Abstract: Treatment for high-risk localized prostate cancer can be particularly challenging because of an elevated risk of disease recurrence. One of the proposed ways to improve the success of definitive localized treatment (such as radical prostatectomy or radiation therapy) for these patients is the addition of neoadjuvant therapy. Thus, therapeutic strategies that have demonstrated benefit in metastatic prostate cancer settings have been translated to and evaluated in the neoadjuvant setting. The therapies studied include androgen deprivation therapy, ranging from androgen receptor–specific blockade to more comprehensive androgen signaling pathway blockade; chemotherapy, especially taxane-based therapy; immunotherapy; and most recently, prostate-specific membrane antigen radioligand therapy. In this review, we provide an overview of various trials that have explored the pathologic and oncologic results of these therapies in various prostate cancer settings and discuss the emerging role of theranostics in this space.
Introduction
Prostate cancer is often diagnosed at a localized stage, but its clinical course and treatment recommendations vary widely depending on the risk stratification of the cancer. Low-risk prostate cancer is defined by the presence of all the following disease characteristics: clinical stage T1-T2a (cT1-T2a), Gleason Grade Group of 1, and a prostate-specific antigen (PSA) level of less than 10 ng/mL. Intermediate-risk prostate cancer is defined by the following: no high- or very high-risk features, cT2b-cT2c, Gleason score of 2 or 3, and/or a PSA level of 10 to 20 ng/mL.1 High-risk prostate cancer is typically defined by one or more of the following features: Gleason score of at least 8, PSA level above 20 ng/mL, and/or clinical stage of at least T3.1 Of note, very high-risk disease is defined by the presence of at least 2 high-risk features or a PSA level of at least 40 ng/mL.1
Disease progression in patients with low-risk prostate cancer is often slow, with low rates of cancer-specific mortality on active surveillance protocols (0.1% to 3.1%).2,3 In contrast, high-risk localized prostate cancer is a fairly heterogeneous disease, particularly because patients can be classified as having high-risk disease on the basis of just one qualifying feature. As a result, high-risk localized prostate cancer requires unique therapeutic strategies and considerations. Patients with intermediate- or high-risk disease often undergo definitive treatment such as radical prostatectomy (RP) or radiation therapy (RT), but the literature demonstrates that patients with high-risk disease can have an elevated risk for biochemical recurrence (BCR) after these primary therapies. The risk of BCR after surgery may be as high as 50%.4 This elevated risk is thought to be due to the potential presence of micrometastases at the time of diagnosis,5,6 the increased difficulty of oncologic control during primary localized treatment, and particularly aggressive histologic subtypes.7 Recurrent prostate cancer carries a relatively high risk of prostate cancer–specific mortality in addition to a large logistical burden imposed by the additional treatments required.
The current American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO) guidelines (from 2022) for the treatment of high-risk localized prostate cancer endorse RP or RT plus androgen deprivation therapy (ADT).8 The use of RP has been increasing, driven by studies demonstrating effective local control,9 the ability to stage the tumor pathologically after this monotherapy, and advancements in surgical techniques. Additionally, surgery allows patients to defer or potentially avoid upfront radiation and ADT, thereby delaying exposure to their associated adverse effects, such as cardiovascular, cognitive, and hematologic toxicity.1 These treatments can instead be reserved for salvage therapy if needed.
To maximize the success of primary RP or RT for these patients (and in turn minimize the risk of BCR), the addition of neoadjuvant therapy has been proposed. Neoadjuvant research seeks to optimize the outcomes of treatment by assisting local control—for example, by downstaging the disease before surgery or radiation and/or providing in vivo observation of a systemic response to the administered treatment.6 This review synthesizes the evolution of strategies for maximizing therapeutics in high-risk prostate cancer, including the discoveries of adjuvant and neoadjuvant treatments, notable trials in hormonal therapy and chemotherapy, immunotherapy, and the recently developing forefront of radioligand theranostics.
