Prostate Cancer: Mechanisms, Pathways, Targets, and Treatment Efficacy

Prostate cancer represents one of the most prevalent malignancies affecting men globally, acting as a significant health concern with complex molecular underpinnings and variable therapeutic responses. As a prevalent malignancy affecting the prostate gland, it continues to be one of the leading causes of cancer-related death in the male population despite considerable advancements in treatment approaches269. The progression of prostate cancer involves multiple interconnected pathways from androgen receptor signaling to DNA repair mechanisms, inflammatory processes, and metabolic alterations, all contributing to its development, progression, and therapeutic resistance. Current treatment paradigms include androgen deprivation therapy (ADT), showing efficacy with over 50% of patients surviving at the 10-year mark, though resistance inevitably develops in many cases, necessitating additional therapeutic strategies2. Immunotherapies, targeted molecular approaches, chemotherapy regimens, and radiopharmaceuticals have demonstrated varying levels of success, with some firmly established in clinical practice while others remain investigational. This comprehensive analysis explores the intricate mechanisms driving prostate cancer, examines therapeutic targets, and evaluates the efficacy spectrum of current and emerging treatment modalities.

Pathophysiology and Molecular Mechanisms of Prostate Cancer

Androgen Receptor Signaling Pathway

The androgen receptor (AR) signaling axis represents the cornerstone of prostate cancer pathophysiology, playing a crucial role in both hormone-sensitive and castration-resistant disease states. Androgens, primarily testosterone and dihydrotestosterone, bind to the androgen receptor, triggering a cascade of cellular events that promote prostate cancer cell proliferation, survival, and metastatic potential1. A significant mechanism of resistance to androgen deprivation therapy involves amplification of the androgen receptor gene, which occurs in approximately 28% of recurrent therapy-resistant tumors but is notably absent in untreated primary tumors3. This amplification leads to AR overexpression, enabling cancer cells to respond to minimal androgen concentrations that would otherwise be insufficient to stimulate growth, effectively circumventing the androgen blockade therapy3. Furthermore, the emergence of constitutively active androgen receptor splice variants, particularly AR-V7, represents another critical mechanism of treatment resistance, as these variants lack the ligand-binding domain targeted by conventional hormonal therapies but retain transcriptional activity8.

The complexity of AR signaling extends beyond simple ligand-receptor interactions, encompassing elaborate crosstalk with other cellular pathways that contribute to disease progression. Research has demonstrated significant interaction between AR signaling and the NF-κB pathway, creating a feed-forward loop that promotes cancer cell survival under androgen-depleted conditions10. Additionally, amplified AR signaling drives extensive metabolic reprogramming in prostate cancer cells, particularly affecting lipid metabolism pathways that provide essential building blocks for membrane synthesis and energy production8. Understanding these intricate relationships has led to the development of second-generation AR-targeting agents like enzalutamide, apalutamide, and darolutamide, which display higher binding affinity to the androgen receptor and inhibit multiple steps in the AR signaling cascade, offering improved therapeutic outcomes for patients with advanced disease417.

DNA Damage Repair Mechanisms

Defects in DNA damage repair (DDR) pathways represent a critical molecular vulnerability in prostate cancer that significantly influences disease behavior and treatment responsiveness. Nearly 20% of metastatic castration-resistant prostate cancers (mCRPC) harbor deficiencies in homologous recombination (HR), a high-fidelity DNA repair mechanism essential for fixing double-strand breaks5. BRCA2, ATM, and CHEK2 constitute the most frequently mutated genes within this pathway, with BRCA2 alterations particularly associated with aggressive clinical and pathological characteristics, including intraductal carcinoma features5. These genetic aberrations can be inherited (germline) or acquired (somatic), with germline mutations linked to hereditary predisposition for early prostate cancer development and more aggressive clinical behavior5. The presence of DDR defects fundamentally alters the genomic landscape of the tumor, leading to heightened genomic instability that drives disease progression but simultaneously creates therapeutic vulnerabilities that can be exploited9.

