prostate-specific antigen (PSA) serum level (21,22). Numerous validation studies and analyses over last decades confirmed the accuracy and reliability of the D’Amico risk classification, although modern regulatory agencies and associations are debating whether it should be updated to more recent and practice-based models (23,24).

Importantly, non-metastatic PCa includes both high-risk localised and locally advanced disease, which differ by anatomical extension and prognosis. High-risk localised disease, as previously mentioned, generally refers to organ-confined tumours that associate with elevated PSA levels (typically >20 ng/mL) and a high Gleason score, while locally advanced disease includes cancers that extend beyond the prostatic capsule (T3) or to adjacent structures (T4), as well as cases with regional lymph node involvement (N1). In this regard, it is worth noting that the definition of nodal disease is not uniform, since several guidelines and clinical trials label N1 stage as non-metastatic, and locally advanced PCa can therefore be sub-classified as N0 or N1—which complicates the interpretation and comparison of results from different studies. For example, the abiraterone arm of the STAMPEDE trial (arm G) defined high-risk non-metastatic disease as either N1 disease or the presence of at least two of the following high-risk features: clinical stage T3–T4, Gleason score ≥8, or PSA ≥40 ng/mL; differently, the EMBARK trial enrolled patients with rising PSA following radical therapy, a PSA doubling time ≤9 months, and no evidence of distant metastases on conventional imaging (irrespective of the local nodal status), as the primary aim of the trial was to investigate the treatment’s impact on the biochemical component of disease relapse (25,26).

Therapy for high-risk, locally advanced, hormone-sensitive PCa

Historically, the management of localised/locally advanced PCa has been either surgery [radical prostatectomy (RP)] or RT, with the latter combined with 6-to-36-month long ADT depending on risk factors (27-31). Also, recent studies reached mixed results in terms of long-term efficacy outcomes and long-lasting side effects (32-34).

Roy and colleagues powered an emulated randomised comparison of RT vs. RP, with the incidence of distant metastasis (DM) as the primary endpoint. Their meta-analysis of 1,290 patients found that the 8-year cumulative incidence of DM was lower in patients treated with RT compared to the RP cohort (8-year DM: 16% vs. 23%), with an 8-year death rate after DM of 10% vs. 8% in RP and RT cohorts, respectively. A secondary analysis comparing the addition of long-term ADT (LT-ADT) to RT with the RP plus ADT and 6-cycle docetaxel showed the 8-year cumulative incidence of DM was 18% for the RT + LT-ADT group vs. 21% for the ADT + docetaxel + RP group, suggesting how post-operative RT or ADT + docetaxel chemotherapy may help close the gap between RP and standard of care (SoC) RT + LT-ADT—although this sub-analysis did not reach statistical significance (35). So far, in absence of clear benefits, the physician’s choice has been based on patient’s characteristics, such as age and comorbidities, and on disease’s features, primarily the risk group and patient’s preference. Importantly, treatment recommendations differ between high-risk localized and locally advanced disease. For patients with high-risk localised PCa, both RP and RT are considered standard options, with the European Association of Urology (EAU) 2024 guidelines assigning a strong recommendation to surgery in this setting. In contrast, for locally advanced disease, RP is given only a weak recommendation, and RT combined with LT-ADT remains the preferred SoC (18).

Previously, trials of combining classical ADT or first-generation anti-androgens (such as bicalutamide and flutamide) to RP failed to demonstrate any benefit in improving patient outcomes, including high-risk subgroups (36,37). With the advent of ARPIs in the metastatic castration-resistant, non-metastatic castration-resistant, and metastatic hormone-sensitive settings (10,12,38-41), which improved survival and QoL with good safety profiles, testing these drugs in the localised setting became of interest.

ARPI in the neoadjuvant setting

The rationale of using pre-surgery medical treatment in localised PCa lies in the potential benefits granted by disease downstaging, as neoadjuvant drugs are supposed to shrink tumour volume and to lower the risk of positive margins for surgery—or to provide radiation oncologists with a reduced disease volume to target (42,43).

Since the early nineties, many neoadjuvant ADT regimens have been tested—also as part of perioperative schedules. Most consisted of luteinising hormone-releasing hormone (LHRH) agonists or analogues ± first-generation anti-androgens, with the majority of patients presenting low-risk disease (44-51). These trials did not impact on clinical practice, as only negligible gains were reported in response outcomes (4–8% improvement in terms of complete response rates across small, heterogenous study populations), not showing any meaningful difference in biochemical recurrence rates and metastasis-free survival (MFS) (44). Hence, for many years adopting a neoadjuvant treatment for the high-risk population was deemed futile.