Decision-Making Tools in the Treatment of Prostate Cancer
The probability of BCR after local treatment is difficult to estimate because it is influenced by multiple tumor characteristics.10 Current literature also implicates factors such as lymph node involvement, adverse pathologic features (eg, positive surgical margins, extracapsular extension),10,11 tumor volume, and aggressive histologic subtypes in the development of BCR. Two pathologic variants of prostate cancer that are deemed to be particularly high-risk are cribriform pattern and intraductal carcinoma. The presence of cribriform pattern has been associated with an increased risk of BCR,7 as has the presence of intraductal carcinoma.12
Thus, the identification of these risk-associated characteristics offers important guidance for physicians when they are developing treatment strategies aimed at reducing recurrence. Biopsy tissue analysis alone may not reflect the true aggressiveness of a patient’s disease, given the diversity of contributing factors to consider. For this reason, additional assessment with tissue-based genomic classifying tools, such as molecular biomarkers, has gained traction. Pretreatment tools that are used before definitive prostatectomy include the Decipher, Prolaris, and Oncotype DX genomic tests, which analyze tumor tissue from the patient’s biopsy specimen. Testing options before radiation include Altera, which offers comprehensive genomic profiling by incorporating both tissue and blood samples and facilitates personalized treatment. Although currently no validated clinical trials have examined the effect of these tools, the current post hoc analyses and retrospective literature suggest that the classifier scores are of clinical utility in treatment decision making and are independently associated with risk of metastases and/or cancer-specific mortality.13-15
Therapeutic Targets in Prostate Cancer
In terms of treatment decision making and planning, options often target the androgen synthesis and signaling pathways. The androgen signaling pathway is considered the key modulator in the development and progression of prostate cancer.16 The androgen receptor (AR) plays a key role and is expressed to some degree in all prostate cancers, including both primary and metastatic lesions. Androgens (eg, testosterone and dihydrotestosterone [DHT]) bind to this receptor, activating AR transcriptional activity17 and inducing a cascade of proliferative and differentiation cellular events that are important for the controlled growth and development of epithelial and stromal prostate cells.18,19 For example, the AR/androgen signaling axis is thought to influence homeostasis and the controlled growth of these specific types of prostate cells.20 Such processes are essential for normal prostate physiology but can contribute to tumorigenesis when dysregulated. The AR typically plays a regulatory and suppressive role in the growth of prostatic epithelial cells, but in cancerous cells, it encourages proliferation over differentiation.20
Given the central role of androgen binding and the AR in tumorigenesis, therapeutic targets stem from early observations revealing the dependence of prostate cancer on this pathway. The role of ADT was first established in 1941, when Huggins and Hodges demonstrated that blocking androgens produces clinical responses in advanced prostate cancer. Testosterone readministration reversed these effects, supporting androgen dependence. This work led to the development of pharmacologic ADT, including luteinizing hormone–releasing hormone (LHRH) agonists and antagonists as well as AR antagonists.21,22
Early AR antagonists, such as flutamide, nilutamide, and bicalutamide, exert their effect by binding directly to the ligand-binding domain of ARs, thus blocking the binding of testosterone or DHT. Subsequent trials confirmed the efficacy of ADT in metastatic prostate cancer. Combined androgen blockade with goserelin (Zoladex, TerSera Therapeutics) plus flutamide delayed disease progression more effectively than orchiectomy, and the addition of flutamide to leuprolide improved progression-free survival in metastatic disease.23,24 Research then expanded to localized prostate cancer; multiple studies demonstrated improved disease-free and overall survival (OS) when these ADT regimens were compared with RT alone.25-27