The mismatch repair (MMR) system represents another DNA repair mechanism implicated in prostate carcinogenesis, although it affects a smaller proportion of cases, with deficiencies present in approximately 5% of metastatic prostate cancers5. MMR deficiency typically results in microsatellite instability (MSI) and elevated tumor mutational burden, characteristics that have been associated with aggressive disease behavior but paradoxically increased responsiveness to certain therapeutic approaches, particularly immunotherapy9. These DNA repair pathway defects have been systematically leveraged for therapeutic targeting through synthetic lethality approaches, wherein PARP inhibitors selectively kill cancer cells with HR deficiencies by blocking an alternative DNA repair pathway, making the accumulation of DNA damage lethal specifically to tumor cells5. The approval of PARP inhibitors for mCRPC patients with HRD alterations represents a significant advance in precision medicine for prostate cancer, demonstrating improved outcomes in these molecularly defined patient subsets and highlighting the importance of comprehensive genomic profiling in treatment planning59.

Inflammatory Pathways and NF-κB Signaling

Inflammation plays a multifaceted role in prostate cancer initiation, progression, and therapeutic resistance, with the NF-κB signaling pathway serving as a central mediator of these pro-tumorigenic effects. The increased prevalence of prostate cancer in Western populations has been partially attributed to elevated inflammation associated with metabolic syndrome and related comorbidities, establishing a mechanistic link between inflammatory processes and carcinogenesis10. NF-κB activation drives the expression of numerous genes involved in cell survival, proliferation, angiogenesis, and metastasis, collectively promoting an aggressive cancer phenotype10. This transcription factor exists in a latent form in the cytoplasm and translocates to the nucleus upon activation by various stimuli, including cytokines, growth factors, and oxidative stress, subsequently binding to target gene promoters and enhancing their transcription10. Chronic NF-κB activation contributes substantially to the development of castration resistance by promoting androgen-independent cell survival and proliferation pathways that bypass the need for canonical AR signaling10.

The intricate crosstalk between NF-κB and AR signaling represents a critical mechanism underlying therapeutic resistance in prostate cancer. Research has demonstrated that NF-κB can directly enhance AR expression and activity through various mechanisms, including promoter activation and post-translational modifications, while AR can reciprocally modulate NF-κB signaling, creating a self-reinforcing circuit that sustains cancer cell viability despite androgen deprivation10. Additionally, NF-κB activation induces the expression of anti-apoptotic proteins such as Bcl-2, survivin, and inhibitors of apoptosis proteins (IAPs), protecting cancer cells from treatment-induced cell death and conferring resistance to multiple therapeutic modalities10. The tumor microenvironment further contributes to this inflammatory milieu through infiltrating immune cells that secrete pro-inflammatory cytokines, perpetuating NF-κB activation and creating a permissive niche for cancer progression10. Therapeutic targeting of the NF-κB pathway has emerged as a promising strategy for overcoming treatment resistance, with several inhibitors currently under investigation that may potentially enhance the efficacy of conventional therapies when used in rational combinations110.

Angiogenesis in Prostate Cancer

The formation of new blood vessels, or angiogenesis, represents a fundamental process in prostate cancer development, enabling tumor growth beyond 1-2 mm diameter by providing essential oxygen and nutrients while facilitating metastatic dissemination. Prostate cancer cells secrete various pro-angiogenic factors, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF), which stimulate endothelial cell proliferation, migration, and vessel formation6. The hypoxic tumor microenvironment serves as a primary driver of angiogenesis through the stabilization of hypoxia-inducible factor-1α (HIF-1α), a transcription factor that upregulates numerous genes involved in the angiogenic cascade6. Interestingly, androgen signaling directly regulates several angiogenic factors, with studies demonstrating that androgen deprivation therapy initially reduces tumor vascularity, though this effect is often transient as alternative angiogenic pathways become activated during disease progression6.