Neoadjuvant ARPI trials for patients who underwent RP

Taplin et al. were the first to investigate the second-generation ARPI abiraterone acetate in the neoadjuvant setting, when it was administered along with prednisone and an LHRH agonist (LHRHa) and compared to treatment with LHRHa alone (COU-AA-201 trial) (52). Their phase II trial enrolled 58 men with high-risk localised PCa into two cohorts and randomised them to receive LHRHa alone or LHRHa plus abiraterone for the first 4 months. Following a research prostate biopsy, both cohorts received 3 months of LHRHa plus abiraterone acetate followed by radical surgery, with the primary endpoint of assessing the 4-month on-tissue testosterone and dihydrotestosterone (DHT) levels both on research biopsy and on prostatectomy samples. Results showed an overall reduction in intraprostatic levels of testosterone and DHT, and a rise in upstream CYP17 hormones pregnenolone and progesterone for those treated with abiraterone acetate. Nonetheless, the study failed to show any benefit on primary tumour shrinkage.

As serum concentrations of DHEA-sulphate and DHEA-glucuronide eventually plateaued around 10% of baseline levels after 6 months of treatment, authors concluded that this, along with treatment-enhanced intratumoural testosterone and DHEA production—which is usually observed on more advanced stages of disease—could still have provided the cancers with a valuable supply of androgen precursors and hormones, facilitating sub-clonal adaptation.

Shortly after, enzalutamide was tested either alone or in combination with abiraterone acetate, with the assumption that the dual blockade of the hormone production (with abiraterone acetate) and androgen signalling (with enzalutamide) would improve disease control (53).

In 2021, McKay et al. reported on the outcomes of patients enrolled in 3 randomised clinical trials of ARPIs plus ADT prior to RP (54). Out of the 92 patients enrolled across these three randomized controlled trials (RCTs), 78.6% presented with high-risk disease. After neoadjuvant treatment, which for the experimental arms consisted of abiraterone acetate/prednisone + ADT, enzalutamide + ADT or enzalutamide + abiraterone/prednisone + ADT, 21.4% of patients presented 0–5 mm of residual tumour, including the 9.4% achieving a pathological complete response (pCR); after 3 years, 59.1% were free from biochemical recurrence.

Importantly, no clear advantage in exerting maximal androgen blockage prior to radical surgery was found in terms of disease reduction compared to LHRHa and single-ARPI arms. Similarly to the aforementioned COU-AA-201 trial, authors suggested that some of the alterations seen in the advanced disease, such as AR amplification or splicing variants, may be therapy-induced early events in cancer growth, and therefore pushing sub-clonal development from the localised stage—providing a biological rationale for the observed primary resistance and the subsequently observed low response rates.

The combination of neoadjuvant apalutamide plus ADT was investigated in the ARNEO and NEAR phase II trials, both enrolling high-risk patients. The ARNEO study was a double-arm trial where patients in the experimental arm treated with degarelix plus apalutamide showed improved pathological response rates in terms of pT2 disease (51% vs. 27%) and minimal residual disease (MRD) (37.8% vs. 9.1%) compared to patients receiving degarelix alone (55). Nonetheless, Giesen et al. disclosed recently that such findings did not translate into improvements of biochemical relapse rates (BCRs) between the two study arms (56).

Similarly, investigators of the NEAR trial, a single-arm study of neoadjuvant apalutamide monotherapy and subsequent RP enrolling men with intermediate- and high-risk PCa, reported that no pCR was recorded on their trial population of 25 patients, despite a median reduction of disease burden of 41.7%. Additionally, 18 patients (72%) achieved a biochemical response (57).

As well as ARPI, also taxane-based chemotherapies were tested in the neoadjuvant setting. Chemo-hormonal schedules were tested in the multicentre, phase II trial ACDC-RP, which enrolled 70 localised high-risk patients to neoadjuvant cabazitaxel plus abiraterone acetate and leuprolide vs. abiraterone acetate and leuprolide prior to RP, with the hypothesis that cabazitaxel would limit the emergence of androgen-resistant, but chemo-sensitive, subclones. Nevertheless, the trial failed to demonstrate an advantage for the experimental arm in pCR rates (43.2% and 45.5% in experimental and control arms, respectively) but reported an increased rate of adverse events in the chemo-treated cohort (grade ≥3 adverse events affected 42.5% and 23.7% of patients in the experimental and control arms, respectively) (58).