Historically, antiandrogen agents were classified as steroidal or nonsteroidal. The early steroidal antiandrogens (cyproterone acetate, megestrol acetate) and nonsteroidal antiandrogens (flutamide, bicalutamide, nilutamide) had a similar AR-blocking function. However, the steroidal antiandrogens demonstrated progestational activity, resulting in partial LH suppression and a corresponding reduction of testosterone, likely affecting the patient’s potency and libido. The steroidal antiandrogens also showed a wider range of interactions with nuclear receptors beyond the AR. In comparison, the nonsteroidal antiandrogens did not possess the same testosterone-lowering qualities or interactions beyond the AR.28,29 For this reason, use of these medications shifted more toward regimens that included nonsteroidal antiandrogens for maximal antiandrogen blockade with minimal off-target effects.30
As noted, the binding affinity of the early AR antagonists were limited in scope.8 This feature, plus the common androgen withdrawal symptoms, often hindered their long-term use.8 On the other hand, the newer androgen receptor pathway inhibitors (ARPIs) provide a more comprehensive blockade; these medications are now considered the standard of care.8 ARPIs provide a wider efficacy by exerting multiple inhibitory effects across the androgen signaling pathway. They competitively inhibit androgen binding to the AR with a higher degree of affinity than the early AR antagonists, inhibiting nuclear translocation of the hormone-AR complex and inhibiting DNA binding to the complex.31-33 ARPIs inhibit androgens from adrenal and intratumoral sources as well; this is important, given that extratesticular androgen production has been implicated in the development of castration-resistant prostate cancer (CRPC).34 These pharmacologic advantages have prompted extensive evaluation of the utility of ARPIs at various stages of prostate cancer.
Studies Exploring ARPIs as Primary Therapy in the Metastatic and Nonmetastatic Settings
ARPIs have demonstrated significant benefit to patients in the treatment of metastatic prostate cancer of various types. National Comprehensive Cancer Network guidelines endorse the incorporation of ARPIs (abiraterone, apalutamide [Erleada, Janssen], enzalutamide [Xtandi, Astellas], and darolutamide [Nubeqa, Bayer HealthCare]) for metastatic hormone-sensitive prostate cancer (mHSPC). Multiple landmark trials have helped demonstrate that the intensification of androgen-blocking agents can improve outcomes in metastatic prostate cancer (Table).
Given that metastatic cancer often has some level of androgen-independent growth, androgen-dependent pathway blockade may be useful in the nonmetastatic setting.35 Several trials have been crucial in establishing the safety and efficacy of ARPIs in the management of high-risk localized prostate cancer. For example, the EMBARK trial studied the effect of enzalutamide in patients with high-risk prostate cancer after RP with recurrence of disease (defined as a PSA doubling time of ≤9 months and a PSA level of ≥2 ng/mL above the nadir after RT or of ≥1 ng/mL).36 A combined therapy of enzalutamide and ADT was found to have a 5-year metastasis-free survival (MFS) rate of 87%, significantly higher than the rate for either enzalutamide monotherapy (80%) or ADT alone (71.4%).37 Similarly, the STAMPEDE trial explored the addition of abiraterone or abiraterone plus enzalutamide (2 experimental groups) to standard ADT (control group) as a first-line therapy for patients with nonmetastatic prostate cancer. Intermediate-term results demonstrated longer MFS in the combination groups than in the control group. The hazard ratio (HR) for MFS was 0.54 (95% CI, 0.43-0.68) for abiraterone and 0.53 (95% CI, 0.39-0.71) for abiraterone plus enzalutamide, and the HR for OS was 0.63 (95% CI, 0.48-0.82) for abiraterone and 0.54 (95% CI, 0.39-0.76) for abiraterone plus enzalutamide.37
Hormone Therapy in the Neoadjuvant Setting
Given the demonstrated efficacy of ADT and ARPIs in the primary treatment of prostate cancer, research efforts have aimed to extend these therapeutic benefits to the neoadjuvant setting. One goal of neoadjuvant hormonal therapy is to reduce the disease burden before surgery to maximize the chance of achieving complete tumor removal and negative surgical margins. These are thought to be helpful for patients with an elevated risk of recurrence—that is, patients with high-risk or very high-risk prostate cancer.
