Evolving Treatments and Resistance Mechanisms in Prostate Cancer Therapeutics.

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Learn more: PMC Disclaimer | PMC Copyright Notice ACS Pharmacol Transl Sci . 2026 Mar 4;9(4):815–838. doi: 10.1021/acsptsci.5c00757 Search in PMC Search in PubMed View in NLM Catalog Add to search Evolving Treatments and Resistance Mechanisms in Prostate Cancer Therapeutics Gali Sri Venkata Sai Rishma Reddy Gali Sri Venkata Sai Rishma Reddy † Department of Biological Sciences, SRM University-AP, Amaravati 522240, India Find articles by Gali Sri Venkata Sai Rishma Reddy † , Anuj Kumar Anuj Kumar ‡ Department of Physics, SRM University-AP, Amaravati 522240, India Find articles by Anuj Kumar ‡ , Neeraj Kumar Sharma Neeraj Kumar Sharma § Department of Computer Science Engineering, SRM University-AP, Amaravati 522240, India Find articles by Neeraj Kumar Sharma § , Krishna Samanta Krishna Samanta ∥ Department of Biotechnology, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Guntur 522302, India Find articles by Krishna Samanta ∥ , Debabrata Pramanik Debabrata Pramanik ‡ Department of Physics, SRM University-AP, Amaravati 522240, India + Centre for Computational and Integrative Sciences, SRM University AP, Amaravati 522 240, India Find articles by Debabrata Pramanik ‡, + , Naga Bhushana Rao Karampudi Naga Bhushana Rao Karampudi † Department of Biological Sciences, SRM University-AP, Amaravati 522240, India Find articles by Naga Bhushana Rao Karampudi † , Pulak Kar Pulak Kar † Department of Biological Sciences, SRM University-AP, Amaravati 522240, India Find articles by Pulak Kar †, * Author information Article notes Copyright and License information † Department of Biological Sciences, SRM University-AP, Amaravati 522240, India ‡ Department of Physics, SRM University-AP, Amaravati 522240, India § Department of Computer Science Engineering, SRM University-AP, Amaravati 522240, India ∥ Department of Biotechnology, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Guntur 522302, India + Centre for Computational and Integrative Sciences, SRM University AP, Amaravati 522 240, India * Email: [email protected] . Received 2025 Nov 19; Accepted 2026 Feb 24; Revised 2026 Feb 2; Collection date 2026 Apr 10. © 2026 American Chemical Society PMC Copyright notice PMCID: PMC13077499  PMID: 41988377 Abstract Prostate cancer remains a leading cause of cancer-related morbidity and mortality among men, fundamentally driven by gain-of-function alterations in the androgen receptor (AR) signaling axis. Although major therapeutic advances from androgen deprivation therapy to next-generation antiandrogens have significantly improved clinical outcomes, disease progression and the emergence of therapeutic resistance continue to pose substantial clinical challenges. This review provides a comprehensive overview of historical and contemporary treatment strategies in prostate cancer with particular emphasis on the molecular mechanisms underlying therapeutic resistance and disease evolution. To support the narrative presented in this review, we incorporate selected in silico analyses, such as molecular docking studies of antiandrogen AR interactions, which are intended to complement published structural and functional studies and provide a mechanistic context to the reviewed literature. In addition, we highlight emerging and evolving therapeutic modalities, including adoptive cell therapy, nanomedicine-based drug delivery, poly­(ADP ribose) polymerase (PARP) inhibition, proteolysis-targeting chimera (PROTAC) technologies, and RNA-based approaches, with emphasis on their translational potential and current limitations. By integrating the existing literature with targeted in silico insights, this perspective presents a forward-looking perspective on overcoming resistance and advancing precision therapeutics in prostate cancer. Keywords: prostate cancer, androgen receptor, androgen deprivation therapy, antiandrogen resistance, molecular docking, therapeutics Prostate cancer (PCa) is among the leading causes of cancer-related mortality in men worldwide. Its incidence varies markedly across geographical regions, ranging from approximately 6.3 to 83.4 cases per 100,000 individuals. According to the American Joint Committee on Cancer (AJCC), PCa is clinically classified into three stages: localized, locally advanced, and metastatic disease. , Localized PCa often presents in an indolent state without metastasis, while locally advanced cases may involve the seminal vesicles, bladder, or rectum. Metastasis typically spreads via lymphatic pathways to pelvic and para-aortic lymph nodes and subsequently to the bones, , with visceral dissemination to the lungs, liver, and other organs being associated with more aggressive disease phenotypes. Genetic predisposition plays a major role in PCa susceptibility, with first-degree relatives of affected individuals carrying more than 50% increased risk of early onset disease. Approximately 5.5% of