Table 2 summarises some of the trials which investigated a second-generation ARPI as neoadjuvant therapy for high-risk, non-metastatic PCa. Despite the notable heterogeneity across drug schedules and combinations, as well as timings of surgery and surrogate endpoints for pathological response, some of the displayed studies show that neoadjuvant therapies of androgen axis inhibition may improve local disease control at the time of surgery, granting lower BCR and higher pCR rates. Nevertheless, up to date no clear benefit of adopting hormonal treatments before RP has emerged, and still no progress has been made with regards to long-term oncological endpoints, such as cancer-related death or overall survival (OS).

Considering that different genomic backgrounds might have an impact on patients’ outcomes and responses to treatment in the advanced setting, it remains to be defined whether applying a gene panel-based approach could help selecting patients that would benefit from neoadjuvant systemic treatments.

Adjuvant ARPI treatment for patients who underwent RP

Primary aim of adjuvant therapies for PCa is to prevent the disease from relapsing after a supposed ‘radical’ treatment such as RT or surgery. In this regard, the number of involved lymph nodes proved a relevant factor for predicting risk of disease recurrence (74,75), irrespectively of the initial cT stage or Gleason grade, and current guidelines recommend an adjuvant course of ADT for these patients. To lower rates of relapse in high-risk patients, both adjuvant chemotherapy and ARPI were evaluated alongside ADT for pN0 and pN1 patients after RP.

Specifically, in two RCTs docetaxel plus ADT was compared to ADT alone (76) or surveillance (77), while the SWOG S9921 trial compared mitoxantrone to ADT, but none of the trials testing adjuvant combinations of ADT and chemotherapy reported any benefit after RP for locally advanced PCa.

More in detail, the SWOG S9921 evaluated ADT (bicalutamide and goserelin for 2 years) alone or in combination with mitoxantrone and prednisolone after RP in patients with high-risk PCa. Inclusion criteria included pT3b-pT4, or N1 disease. Recruitment started in October 1999 and the study stopped accrual in January 2007, since three of the 487 patients in the mitoxantrone arm were diagnosed with acute myeloid leukaemia. Final efficacy results displayed no improvement in OS or recurrence-free survival rates (78).

When it comes to second-generation ARPI, no large phase III trial is evaluating efficacy of these hormonal agents in the adjuvant setting. To date, only preliminary data from phase II trials are available—which we briefly discuss below.

The CASE12812 phase II trial is testing adjuvant 24-month course of single-agent enzalutamide after RP (79). The primary endpoint is time-to-progression, defined as a PSA value >0.2 ng/mL on two different measurements. In their latest update, study investigators report that five patients out of the 42 enrolled have progressed, and that their median time of progression was 31 months.

More recently, results have been published from a single arm phase II trial investigating the adjuvant combination of 12-month apalutamide and ADT for high-risk patients (Apa-RP trial) (80,81); specifically, the investigators presented a 12-month BCR-free survival of 100%, with 77% of patients reaching post-adjuvant serum testosterone recovery (threshold defined as ≥150 ng/dL). As the trial’s primary objective was the confirmed BCR-free rate at 24 months, no other data on long-term endpoints is available.

Similarly, the ADAM trial (82) is testing apalutamide in patients with high risk localised or locally advanced PCa. Patients enrolled are randomised 1:1 into two treatment arms within 9 weeks of undergoing RP; in arm A, patients receive SoC, that includes observation or adjuvant prostate radiation if positive margins have been detected after RP, plus apalutamide for 30 cycles of 28 days each; patients assigned to arm B only receive SoC treatment.

Table 3 displays most recent findings in this setting, that mainly involve phase II trials. The absence of large trials may have several explanations—but primarily, the trial duration. Patients with localised or locally advanced PCa tend to live longer and not necessarily die from their disease; therefore, it is challenging to demonstrate meaningful differences in OS. Adopting surrogate endpoints is necessary to shorten study follow-up, and currently, MFS appears the most appropriate as one of the most adopted in clinical trials testing adjuvant treatments.

Adjuvant ARPI trials for patients who underwent definitive RT

High-risk patients who undergo RT are additionally treated with an ADT course before and after their treatment, as this combination showed to lower BCR and disease relapse rates (88).