Despite the clear biological importance of angiogenesis in prostate cancer, clinical trials evaluating anti-angiogenic monotherapies have demonstrated only marginal benefits compared to their substantial impact in other cancer types6. This limited efficacy may be attributed to several factors, including the activation of compensatory angiogenic pathways, the heterogeneous nature of tumor vasculature, and the development of resistance mechanisms such as vessel co-option, where tumor cells grow along existing blood vessels rather than inducing new ones6. Furthermore, anti-angiogenic therapies in refractory castration-resistant prostate cancer have shown increased toxicity without corresponding clinical benefit, highlighting the need for improved patient selection strategies and rational combination approaches6. Ongoing research focuses on identifying specific patient subsets who might benefit from anti-angiogenic strategies, possibly through the development of predictive biomarkers or by targeting multiple angiogenic pathways simultaneously to overcome resistance mechanisms6. Additionally, the combination of anti-angiogenic agents with immunotherapy holds promise, as vascular normalization may enhance immune cell infiltration and function within the tumor microenvironment, potentially augmenting treatment responses16.

Metabolic Alterations and Lipid Synthesis

Metabolic reprogramming represents a hallmark of prostate cancer progression, with de novo lipogenesis emerging as a critical pathway that supports tumor growth and therapeutic resistance. A defining feature of advanced prostate cancer is the upregulation of fatty acid synthase (FASN), a key enzyme in de novo fatty acid synthesis that converts acetyl-CoA to long-chain fatty acids essential for membrane production, energy storage, and signaling molecule generation8. This metabolic adaptation provides substrates and fuel for aggressive growth and metastatic spread, particularly in the nutrient-limited microenvironments often encountered during cancer progression8. Research has demonstrated that selective FASN inhibition antagonizes castration-resistant prostate cancer growth through comprehensive metabolic reprogramming, suggesting a therapeutic vulnerability that could be exploited8. Remarkably, FASN inhibition also reduces protein expression and transcriptional activity of both full-length AR and the constitutively active AR-V7 variant, establishing a mechanistic link between lipid metabolism and androgen signaling that potentially offers a strategy to overcome resistance to conventional AR-targeting therapies8.

The interconnection between metabolic pathways and oncogenic signaling extends beyond lipogenesis, encompassing glucose metabolism, glutaminolysis, and cholesterol synthesis, collectively creating an integrated metabolic network that supports prostate cancer cell survival and proliferation. The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT/mTOR pathway plays a central role in this metabolic orchestration, promoting glucose uptake, glycolysis, and lipid synthesis while simultaneously regulating protein translation and cell growth917. Notably, the tumor suppressor PTEN, which negatively regulates this pathway, is frequently lost in prostate cancer, leading to constitutive activation of AKT signaling and subsequent metabolic reprogramming that drives disease progression9. The recognition of these metabolic dependencies has spurred the development of numerous therapeutic agents targeting key metabolic enzymes and regulators, including FASN inhibitors, AKT inhibitors, and mTOR inhibitors, some of which have shown promising activity in preclinical models and early-phase clinical trials8917. Combination strategies that simultaneously target metabolic vulnerabilities and canonical oncogenic pathways may provide synergistic effects and help overcome the compensatory mechanisms that often limit the efficacy of single-agent approaches817.

Prostate Cancer Progression and Treatment Resistance

Development of Castration-Resistant Prostate Cancer

The progression from hormone-sensitive prostate cancer to castration-resistant prostate cancer (CRPC) represents a critical inflection point in disease management, marking the transition to a more aggressive and therapeutically challenging phase. CRPC is defined by disease progression despite castrate levels of testosterone (<50 ng/dL), indicating that the cancer has developed mechanisms to thrive in an androgen-depleted environment20. This adaptation typically occurs within 2-3 years of initiating androgen deprivation therapy, though the timeframe varies considerably between patients4. Multiple molecular mechanisms underlie this transition, including androgen receptor gene amplification, expression of constitutively active AR splice variants, alterations in AR co-regulators, intratumoral androgen synthesis, and activation of bypass pathways that sustain cancer cell viability independent of canonical AR signaling320. AR gene amplification, found in approximately 28% of recurrent therapy-resistant tumors but absent in untreated primary tumors, enables cancer cells to respond to trace amounts of androgens, effectively circumventing the androgen blockade imposed by conventional therapies3.