patients harbor detectable germline mutations in DNA repair genes such as ataxia telangiectasia mutated ( ATM ) and breast cancer susceptibility (BRCA) 1 and 2. Notably, the relative risk of prostate cancer is increased by approximately 3.75-fold in individuals harboring BRCA1/2 mutations, with BRCA2 variants being predominant. Prostate cancers arising in BRCA2 mutation carriers are frequently associated with elevated serum prostate-specific antigen (PSA) levels at diagnosis, a higher proportion of high Gleason score tumors, increased nodal and distant metastatic burden, and higher rates of disease recurrence, underscoring their aggressive clinical behavior. In conjunction, disease evaluation encompasses digital rectal examination, needle biopsy, multi-parametric magnetic resonance imaging (MRI), and serum PSA testing. , In contrast to conventional tissue biopsies, liquid biopsy approaches are increasingly preferred due to their minimally invasive nature and their ability to capture systemic tumor heterogeneity. Among these, urinary liquid biopsy has emerged as a promising and effective method for prostate cancer detection. Beyond urine-specific biomarkers, circulating serum biomarkers, including androgen receptor (AR) variants, markers of neuroendocrine differentiation, and indicators of bone metabolism, are increasingly driving precision medicine-based strategies. Notably, exosome-derived biomarkers isolated from blood, urine, and other bodily fluids provide valuable insights into tumor molecular composition. Recent studies have demonstrated that exosomal miRNAs, characterized by distinct and quantifiable exosomal cargo, serve as potential biomarkers for disease diagnosis, prognosis, and treatment response prediction in prostate cancer. Together, these approaches complement established prognostic factors such as the tumor–node–metastasis (TNM) stage, baseline PSA levels, and Gleason score in guiding clinical decision-making. Over decades, substantial research has sought to reduce PCa mortality and standardize therapeutic options. − There is growing interest in integrating radiomics into multiomics frameworks to combine biomolecular-level information with quantitative imaging features for improved disease characterization and outcome prediction. Radiomic analyses have been applied across multiple imaging modalities, including multiparametric MRI, transrectal ultrasound, conventional and cone-beam CT, and molecular imaging techniques. Notably, positron emission tomography using prostate-specific membrane antigen (PSMA)-targeted radiotracers has significantly enhanced tumor detection, staging accuracy, and assessment of indeterminate lesions in prostate cancer. For example, a prospective study by Alongi et al. utilized 18 F-choline PET imaging to predict disease outcomes in prostate cancer patients. Furthermore, the integration of radiomics with artificial intelligence and molecular profiling has demonstrated improved detection of both primary tumors and metastatic lesions, supporting precision medicine-driven clinical decision-making in prostate cancer. Current stage-specific management strategies continue to include prostatectomy, active surveillance, and radiotherapy for stages I–III disease, while androgen deprivation and antiandrogen therapies remain central for stage IV metastatic disease. Active surveillance benefits patients with low life expectancy by delaying or avoiding unnecessary interventions while preserving quality of life, including erectile function. Radical prostatectomy remains an option for locally recurrent, nonmetastatic disease following radiation therapy, cryotherapy, or brachytherapy. External beam radiation therapy (EBRT), often combined with androgen deprivation therapy (ADT), reduces metastatic progression by targeting and destroying tumor cells within the prostate. The development of antiandrogens, agents that directly antagonize the AR, marked a major therapeutic milestone, significantly improving survival in advanced PCa and complementing chemotherapy regimens. , First- and second-generation antiandrogens are widely employed; however, resistance inevitably emerges, necessitating the exploration of novel combinatorial and sequential strategies. In recent years, alternative biotechnological approachessuch as RNA-based therapeutics, PARP inhibitors, and PROTACshave shown promise in overcoming resistance. , RNA technologies, including small interfering RNAs (siRNAs) targeting immune checkpoint regulators cytotoxic T-lymphocyte antigen (CTLA-4), programmed death ligand (PD-L1), antisense oligonucleotides, and microRNAs (miRNA), have demonstrated the ability to suppress oncogenic signaling in metastatic castration-resistant prostate cancer (CRPC) (mCRPC) models. In this review, we provide an integrated overview of historical and contemporary treatment modalities for PCa, alongside the molecular mechanisms underpinning therapeutic resistance. We also discuss cutting-edge innovationsincluding