James and colleagues investigated combination of abiraterone acetate plus ADT with or without enzalutamide in the adjuvant setting (25). Results from this STAMPEDE trial sub-cohort unveiled meaningful improvements in MFS and OS rates with the addition of 2 years of abiraterone acetate to ADT in men with high-risk non-metastatic PCa [OS: hazard ratio (HR) =0.63, 95% confidence interval (CI): 0.48–0.82; MFS: HR =0.54, 95% CI: 0.43–0.68], while combining enzalutamide and abiraterone only resulted in greater toxicity with no significant benefit on efficacy outcomes. As a result, 2-year treatment with abiraterone acetate in addition to the standard 3-year ADT is advised as the standard treatment for newly diagnosed non-metastatic PCa patients who undergo RT and present with high-risk features. Notably, real-world evidence is suggesting higher discontinuation rates than those observed in the study (89). In summary, while the addition of adjuvant ADT plus ARPI to definitive RT showed benefit and is therefore recommended for intermediate and high-risk localised disease, there is no indication for adjuvant ARPI after RP.

ARPI in the perioperative setting for patients with localised or locally advanced PCa who are candidates to RP or RT

Alongside trials testing neo- or adjuvant therapies, several studies have assessed the addition of ARPIs perioperatively in patients eligible for RP or RT.

The PROTEUS study is a large phase III RCT evaluating the efficacy of a 6-month neoadjuvant ADT + apalutamide course before RP with pelvic lymph node dissection; surgery is then followed by a 6-month adjuvant ADT + apalutamide vs. ADT alone. So far, it has enrolled over 1,500 patients with localised/locally advanced high-risk PCa. The primary endpoint is the pCR rate and MFS; importantly, study investigators implemented prostate-specific membrane antigen (PSMA)-positron emission tomography (PET) imaging into post-surgery staging procedures to reflect the evolving standards in practice. Started in June 2019, no result is available to date (83).

Furthermore, the ENZARAD and ATLAS trials are testing either enzalutamide or apalutamide in localised/locally advanced PCa patients alongside definitive RT.

ENZARAD is an open-label, phase III study of comparing enzalutamide plus RT in the high-risk population of patients with localised disease (84). Enrolled participants are randomised to 24-month treatment with LHRHa plus 24-month enzalutamide or conventional 6-month ADT with non-steroidal anti-androgen (NSAA), as well as to an external beam radiation therapy (EBRT) course starting at week 16 from enrolment. Similarly, within the ATLAS trial patients with localised, high-risk disease receive apalutamide for 30 months overall in addition to bicalutamide placebo for 4 months, or apalutamide-placebo for 30 months plus bicalutamide for 4 months (85). Both cohorts also receive LHRHa for 30 months from randomization, while radiation therapy to the prostate is scheduled at about 8 weeks after randomisation. The primary end point for both the ATLAS and ENZARAD trials is MFS, with no results published to date.

ARPI for the treatment of biochemical recurrence

Of all patients treated with RP or RT for localised disease, between 47% and 82% show an increase of PSA levels at 10 years (18). PSA persistence after radical treatment might not necessarily imply the presence of micro-metastatic disease; this could be particularly relevant in patients treated with RT, since some of the non-cancerous prostate cells may be functional and produce PSA. Nevertheless, in most cases, PSA elevation after local treatment indicates disease progression, and biochemically relapsed PCa is diagnosed when there is no radiographical evidence of metastases.

In recent years, new functional imaging techniques such as PSMA-PET scanning showed increased sensitivity in detecting metastatic disease over conventional imaging [computed tomography (CT) and bone scans] (90). Novel imaging techniques will reduce the group of patients diagnosed with biochemically recurrent disease. Clinical management of these patients to date relies on some indirect signs of the disease’s aggressiveness, i.e., the velocity of PSA increase.

BCR PCa patients with slow rising PSA could benefit, for example, from salvage RT to the prostatic bed or pelvic lymph nodes, while men with a short PSA doubling time are at high risk of failing salvage treatment after RT (91). Numerous trials investigated the addition of ARPIs ± salvage RT in this setting.