The genomic landscape of CRPC is characterized by increased mutational burden and chromosomal instability compared to hormone-sensitive disease, reflecting the selective pressures imposed by treatment and the inherent genomic plasticity of advanced tumors59. Emerging evidence suggests that epigenetic alterations, including changes in DNA methylation patterns and histone modifications, also contribute significantly to the CRPC phenotype by reprogramming gene expression profiles to support androgen-independent growth1. Additionally, the tumor microenvironment undergoes profound changes during CRPC development, with increased infiltration of immunosuppressive cell populations, enhanced angiogenesis, and extensive extracellular matrix remodeling collectively creating a niche conducive to treatment resistance and metastatic dissemination610. The recognition of these diverse resistance mechanisms has driven the development of novel therapeutic strategies, including second-generation AR antagonists (enzalutamide, apalutamide), CYP17 inhibitors (abiraterone), taxane-based chemotherapy, and various targeted approaches that aim to overcome or bypass specific resistance pathways41720. Despite these advances, CRPC remains incurable, underscoring the need for continued research into the fundamental biology of treatment resistance and the development of more effective therapeutic combinations420.

Mechanisms of Therapy Resistance

Therapeutic resistance in prostate cancer emerges through diverse molecular mechanisms that collectively enable tumor cells to evade treatment-induced cell death and maintain proliferative capacity. Resistance to androgen deprivation therapy often involves alterations in the androgen receptor signaling axis, including AR gene amplification, point mutations that broaden ligand specificity, expression of constitutively active splice variants lacking the ligand-binding domain, and aberrant activation of AR coactivators38. Beyond these AR-centric mechanisms, prostate cancer cells develop resistance through parallel pathway activation, particularly the PI3K/AKT/mTOR signaling cascade, which provides pro-survival and pro-growth signals independent of androgen signaling917. The frequent loss of PTEN tumor suppressor in advanced disease constitutively activates this pathway, creating a significant challenge for therapeutic targeting9. Additionally, abnormal activation of the WNT/β-catenin pathway, often through loss of inhibitory regulators, contributes to therapy resistance by promoting epithelial-to-mesenchymal transition and cancer stem cell-like properties that enhance survival under therapeutic pressure1.

Resistance to taxane-based chemotherapy, a standard treatment for metastatic castration-resistant prostate cancer, develops through multiple mechanisms including overexpression of drug efflux pumps, alterations in microtubule composition and dynamics, activation of pro-survival pathways, and impaired apoptotic machinery14. Similarly, resistance to PARP inhibitors, which have shown efficacy in patients with DNA repair defects, can emerge through reversion mutations that restore homologous recombination function, upregulation of alternative repair pathways, or drug efflux mechanisms59. Immunotherapy resistance in prostate cancer involves complex interplay between tumor cells and the immune microenvironment, characterized by reduced neoantigen expression, impaired antigen presentation, upregulation of immune checkpoint molecules, and recruitment of immunosuppressive cell populations1017. The molecular heterogeneity of prostate cancer further complicates therapeutic targeting, as subclonal populations with distinct resistance mechanisms may exist within the same tumor or across different metastatic sites, necessitating combination approaches that simultaneously address multiple resistance pathways1417. Advanced molecular profiling technologies, including next-generation sequencing and liquid biopsies, increasingly enable real-time monitoring of resistance emergence, potentially allowing for adaptive therapeutic strategies that evolve in response to the changing molecular landscape of the disease5917.