PARP inhibitors, nanomedicine, and PROTACsthat hold potential for reshaping the therapeutic scenery. To enhance the translational value of this synthesis, we incorporate illustrative computational perspectives, including molecular docking analyses assessing the binding interactions between antiandrogens and conventional AR. These computational insights are not intended as primary research findings but rather as contextual tools, enriching the literature by combining forward-looking perspectives for personalized treatment planning. By combining critical literature assessment with targeted in silico approaches, this review aims to inform the development of more precise and durable therapeutic strategies for prostate cancer. Androgen Receptor Signaling in Prostate Cancer The cascade of events beginning from pituitary secretion of the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) into the endoplasmic reticulum of Leydig cells acts as the primary point for synthesis of androgens like testosterone (T) and dihydrotestosterone (DHT) ( Figure ). T is reduced to DHT in the cytoplasm of cells, marking the availability for receptor interaction and activation. The conventional signaling pattern involves AR, a transcription factor, triggering the expression of target genes like PSA, transmembrane protease serine 2 (TMPRSS2), upon DHT binding, causing conformational changes in receptor-dissociating heat-shock protein (HSPs), promoting dimerization and translocation into the nucleus ( Figure ). Alternate mechanisms include activation of intracellular signaling pathways via membrane-bound receptors at low androgen concentrations, reducing the scope of initial androgen-dependent targeted treatments. Hence, on a therapeutic note, several agonists and antagonists directly or indirectly inhibit the production of androgen in cells as well as target ligand binding to the receptor, alleviating disease incidence and metastasis in prostate cancer patients, which will be explained further in later sections ( Table ). 1. Open in a new tab Targeting AR signaling pathways in prostate cancer. The schematic illustrates therapeutic strategies aimed at disrupting AR-driven transcriptional activity in prostate cancer. The pituitary gland releases luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which stimulate Leydig cells in the testes to produce testosterone. Testosterone is subsequently converted into the more potent dihydrotestosterone (DHT), which binds to cytoplasmic AR, causing its dissociation from heat-shock proteins (Hsp) and translocation into the nucleus. Nuclear AR–DHT complexes activate transcription of target genes such as PSA, driving tumor cell proliferation and survival. Pharmacological intervention occurs at multiple levels: GnRH agonists or luteinizing hormone-releasing hormone (LHRH) antagonists suppress androgen production by feedback inhibition of pituitary signaling, whereas androgen receptor signaling inhibitors (ARSIs) such as flutamide, enzalutamide, and darolutamide competitively inhibit AR binding to DHT, thereby preventing AR-mediated transcription, halting tumor growth, and promoting cancer cell death. 1. Chemical Structures of Compounds Targeting Prostate Cancer. Open in a new tab Structure–Function Relationship with AR and Antiandrogens To begin with, several antiandrogens, including flutamide, nilutamide, enzalutamide, bicalutamide, apalutamide, and darolutamide, have been widely used in prostate cancer treatment. These antiandrogens act by competitively inhibiting androgen binding, AR nuclear translocation, and androgen-mediated transcription. However, approximately one-third of patients develop disease progression despite standard ADT, resulting in CRPC. Resistance mechanisms, including gene mutations, demonstrate the need for alternative therapeutic strategies. Advancements in the study of physicochemical properties of drugs and in silico analyses have enhanced our understanding of drug–receptor interactions and facilitated novel drug design. Despite the availability of several AR cocrystal structures in the Protein Data Bank, experimentally resolved complexes corresponding to wild-type AR and clinically approved antiandrogens are not uniformly available. Most reported structures involve mutant AR variants, truncated ligand-binding domains, and ligand-specific combinations that are not directly comparable across different antiandrogens. Hence, for a systematic and uniform analysis of structure–function relationships, molecular docking was employed as a supportive tool to complement the literature. Docking studies were performed using the Autodock Vina software to analyze androgen receptor protein–ligand interactions and explore the binding sites and binding energies associated with six antiandrogens: flutamide (C 11 H 11 F 3 N 2 O 3 ), nilutamide (C 12 H 10 F 3 N 3 O 4 ), bicalutamide (C 18 H 14 F 4 N 2 O 4 S), enzalutamide (C 21 H 16 F 4 N 4 O 2 S), apalutamide (C 21 H 15 F 4 N 5 O 2 S), and darolutamide (C 