The randomised phase III trial EMBARK (26) enrolled patients who had high-risk biochemical recurrence, defined as a PSA-doubling time of ≤9 months and a PSA level of ≥2 ng/mL above the nadir after RT or ≥1 ng/mL following RP with or without post-operative RT. Patients were randomly assigned 1:1:1 to receive either enzalutamide plus leuprolide (combination group), placebo plus leuprolide, or enzalutamide monotherapy (monotherapy groups). The primary endpoint was to assess MFS in the combination group as compared with the leuprolide-alone group, while comparison of MFS between the enzalutamide monotherapy group and the leuprolide-alone group was a key secondary endpoint. After a median follow-up of 60.7 months, the 5-year MFS was 87.3% in the combination group, 71.4% in the leuprolide-alone group, and 80.0% in the monotherapy group; the combination of enzalutamide plus leuprolide outperformed leuprolide alone with regards to MFS (HR =0.42; 95% CI: 0.30–0.61). Based on these findings, the EAU recommends offering enzalutamide with or without ADT to M0 patients with high-risk BCR (18). More recently, secondary endpoints of the trial were published, showing a benefit for enzalutamide monotherapy over the leuprolide-alone in all patient subgroups, but due to small sample size such findings need to be interpreted cautiously (92).

The INDICATE trial (93) is evaluating the efficacy of combining apalutamide with metastasis-directed RT in patients with BCR after RP. A PET/CT or PET/magnetic resonance (MR) scan with ¹⁸F-fluciclovine, ¹⁸F-DCFPyL or ⁶⁸Ga-PSMA-11 is used to randomise patient to four different treatment arms. PET-negative patients are candidate to SoC EBRT on prostate bed and ADT for 6 months in arm A. Arm B also includes PET-negative patients, who are then treated with EBRT plus apalutamide once daily and ADT for 6 months. In case of PET-positive extra-pelvic metastases, patients are randomised to either arm C, to receive SoC EBRT plus ADT and apalutamide, or SoC EBRT, ADT + apalutamide and ablative RT of 30 Gy in 3 fractions [stereotactic body radiation therapy (SBRT)] or 50 Gy in 10 fractions (non-SBRT) targeting the PET-avid sites (arm D). The primary end point is progression-free survival (PFS), defined as the time from enrolment to clinical or radiographical disease progression assessed by conventional imaging.

Other clinical trials are investigating possible benefits of offering intermittent ARPI-based treatment to BCR patients, limiting the toxicity of exerting a continuous treatment. As intermittent ADT showed non-inferiority to continuous therapy in biochemically recurrent PCa (94). Hahn et al. tested whether a finite schedule of abiraterone plus LHRHa in BCR patients could be beneficial in terms of PSA-free survival, defined as the time a patient’s PSA value reached <1 ng/mL. In their FINITE trial, patients were randomly assigned to either 8-month treatment with abiraterone acetate plus LHRHa or LHRHa alone, followed by an off-treatment interval if there was no evidence of disease progression. Whenever PSA climbed again to ≥1 ng/mL, patients were offered cross-over to the alternative treatment arm. Patients treated with upfront abiraterone + LHRHa achieved higher 12-month PSA-free rate compared to LHRHa alone (34% vs. 19%) (95). Eighty-five percent of patients experienced PSA progression after a median time of 24.3 months, supporting the use of abiraterone + LHRHa (Table 4).

Future directions

Alongside improving treatment efficacy through combinational approaches, research is exploring the potential of biomarker-driven treatments able to tackle cancer heterogeneity within high-risk localised disease, aiming to identify putative druggable targets for tailored treatments. Here we provide some examples.

The Genomic Umbrella Neoadjuvant Study (GUNS) is a platform-trial enrolling high-risk PCa patients whose tumours get pre-screened for genomic alterations. Specifically, all patients are treated with LHRHa and apalutamide for the first 8 weeks; subsequently, patients are enrolled into one of four sub-protocols that combine 16 weeks of an ARPI doublet with other drugs based on specific genomic alterations. Patients can be assigned to addition of abiraterone if their tumour harbours gene alterations that would predict for an increased androgen sensitivity (i.e., ETS fusion, FOXA1, SPOP), or addition of docetaxel in case their tumour shows loss of function alterations of TP53. Furthermore, the addition of niraparib or monotherapy with atezolizumab is considered if a tumour harbours alterations in either DNA repair or breast cancer (BRCA) genes, or an immunogenic cancer subtype based on alterations indicating microsatellite instability (MSI), Lynch syndrome, or CDK12 pathway alterations (101).