Established and Emerging Therapeutic Approaches

Androgen Deprivation Therapy and AR-Targeted Agents

Androgen deprivation therapy (ADT) remains the cornerstone of systemic treatment for advanced prostate cancer, demonstrating significant efficacy with over 50% of patients surviving at the 10-year mark despite the eventual development of resistance mechanisms2. The fundamental principle of ADT involves reducing circulating testosterone levels to castrate range (<50 ng/dL), typically achieved through surgical orchiectomy or, more commonly, medical castration using gonadotropin-releasing hormone (GnRH) agonists or antagonists4. The therapeutic landscape has expanded considerably with the development of second-generation androgen receptor (AR) antagonists, including enzalutamide, apalutamide, and darolutamide, which demonstrate higher binding affinity to the AR and block multiple steps in the signaling cascade, including nuclear translocation and DNA binding417. Additionally, abiraterone acetate, a CYP17 inhibitor that blocks androgen biosynthesis in testicular, adrenal, and tumoral tissues, has shown remarkable efficacy in both hormone-sensitive and castration-resistant disease settings417. The clinical benefit of these agents has been conclusively demonstrated in multiple randomized controlled trials, establishing them as standard-of-care options across the disease spectrum4.

Recent paradigm-shifting clinical trials have established the superiority of combination approaches involving ADT intensification for newly diagnosed metastatic hormone-sensitive prostate cancer417. Adding abiraterone acetate to conventional ADT to achieve complete androgen blockade has proven highly beneficial for treatment of locally advanced prostate cancer and metastatic hormone-sensitive disease, significantly extending overall survival compared to ADT alone17. Similarly, combining ADT with docetaxel chemotherapy has demonstrated substantial survival benefits in the metastatic hormone-sensitive setting, particularly for patients with high-volume disease17. The National Comprehensive Cancer Network (NCCN) Guidelines now strongly recommend ADT with treatment intensification for patients with metastatic castration-sensitive prostate cancer, reflecting the robust evidence supporting this approach4. For patients who develop non-metastatic castration-resistant prostate cancer, characterized by rising PSA despite castrate testosterone levels but without detectable metastases, the addition of second-generation AR antagonists (enzalutamide, apalutamide, or darolutamide) to ongoing ADT significantly delays metastasis development and improves overall survival4. Despite these impressive advances, resistance inevitably develops in most patients, underscoring the need for continued research into novel AR-targeting strategies and rational combinations that address multiple resistance mechanisms simultaneously1420.

DNA Damage Response Targeting Approaches

The recognition of DNA damage repair (DDR) deficiencies in a significant proportion of advanced prostate cancers has revolutionized treatment approaches, establishing a new paradigm of precision medicine based on specific genomic alterations. Approximately 20% of metastatic castration-resistant prostate cancers harbor defects in homologous recombination repair genes, most commonly BRCA2, ATM, and CHEK2, creating a therapeutic vulnerability that can be exploited through synthetic lethality strategies59. PARP (poly-ADP ribose polymerase) inhibitors have emerged as the primary therapeutic approach targeting this vulnerability, with olaparib and rucaparib receiving regulatory approval for metastatic CRPC patients with specific DDR gene alterations based on compelling clinical trial data demonstrating improved radiographic progression-free survival and overall survival in these molecularly defined subgroups59. These approvals represent a significant milestone in prostate cancer treatment, marking the first biomarker-selected therapies specifically indicated for patients with particular genetic alterations and highlighting the increasingly personalized approach to disease management59.

The clinical implementation of DDR-targeted therapies necessitates comprehensive genomic profiling, which has become increasingly integrated into routine clinical practice for advanced prostate cancer5. Mutations are typically detected in metastatic tissue biopsies, though liquid biopsy approaches analyzing circulating tumor DNA (ctDNA) have gained traction as less invasive alternatives, particularly useful during treatment monitoring to identify emerging resistance mechanisms5. Beyond PARP inhibition, numerous other therapeutic strategies targeting the DNA damage response are under investigation, including ATR inhibitors, DNA-PK inhibitors, and CHK1/2 inhibitors, some showing promising activity in early-phase clinical trials, particularly in combination with standard therapies or other targeted agents917. Mismatch repair (MMR) deficiency, present in approximately 5% of metastatic prostate cancers, represents another DNA repair-related vulnerability that can be therapeutically targeted, with PD-1 inhibitors demonstrating efficacy in MMR-deficient tumors across multiple cancer types5. This has led to the recommendation that MMR status should be assessed in all metastatic prostate cancer cases to identify patients who might benefit from immunotherapy approaches5. Additionally, tumor mutational burden (TMB), often elevated in cancers with defective DNA repair mechanisms, has emerged as a potential biomarker for immunotherapy response, though its predictive value in prostate cancer requires further validation in prospective clinical trials517.