19 H 19 C l N 6 O 2 ) ( Figure ). The 3-dimensional structures of these molecules were obtained from the PubChem database. Using a grid box centered at ( x = 17.084, y = 5.33, z = 11.207) with dimensions of 47.25 units, an exhaustiveness of 24, and an energy range of 3, we conducted 100 independent blind and rigid docking simulations. The details of the binding sites and average binding scores are presented in Table . For flutamide, nilutamide, and apalutamide, single specific binding sites were identified, whereas multiple binding sites were observed for bicalutamide, enzalutamide, and darolutamide. The percentage of binding for each ligand was calculated across the 100 docking runs. The average docking scores for the most probable binding sites are summarized in Table . Based on the docking scores, we can speculate that enzalutamide might be the most suitable ligand to form a complex with the AR protein. These provide valid insights for future drug remodeling studies on enzalutamide to further combat resistance to some extent. However, we must mention here that docking scores of all six ligands are close, and in simulation, water and ions are not present in the system. Hence, for accurate prediction, a more advanced-level simulation is necessary. 2. Open in a new tab Antiandrogen docking with the AR ligand-binding domain. Several small-molecule antiandrogen drugs interact with the ligand binding domain (LBD) of the AR (PDB Id: 2AM9 ). The following interactions are illustrated: (a) AR–flutamide, (b) ARnilutamide, (c) ARapalutamide, (d) ARbicalutamide, (e) ARdarolutamide, and (f) ARenzalutamide. The receptor is shown in a cartoon representation, and ligands are shown as sticks. All the protein ligand interactions were visualized using color-coded dashed lines. Green dashed lines indicate conventional hydrogen bonds, and carbon–hydrogen bonds along with pi–pi interactions are denoted by cyan and purple dashed lines for easier differentiation. A total of 100 independent docking samples were analyzed, and the interactions depicted correspond to the best binding site and pose based on percentage of binding and docking scores. Conventional Hydrogen Bond (Green); Carbon Hydrogen Bond (Light Green); Halogen (Cyan); Pi-Anion and Pi-Cation (Orange); Pi-Pi T-shaped (Pink); Alkyl and Pi-Alkyl (Light Pink); Pi-Sigma (Violet); Van der Waals (Medium Green). 2. Ligand Binding Probability at AR Sites and Average Docking Scores (±Error) from 100 Simulations per System. Open in a new tab Therapeutic Strategies in Prostate Cancer Standard medical treatments have emerged over time, potentiating tumor regression in early as well as metastatic cases of prostate cancer patients. Postsurgical management strategies, including radiotherapy, ADT, androgen receptor signaling inhibitors (ARSI), and chemotherapy, often in combination, remain dominant and effective in recurrent disease. However, in the context of hormone-sensitive oligo metastatic prostate cancer, prospective randomized clinical trials evaluating the optimal use and timing of ADT in combination with stereotactic ablative radiotherapy (SABR) are currently lacking. Given that AR signaling activates DNA damage response and repair pathways, combining ADT with SABR may enhance radiosensitivity and improve localized control of oligo metastatic lesions, a hypothesis that warrants further clinical validation. However, in most of the cases, resistance has always been a major hurdle for complete prevention of disease progression, raising the need for systemic as well as specific treatment options. In recent years, several therapeutic advancements like adoptive cell therapies, nanotechnology, PARP inhibitors, and PROTACs have been profoundly impactful in alleviating prostate tumors. , Also, RNA technology robustly transformed the way of predicting biomarkers, which is equally important for early detection and prevention. Androgen Ablation and Antiandrogen Therapy in PCa Androgen Deprivation Therapy Over the years, extensive research has investigated various treatment options for prostate cancer, tracing the evolution and advancement of therapeutic strategies from the 1940s to the present day ( Figure ). Androgens primarily produced in men are testosterone and dihydrotestosterone, through the Leydig cells of the testis and peripheral tissues ( Figure ). Research on “Androgen hypothesis” has dictated the role of androgens in PCa development, which further led to the study of circulating testosterone levels and the importance of the tumor microenvironment, and their role in disease progression. Hudgins and Hodges first reported the effect of surgical castration or suppression of LHRH production at the hypothalamic level, thereby suppressing serum testosterone levels in men. ADT has been universal front-line hormonal treatment for high risk localized, metastatic, or advanced prostate cancer patients. , Recent evidence supports the combination of abiraterone acetate with prednisolone alongside ADT as