The results of neoadjuvant hormonal therapy before surgery date back to the 1990s, when Labrie and colleagues found decreased rates of positive surgical margins in patients with cT2-cT3 disease who received neoadjuvant flutamide and an LHRH agonist before RP (neoadjuvant therapy + RP: 7.8%, RP alone: 33.8%).38 Intermediate-term results of studies that explored the use of goserelin, leuprolide, and/or flutamide before RP often showed decreased rates of positive surgical margins and other pathologic results, but these results did not translate into meaningful oncologic improvements, such as increased OS or BCR-free rates.39,40
Multiple systematic reviews have summarized the literature about neoadjuvant AR antagonists, explaining that although the results show improved pathologic findings, the literature is still lacking proven long-term oncologic outcomes, especially in the setting of high-risk localized disease.7 Given the documented benefits of ARPIs in patients with metastatic and nonmetastatic disease, further emphasis was placed on testing the effects of neoadjuvant ARPIs.34
The ARNEO trial evaluated the addition of neoadjuvant apalutamide to a regimen of degarelix (Firmagon, Ferring) before RP. All patients were followed after surgery until PSA relapse, and no median follow-up time was reported. This study found improved rates of measurable residual disease (MRD; 38% vs 9.1%; P=.002) and tumor downstaging (40% vs 30%; P=0.3); however, changes in the BCR rates were not significant (control group, 96% BCR-free; apalutamide group: 93% BCR-free).41 As noted by the study, longer-term trials are required for a better evaluation of oncologic outcomes.
A recent phase 2 study from China explored the addition of darolutamide, another ARPI, to a neoadjuvant regimen of ADT before RP in patients with high-risk or very high-risk prostate cancer.42 At 12-month follow-up, the progression-free survival (PFS) rate was 90%. The relatively short follow-up limits the evaluation of oncologic outcomes, but at present, no other studies with long-term oncologic outcomes are available for comparison. Millan and colleagues also recently conducted an analysis of an open-label trial and described the long-term outcomes (median follow-up, 7.3 years) of patients with intermediate-, high-, or very high-risk localized or regional prostate cancer who had received a regimen of neoadjuvant ADT and enzalutamide before RP. This study found a 5-year BCR-free rate of 64.15% and a cancer-specific survival rate of 94.3% for this group. Although the study was limited by the lack of a control group, it concluded that the use of neoadjuvant enzalutamide and ADT is associated with favorable long-term outcomes and supported continued investigation into this therapy for patients with localized prostate cancer.43
Devos and colleagues performed a systematic review of the role of neoadjuvant hormonal therapy in localized prostate cancer (unfavorable intermediate-risk or high-risk disease). This review discussed the documented decreases in positive surgical margins and residual cancer burden observed when patients in the ARPI arms were compared with those who received classic ADT, but the authors noted that long-term and oncologic outcomes data are still scarce.34
Results from the currently active PROTEUS study will also contribute meaningfully. PROTEUS is a randomized, double-blind, placebo-controlled phase 3 trial evaluating the addition of neoadjuvant apalutamide to ADT for localized high-risk prostate cancer or locally advanced prostate cancer.44 Primary outcomes will examine pathologic complete response (pCR) and MFS, with secondary endpoints including PSA-free survival and PFS; the estimated study completion is in 2028.