Chemotherapy in Prostate Cancer Management

Chemotherapy, particularly taxane-based regimens, remains a vital component of the prostate cancer treatment armamentarium despite the emergence of numerous targeted approaches. Docetaxel, a microtubule-stabilizing agent that inhibits cell division by preventing microtubule depolymerization, was the first chemotherapy to demonstrate a survival benefit in metastatic castration-resistant prostate cancer (mCRPC) and continues to be a standard first-line option for patients with symptomatic disease or visceral metastases41417. The therapeutic landscape expanded with the approval of cabazitaxel, a second-generation taxane developed to overcome docetaxel resistance, which has shown efficacy in patients who progress after docetaxel treatment414. Beyond their established role in the castration-resistant setting, taxanes have increasingly been incorporated into earlier disease stages, with docetaxel demonstrating significant survival benefits when combined with androgen deprivation therapy (ADT) for newly diagnosed metastatic hormone-sensitive prostate cancer, particularly in patients with high-volume disease17. This treatment intensification approach has been rapidly adopted into clinical practice guidelines, reflecting the robust evidence supporting its use417.

Despite the proven benefits of chemotherapy, resistance inevitably develops through various mechanisms, including drug efflux via P-glycoprotein overexpression, alterations in microtubule composition and dynamics, activation of pro-survival pathways, and impaired apoptotic machinery14. Additionally, the taxane class is associated with notable toxicities, including myelosuppression, peripheral neuropathy, and fatigue, which may limit treatment duration or necessitate dose modifications, particularly in elderly patients or those with significant comorbidities414. Numerous strategies to overcome chemotherapy resistance are under investigation, including novel taxane formulations with improved pharmacokinetic properties, combination approaches targeting resistance pathways, and the development of predictive biomarkers to identify patients most likely to benefit from chemotherapy1417. The optimal sequencing of chemotherapy relative to hormonal agents and other targeted therapies remains an area of active research, with ongoing clinical trials evaluating various treatment sequences and combinations to maximize clinical benefit while minimizing cumulative toxicities41417. As the therapeutic landscape continues to evolve, personalized approaches incorporating patient preferences, disease characteristics, comorbidities, and increasingly, molecular profiling data, will be essential for optimizing chemotherapy use in prostate cancer management417.

Immunotherapy Approaches and Challenges

Immunotherapy has transformed the treatment landscape across multiple cancer types, though its impact in prostate cancer has been more modest compared to melanoma or lung cancer, reflecting the unique immunobiological characteristics of prostatic malignancies. Sipuleucel-T, an autologous cellular immunotherapy, represents the first and currently only FDA-approved immunotherapy specifically for prostate cancer, demonstrating a modest but statistically significant improvement in overall survival for minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC) patients417. This personalized vaccine approach involves collecting a patient's own immune cells, exposing them ex vivo to a fusion protein consisting of prostatic acid phosphatase (PAP) linked to granulocyte-macrophage colony-stimulating factor (GM-CSF), and reinfusing the activated cells to stimulate an immune response against PAP-expressing prostate cancer cells17. Despite its proven survival benefit, sipuleucel-T has faced challenges in clinical adoption due to its complex manufacturing process, high cost, modest clinical benefit compared to other available therapies, and lack of conventional response markers417.