More recently, results from the trial subprotocol-1 (SP-1) were presented. In this arm, men with mutations known to enhance AR activity, are randomised to either LHRHa + apalutamide or LHRHa + apalutamide + abiraterone acetate/prednisone, to investigate whether intensification with an ARPI-based triplet would increase the depth of pathologic response. Interestingly, higher rates of MRD for ARPI triplet cohorts were found, thus supporting further evaluation in the expansion of this arm (59). Indeed, the trial design is set to adapt according to its’ interim results—as only arms which achieve complete response rates of >20% will keep enrolling, besides the opportunity for adding new arms based on the identification of new genomic biomarkers. This is particularly relevant, as other pathways alongside androgen inhibition are being investigated for localised disease—including CDK4/6 and B7H3.

In this regard, a phase I trial is currently testing the combination of neoadjuvant darolutamide plus the CDK4/6 inhibitor abemaciclib in a 3+3 design. Primary objective is determination of RP2D, following which a phase 2 study of ADT plus darolutamide and abemaciclib vs. ADT plus darolutamide followed by RP is planned. The co-primary endpoint is the rate of pCRs assessed via MRD rate (102).

Finally, a phase II trial tested the anti-B7H3 monoclonal antibody enoblituzumab as a neoadjuvant treatment for high-risk localised PCa. After preliminary studies demonstrated substantially higher expression of CD276 messenger RNA (mRNA) and B7-H3 mRNA in PCa models, trial results showed that 21 out of 32 patients (66%) patients treated with this drug achieved an undetectable PSA level 12 months after prostatectomy, with the median PSA recurrence-free survival time not reached at the latest 30-months analysis. Based on its immunoregulatory role, B7-H3 inhibition is hypothesized to trigger a local immune response capable of also targeting early micrometastases. With encouraging safety results, the drug is being further investigated (60).

Conclusions

Despite some progress and various clinical trials, after analysis of gathered literature no significant results have emerged to implement second-generation ARPIs in the perioperative or neoadjuvant treatment of localised PC. The available data suggest a benefit from these drugs in the adjuvant setting, after both RP and primary RT, but such assumption is based on small patients’ cohorts and needs to be confirmed by further evidence on prospective and larger cohort data in order to impact current practice.

Nonetheless, while the research on this strategy is ongoing, there is a potential merit in associating inhibition of other pathways, such as CDK4/6, or exploring the role of other components of the immune response beyond PD-1/CD276. Finally, design of clinical trials exploring surrogate endpoints for OS like MFS or multi-arm design that include molecular profiling may accelerate progress in personalizing treatment for high-risk localized disease, ultimately leading to further advances in this field.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology for the series “New Evidence and Advances in Surgical Treatment of Prostate Cancer”. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-25-35/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-35/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-25-35/coif). The series “New Evidence and Advances in Surgical Treatment of Prostate Cancer” was commissioned by the editorial office without any funding or sponsorship. D.C. served as the unpaid Guest Editor of the series and serves as an unpaid editorial board member of Chinese Clinical Oncology from August 2024 to July 2026. G.L.B. also serves as an unpaid editorial board member of Chinese Clinical Oncology from August 2024 to July 2026. G.L.B. also reports personal fees from Astellas, AstraZeneca, and Amgen. L.F. has received speaking and lecture fees from Merck Sharp and Dohme, Janssen, Novartis, Bristol Myers Squibb, and AstraZeneca. V.C. has served as a consultant/advisory board member for Johnson & Johnson, Astellas, Merck, AstraZeneca, Amgen, EISAI, Recordati, Novartis, Ipsen, and Bayer. V.C. has also received speaker honoraria or travel support from Astellas, Johnson & Johnson, Ipsen, Bayer, Gilead, and BristolMyers Squibb. S.B. received honoraria as a speaker at scientific events and advisory role by BMS, Pfizer, MSD, Ipsen, Roche, Eli Lilly, AstraZeneca, Pierre-Fabre, Novartis, Merck, Gentili, Astellas. G.F. served as an advisory board member for Astellas, Janssen, Pfizer, Bayer, MSD, Merck and received travel accommodation from Astellas, Janssen, Bayer. S.E.R. received honoraria as a speaker at scientific events and travel accommodation from Amgen, GSK, BMS, MSD. P.R. reports payments or honoraria for advisory board roles, presentations, speaker bureaus, manuscript writing, educational events, or travel support from AstraZeneca, Janssen, Pfizer, Merck, MSD Italy, Bayer, and Ipsen outside the submitted work. The authors have no other conflicts of interest to declare.

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