The Role of Chemotherapy
Other systemic treatments, such as chemotherapy, also have been explored for these patient populations. Early trials explored the use of nontaxane treatment regimens that ultimately failed to show significant clinical benefit; for example, SWOG S9921 tested mitoxantrone, and RTOG 9902 tested paclitaxel, estramustine (Emcyt, Pfizer), and oral etoposide.45,46 However, later trials using taxane-based regimens yielded results with more favorable efficacy and tolerability, as described in the Table. One of the most commonly used taxane-based chemotherapeutic agents is docetaxel; literature offers multiple potential mechanisms of action for these agents, including binding to and interfering with microtubule function, thereby leading to cell cycle arrest and the subsequent suppression of cell viability, or micronucleation and subsequent membrane rupture.47 Long-term results of the STAMPEDE trial demonstrated longer OS in patients with metastatic hormone-naive prostate cancer who were treated with docetaxel plus ADT than in those treated with ADT alone48; however, results of another trial arm that evaluated the use of docetaxel with hormonal therapy in patients with nonmetastatic disease did not demonstrate long-term benefit.49
The application of docetaxel was then translated to the neoadjuvant setting. One open-label, nonrandomized, single-center phase 2 trial assigned patients with locally advanced prostate cancer to 6 weeks of neoadjuvant docetaxel therapy before RP. Final pathology demonstrated residual cancer in all specimens, but at 2-year follow-up, 71% of the patients were clinically and biochemically free of disease.50 A 10-year follow-up of this same cohort found a promising OS rate of 79.7% and a prostate cancer–specific survival rate of 92.2%.51
Results from phase 3 trials were congruent. The phase 3 GETUG‑12 trial randomized patients with intermediate- or high-risk disease to RT and ADT alone or to RT and ADT with neoadjuvant/adjuvant docetaxel and estramustine. At a median follow-up of 12 years,addition of the chemotherapy regimen was associated with an increased 12-year relapse-free survival rate (49.4%; 95% CI, 42.5-56.3) in comparison with ADT (36.3%; 95% CI, 29.7-43.5; HR, 0.71; 95% CI, 0.55-0.93; P=.01). The data showed no significant increase in secondary cancer rates in the chemotherapy arm.52 The CALGB 90203 trial tested the addition of neoadjuvant docetaxel plus ADT before RP vs RP alone in patients with clinically localized high-risk prostate cancer. Although some secondary endpoints demonstrated improvement (overall biochemical PFS, OS, MFS), the primary endpoint (improved biochemical PFS at 3 years) was not met, and the study noted that further follow-up is needed to clarify the potential benefits seen.53 Studies have continued to explore this treatment, with some finding significant improvements in oncologic outcomes such as biochemical PFS56 and others finding no significant differences.54
Overall, these trials helped clarify the utility of specific chemotherapies in the management of high-risk localized prostate cancer. Although such neoadjuvant approaches have shown potential for improving pathologic and oncologic outcomes, their use is limited by systemic toxicity and the risk of secondary malignancy, prompting the exploration of more precise cytotoxic strategies such as immunotherapy and radiopharmaceuticals.
Exploring the Use of Immunotherapy
Emerging research has explored immunotherapy as a more “personalized” strategy in the treatment of prostate cancer, leveraging approaches that target tumor-specific immune mechanisms and, ideally, better protect normal cells. One of the most studied is the programmed death 1 (PD-1) inhibitor pembrolizumab (Keytruda, Merck). Given that the expression of PD-1 by T cells allows cancer cells expressing the complementary programmed death–ligand 1 (PD-L1) protein to evade recognition by host immune cells, the blockade of PD-1 is an important anticancer strategy and is also used in numerous other malignancies.55 Pembrolizumab has been evaluated in the locally advanced and metastatic prostate cancer settings with some promise,56,57 but long-term results are pending.