Immune checkpoint inhibitors, which have revolutionized treatment across numerous cancer types, have shown limited efficacy as monotherapy in unselected prostate cancer populations, with disappointing results in several large clinical trials17. However, specific molecular subsets, particularly those with mismatch repair deficiency (MMR-d) or high tumor mutational burden (TMB), have demonstrated more encouraging responses to PD-1/PD-L1 inhibitors, leading to the recommendation that MMR status should be assessed in all metastatic prostate cancer cases517. The generally immunosuppressive microenvironment of prostate cancer, characterized by low mutational burden, limited T-cell infiltration, and high levels of immunosuppressive cell populations, likely contributes to the modest efficacy of checkpoint inhibition in this disease1017. Numerous strategies to enhance immunotherapy effectiveness are under investigation, including combination approaches with conventional therapies, targeted agents, or radiation to increase tumor immunogenicity; novel checkpoint targets beyond PD-1/PD-L1; bispecific antibodies that simultaneously engage T cells and tumor-associated antigens; adoptive cell therapies utilizing engineered T cells; and personalized neoantigen vaccines based on individual tumor mutational profiles217. Advanced clinical studies with immune checkpoint inhibitors have shown limited benefits in unselected prostate cancer populations, underscoring the need for improved patient selection strategies and rational combination approaches that address the unique immunobiological features of this disease17.

Radiopharmaceuticals and Novel Radiotherapy Approaches

Radiopharmaceuticals and advanced radiotherapy techniques have emerged as important components of the prostate cancer treatment armamentarium, particularly for patients with bone-predominant metastatic disease or localized recurrences after primary therapy. Radium-223 dichloride, a calcium-mimetic alpha-emitting radiopharmaceutical that selectively targets areas of increased bone turnover, has demonstrated significant overall survival benefit in patients with symptomatic bone metastases from castration-resistant prostate cancer, establishing it as a standard treatment option for this patient subset417. The therapeutic advantage of alpha particles lies in their high linear energy transfer and short range, allowing for localized tumor cell killing while minimizing damage to surrounding normal tissues, resulting in a favorable toxicity profile primarily characterized by mild myelosuppression and gastrointestinal symptoms417. Beyond radium-223, several next-generation radiopharmaceuticals targeting prostate-specific membrane antigen (PSMA), including lutetium-177-PSMA-617 and actinium-225-PSMA-617, have shown promising results in early clinical trials and represent an area of active investigation17.

Novel radiotherapy techniques utilizing advanced imaging guidance have expanded treatment options for patients with oligometastatic disease or locally recurrent prostate cancer. Biology-guided radiotherapy (BgRT), which uses real-time functional imaging such as PSMA-PET to guide radiation delivery, represents a cutting-edge approach that potentially enhances therapeutic precision by targeting areas of active disease while sparing normal tissues15. For patients with locally recurrent prostate cancer after primary radiation therapy or focal therapy, salvage approaches combining cryoablation with robotic seminal vesiculectomy have demonstrated feasibility and effectiveness in selected cases, offering a potential curative option for patients with limited recurrence11. This novel combined technique has shown promising results with minimal complications, no new urinary incontinence, and preservation of erectile function in patients with pre-operative erections adequate for intercourse, representing an important addition to the therapeutic arsenal for managing local recurrences11. The integration of advanced imaging technologies, particularly PSMA-PET/CT, has dramatically improved the detection of small-volume disease and enabled more precise targeting of radiotherapy, potentially allowing for dose escalation to visible disease while minimizing exposure to surrounding normal tissues1517. These technological advances, coupled with improved understanding of radiation biology and novel combination approaches with systemic therapies, continue to expand the role of radiotherapeutic interventions across the prostate cancer disease spectrum111517.