Poly(ADP-ribose) polymerase (PARP) inhibitors offer another strategy for precisely targeting the offensive immune mechanisms of cancers. These medications are especially important in the treatment of cancers that lack homologous recombination repair (HRR) genes (a specific type of DNA repair), as this lack causes overreliance on a PARP-mediated repair mechanism. Blocking the alternative repair pathway in cancer cells can lead to an accumulation of DNA damage and cell death, so that blockage is an attractive therapeutic target.58 Several US Food and Drug Administration (FDA)–approved medications of this class include olaparib (Lynparza, AstraZeneca), rucaparib (Rubraca, Clovis Oncology), and talazoparib (Talzenna, Pfizer; approved for administration with enzalutamide),59 which showed benefit in patients with mCRPC who had HRR gene mutations.60-62
Research on the neoadjuvant application of PARP inhibitors is growing. The phase 2 NCT04030559 and NePtune trials are testing the utility of niraparib (Zejula, GlaxoSmithKline) and olaparib, respectively, in patients with unfavorable intermediate- to high-risk prostate cancer and HRR gene deficiencies.58 A phase 2 trial is evaluating the addition of pembrolizumab plus olaparib vs the addition of single-agent pembrolizumab to standard ADT with RT for patients with high-risk localized prostate cancer (NCT05568550). Primary outcomes will assess PSA nadir after RT, and secondary outcomes will assess BCR and MFS at 3 years.
Radiopharmaceuticals
Like immunotherapy, radioligand therapy is a new class of precise therapies utilized for several cancer treatments. Radioligand therapies consist of a radiation-emitting component (radionuclide chelator and isotope) complexed to a targeting agent (a small molecule that targets a specific antibody or antigen).63 Radioligand therapy provides the unique advantage of delivering targeted radiation-emitting isotopes to cells expressing tumor-specific characteristics, ideally sparing normal tissue and effectively targeting cancer-specific cells. The first FDA-approved radiopharmaceutical was radium 223, and current clinical trials are evaluating additional radioisotopes for therapeutic use.63
Lutetium 177 (177Lu) PSMA-617 is a new radionuclide being explored for patients with high-risk localized prostate cancer. This is a theranostic therapy based on preoperative imaging with prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT). PSMA PET/CT tags and highlights the membrane-bound glycoprotein PSMA, which is highly expressed on prostate cancer-specific cells.64 Thus, through the targeting of prostate cancer cells via PSMA recognition and the cytotoxic action induced by the beta-emitting radioligand 177Lu, this therapy is thought to provide more precise “on-target” therapeutics while minimizing “off-target” side effects.63,65
First, phase 1 trials demonstrated the safety and feasibility of this therapy.65 Research then moved into phase 2 studies to evaluate its efficacy in metastatic disease. The UpFrontPSMA study is a multi-institutional, open-label, randomized trial that included patients with high-volume mHSPC.66 Patients were randomized to receive either 177Lu-PSMA-617 plus docetaxel (experimental) or docetaxel alone (standard of care), and all patients also received ADT. A total of 41% of patients in the experimental group had undetectable PSA level at 48 weeks, which was the primary endpoint of the study, vs 16% in the standard-of-care group.66
The VISION trial demonstrated the efficacy of 177Lu-PSMA-617 in the mCRPC population.67 This international open-label trial included patients who previously had received at least one course of ADT and 1 to 2 cycles of chemotherapy, as well as a positive PSMA scan result. The 177Lu-PSMA-617 group demonstrated improved image-based PFS (median, 8.7 vs 3.4 months; HR for progression or death, 0.4; 99.2% CI, 0.29-0.57; P<.001) and OS (median, 15.3 vs 11.3 months; HR for death, 0.62; 95% CI, 0.52-0.74; P<.001). The phase 3 PSMAfore trial also studied efficacy in patients with mCRPC. This open-label, randomized study delivered either 177Lu-PSMA-617 or “change of ARPI” to abiraterone or enzalutamide (all patients had experienced disease progression once on a previous ARPI). In the primary analysis, the study found that the experimental 177Lu-PSMA-617 group demonstrated longer radiographic PFS (experimental, 11.6 months vs ARPI, 5.59 months; HR, 0.49; 95% CI, 0.39-0.61).68 Taken together, these trials support the growing role of Lu177-PSMA-617 in the treatment of metastatic prostate cancer.
The results have also prompted investigation into the earlier application of these therapies. The LUNAR trial is an open-label, randomized, 2-arm, single-center phase 2 trial that seeks to compare the efficacy of neoadjuvant Lu-177-PNT2002 with that of traditional stereotactic body radiotherapy in patients with oligorecurrence.69 Current regimens offer metastasis-directed therapy as stereotactic body radiation or surgery, but progression to distant metastatic disease often requires additional therapy.69 In recently reported results, at a median follow-up of 22 months, the Lu-177-PNT2002 group had significantly better PFS (the primary endpoint), at 17.6 vs 7.4 months (HR, 0.37; 95% CI, 0.22-0.61; P<.0001).
Clinical trials are now exploring the role of radioligand therapy in localized high-risk prostate cancer. The first trial to explore this was the LuTectomy trial, a phase 1 trial that tested the safety and feasibility of neoadjuvant 177Lu-PSMA in this category of patients.70 Adverse events were well tolerated, with no Clavien-Dindo grade 3 or higher complications found. Taking this further, the prospective, nonrandomized, single-arm, interventional phase 2 PRELUDE trial will evaluate the outcomes of neoadjuvant 177Lu-PSMA-617 before RP in patients with high-risk, PSMA-defined prostate-only disease. Primary outcomes will focus on the downstaging of prostate cancer following RP. The trial is currently open and accruing patients (NCT06798558).
Despite these advances, radioligand therapy remains limited by the challenge of optimizing the radiation dose to maximize efficacy while minimizing renal toxicity.71 Thus, the concept of radiohybrid PSMA ligands (rhPSMA) is being increasingly studied; this therapy maximizes the theranostic opportunity of radioligands via labeling with diagnostic and therapeutic radiometals (fluorine 18).72 Preclinical studies have identified rhPSMA-10.1 and rhPSMA-10.2 as promising theranostic candidates, with high rates of tumor uptake and fast clearance from the kidneys.73 The phase 1/2 Nautilus trial will explore the safety and efficacy of neoadjuvant 177Lu-rhPSMA-10.1 in patients with high-risk, localized prostate cancer before primary RP. The 2 study arms will include patients with either neoadjuvant 177Lu-rhPSMA-10.1 alone or neoadjuvant 177Lu-rhPSMA-10.1 plus degarelix. Study completion is planned for 2027 (NCT06066437).
As research on lutetium-based radioligand therapy has progressed, other radioisotope candidates have also emerged. Whereas lutetium 177 is a beta-emitting particle, actinium 225 is an alpha-emitting particle, thought to deliver more energy than the former and thus induce more cellular damage with fewer radiation events.74 However, research comparing the efficacy of these treatments is early and ongoing.74 Notably, the phase 1 LUTACT study will compare safety, pathologic response, tumor-absorbed dose, and more in neoadjuvant 177Lu-PSMA-617, neoadjuvant 225Ac-PSMA-617, and control arms (no neoadjuvant therapy before RP) in patients with high-risk localized prostate cancer (NCT07054346). Together, these efforts highlight a broader shift toward optimizing radionuclide selection to enhance therapeutic efficacy while balancing toxicity in radioligand therapy.
Conclusions
The treatment of high-risk localized prostate cancer poses unique challenges owing to the elevated risk of recurrence. The literature has explored multiple methods of decreasing this risk with adjuvant and neoadjuvant hormonal therapy, chemotherapy, immunotherapy, and radioligand therapy. Radioligand therapy offers particular advantages in comparison with the traditional approaches of hormonal therapy and chemotherapy, with improved ability to target prostate cancer cells and use a theranostic approach. Studies so far show potential, and ongoing trials will continue to contribute meaningfully to decision making guidance in the treatment of prostate cancer.
Disclosures
SS, JO, QC, BH, JWC, and CK have no relevant disclosures. MS is a consultant for Intuitive Surgical and Vascular Technology Inc. NY discloses research grant funding from Novartis.
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