Traditional and Complementary Approaches

Chinese Medicine and Alternative Therapies

Traditional Chinese medicine (TCM) has garnered increasing interest in the oncology community as a complementary approach to conventional prostate cancer treatments, with some compounds showing potential mechanistic effects on cancer pathways. Huangqi (Astragalus membranaceus), a widely used traditional Chinese medicinal herb, has been studied for its potential therapeutic effects in castration-resistant prostate cancer through network pharmacology and molecular docking analyses19. Research suggests that Huangqi contains approximately 87 active compounds (with 20 identified as key active compounds) that potentially interact with 33 targets relevant to castration-resistant prostate cancer treatment19. These compounds may exert their effects through multiple mechanisms, including modulation of apoptotic pathways, anti-inflammatory actions, antioxidant properties, and potential interference with androgen receptor signaling19. While these preliminary investigations provide a theoretical framework for understanding potential benefits, it is important to note that much of this research remains at the preclinical stage, with limited high-quality clinical trial data to establish efficacy, optimal dosing, potential drug interactions, or safety profiles in prostate cancer patients19.

The integration of complementary therapies into conventional cancer care requires careful consideration of potential benefits, risks, and interactions with standard treatments. Unlike the robust evidence base supporting conventional therapies such as androgen deprivation therapy, chemotherapy, and targeted molecular approaches, complementary treatments often lack the same level of rigorous clinical validation through randomized controlled trials19. Many traditional herbal medicines contain multiple bioactive compounds that may have synergistic or antagonistic effects and interact with prescription medications, potentially affecting drug metabolism or efficacy19. Additionally, standardization and quality control represent significant challenges in the evaluation and clinical implementation of traditional herbal medicines, as the concentration of active compounds can vary based on cultivation practices, harvesting methods, and processing techniques19. Despite these limitations, there is growing scientific interest in isolating and characterizing specific bioactive compounds from traditional medicines like Huangqi, which may eventually lead to the development of novel therapeutic agents or adjunctive treatments based on these natural products19. Patients considering complementary approaches should discuss these options with their healthcare providers to ensure safe integration with their conventional treatment plan and avoid potentially harmful interactions19.

Conclusion and Future Directions

The management of prostate cancer has evolved dramatically over recent decades, transitioning from a relatively limited therapeutic landscape to an era of precision medicine with multiple treatment modalities targeting specific disease mechanisms. Androgen deprivation therapy remains the foundation of systemic treatment for advanced disease, now frequently enhanced with newer agents such as abiraterone acetate or second-generation AR antagonists, which have demonstrated significant survival benefits across disease states from hormone-sensitive to castration-resistant settings417. The recognition of DNA repair deficiencies in a substantial proportion of advanced prostate cancers has led to the successful development of PARP inhibitors for biomarker-selected patients, representing a paradigm shift toward molecularly guided therapy59. Despite these advances, significant challenges persist, particularly in managing castration-resistant disease, where resistance mechanisms inevitably emerge and sequentially applied therapies offer diminishing returns with each treatment line420. The complexity of prostate cancer biology, characterized by remarkable heterogeneity and adaptability, necessitates continued research into fundamental disease mechanisms and novel therapeutic targets to improve outcomes for patients with advanced disease117.

Future directions in prostate cancer research and treatment will likely focus on several key areas, including the refinement of biomarker-guided approaches to optimize treatment selection and sequencing, the development of rational combination therapies targeting complementary pathways to overcome resistance mechanisms, and the exploration of novel targets beyond traditional androgen signaling517. Emerging therapeutic modalities such as proteolysis-targeting chimeras (PROTACs), bispecific antibodies, antibody-drug conjugates, and engineered cell therapies may provide new avenues for targeting previously "undruggable" pathways or enhancing immune responses against prostate cancer217. Additionally, the integration of advanced molecular profiling technologies, including comprehensive genomic sequencing, transcriptomics, proteomics, and metabolomics, will likely enhance our understanding of disease biology and treatment response/resistance patterns, potentially enabling more personalized therapeutic approaches517. While significant progress has been made in prostate cancer treatment, the ultimate goal of developing curative therapies for advanced disease remains elusive, underscoring the need for continued innovation, collaboration, and patient-centered research efforts41720. As our understanding of prostate cancer biology continues to evolve, so too will our therapeutic approaches, offering hope for improved outcomes and quality of life for the millions of men affected by this disease worldwide217.