a new standard of care for patients with high-risk nonmetastatic prostate cancer. In contrast, clinical trials have demonstrated no additional survival benefit from combining abiraterone with second-generation AR inhibitors such as enzalutamide in patients initiating long-term ADT for metastatic disease; therefore, concurrent use of these agents is not recommended. , Importantly, survival benefits associated with the addition of abiraterone to ADT have been shown to persist for more than seven years, underscoring its durable clinical efficacy. Consequently, frontline ADT continues to be delivered through surgical orchiectomy or pharmacological castration using gonadotropin-releasing hormone (GnRH) agonists or antagonists, often in combination with appropriately selected androgen signaling inhibitors. Gonadotropin-releasing hormone analogues and AR blocking agents are the proposed treatment options in case of localized and metastatic PCa. GnRH analogues downregulate the type-I GnRH receptor, continuously stimulating the pituitary, reducing LH secretion, and affecting the Leydig cell production of testosterone. This only reduces the serum testosterone, having null effects on intratumoral testosterone, which raised the need for antiandrogens to deplete the cell growth. A study conducted by Kuhn and group elucidated that GnRH analogues, at times, lead to the “Flare up” phenomenon that rises LH (LH surge), for which administering the androgen antagonists (at least 2–4 weeks) prior to treatment with GnRH analogues has been suggested. This method prevented the testosterone surge on peripheral androgen receptors. 3. Open in a new tab Chronological timeline of prostate cancer treatment strategies. The schematic illustrates the progressive evolution of therapeutic approaches in prostate cancer (PCa) over the past eight decades. Beginning with the landmark discovery of androgen ablation by Huggins and Hodges in the 1940s, subsequent decades witnessed structural characterization of the AR (1960s), development of flutamide as a testosterone competitor (1970s), and medical castration strategies with GnRH agonists and antiandrogens (1980s–1990s). The 2000s marked the introduction of advanced AR antagonists, such as enzalutamide and combined androgen blockade, followed by the emergence of apalutamide and darolutamide in the 2010s. Recent years (2019–2023) highlight innovative therapeutic platforms including PARP inhibitors and PROTAC-based AR degraders, while ongoing research focuses on addressing AR mutation-driven resistance and stem cell-directed therapies. Looking ahead, novel strategies such as nanomedicine, artificial intelligence-assisted drug development, and rational combination therapies are anticipated to shape the future of PCa management. GnRH Agonists GnRH is released in a rhythmic manner by the hypothalamus, which stimulates secretion of the LH and FSH , ( Figure ). Upon chronic exposure of GnRH agonists to the patients, desensitization of GnRH receptors happens, inhibiting pituitary gland secretions, resulting in reduced LH and FSH secretions, and achieving the castration level of testosterone. , Goserelin was the first approved GnRH agonist in 1986, while leuprorelin (1988), histrelin (2007), and triptorelin (2009) were produced in later years. Studies on goserelin indicate that over 90% of the patients had T levels castrated to <50 ng/dL in 4–6 week time. Comparative analysis by the Shim group elucidated that the castration efficiency of goserelin, triptorelin, and leuprorelin has been equally similar, except that goserelin maintains a more rigorous castration level for a longer time, <30 ng/dL in 100% patients. In another study by Wilke and group, goserelin was more effective than leuprorelin and triptorelin, attaining 50 ng/dL, while buserelin achieving it in the same level, but only in 76% of patients over a period of 4.6 years. , The T-escape phenomenon is highly observed in patients treated with GnRH agonists, where the testosterone level is raised above the castrate level for a temporary period, giving more side effects, although later suppressed by the same. It has been reported that T-escape incidences are lower with goserelin than other GnRH agonists, making it more effective and supporting the above statement. LHRH Antagonists To overcome the physiological effects of agonists, antagonists of GnRH receptors have been introduced that direct immediate blockade of GnRH/LHRH receptors, reducing testosterone load ( Figure ). Abarelix, degarelix, and relugolix are the antagonists used in the treatment of PCa, so far. , Abarelix, being the first antagonist approved by the United States Food and Drug Administration (US FDA), showed testosterone castration levels by 84 days in a phase III trial compared with goserelin and bicalutamide combination. Despite this, it was discontinued due to adverse hypersensitivity reactions and negative impact on T levels on prolonged usage. Degarelix is a highly potent antagonist (injectable), approved by the US FDA in 2008, for managing advanced prostate cancer. Despite its high affinity, injection site reactions have been a major drawback in degarelix usage. To compensate, Relugolix (TAK-385), an oral antagonist, was approved in 2020. It is highly selective in nature, reducing the T levels continuously and reversibly and rapidly preventing tumor flare. The HERO phase-III study compared leuproline to relugolix and observed that the required castration level of T from day 29 is achieved and consistently shown to be superior to leuproline in each subset of patients. It has been reported that cardiovascular effects like hypertension, hyperlipidemia, and adverse hypersensitivity reactions are more frequent with the usage of GnRH agonists compared to LHRH antagonists, for which these are suggested as a good choice for treatment in some PCa patients. Antiandrogen Therapy Although antiandrogen therapy is effective, AR mutants make them resistant, thereby creating a need for further development of new drugs, which are in high demand. Androgen metabolism is the basis for prostate cancer drug development. , “ n ” number of signaling mechanisms include classical, bypass, or alternative and background pathways, which can be targeted for controlling the disease. − One of the notable targets can be the cytochrome P450 family 17 subfamily A member 1 (CYP17A1) gene, which is essential for synthesizing the 17 alpha hydroxylase enzyme that converts 17 hydroxy pregnenolone to dehydroepiandrosterone (DHEA). Conversion of 17-hydroxy pregnenolone to androstenedione [a weak androgen] by S5AR1 instead of DHEA to testosterone directly [but later converted to DHT] is commonly seen in CRPC patients. In this case, antiandrogens target the CYP17A1 gene, controlling the progression of the disease. DHEA synthesis from cholesterol is of great importance in patients having elevated androgen levels and constitutive AR. Abiraterone, flutamide, enzalutamide, apalutamide, and darolutamide target the androgen signaling axis and are so-called androgen receptor signaling inhibitors (ARSI) ( Figure ). Decades of research have aimed at identifying efficient drugs for treating PCa patients ( Figure ). Antiandrogens are those therapeutically used drugs that competitively inhibit the binding of ligand to the AR. This induces apoptosis or programmed cell death, ultimately improving the survival rate in malignant and benign cases. Depending on their effects on testosterone levels in the serum and activity on the receptor, they are classified into steroidal antiandrogens and nonsteroidal antiandrogens. , The androgen signaling axis hypothesis led to identification of steroidal antiandrogens that are weak partial agonists as well as competitive inhibitors of AR in target tissues. They include cyproterone acetate and megestrol acetate, which cause negative feedback in the pituitary level, reducing LH secretion and further reducing testosterone levels. Nonsteroidal antiandrogens, on the other hand, are competitive inhibitors that are clinically not agonistic to AR and block the testosterone binding to the receptor, interrupting the negative feedback of testosterone, reducing adverse side effects in patients, hence considered to be mostly used and efficient ( Figure ). They include flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, and darolutamide , ( Table ). Flutamide and Nilutamide Flutamide (a biologically active form of hydroxyflutamide) is used for the first time in the treatment of PCa patients. A low half-life of about 5–6 h, associated with side effects like diarrhea, led to its discontinuation in most of the patients. Antiandrogen withdrawal syndrome was first reported in flutamide-treated patients, which reduces PSA levels, resulting in tumor regression, but the presence of mutations challenged this effect. Resistant mechanisms studies have reported that dormancy is an adaptation mechanism of tumor cells, which allows them to survive in aggressive conditions. , Rodriguez and group gave a detailed emphasis that resistance to drugs, specifically 2-hydroxy flutamide, is due to phenotypic changes in cancer cells upon prolonged treatments that allow drugs to protect them under stressed conditions instead of inducing death. A significant decrease in mechanistic target of rapamycin (mTOR) and protein kinase B (Akt) pathways, choline metabolites, and cell cycle inhibition on a mild scale is observed, allowing cells to be nonproliferative but dormant enough to survive. At the molecular level, heat-shock protein 90 (HSP90) functions as a critical molecular chaperone that stabilizes and properly folds multiple oncogenic client proteins, including AKT, ERK1/2, receptor tyrosine-protein kinase erbB-2, proto-oncogene tyrosine p60-Src, cyclin-dependent kinases (CDKs), and surviving, thereby preventing their degradation via the ubiquitin–proteasome system. Preclinical studies have demonstrated that HSP90 inhibition elicits favorable responses in CRPC. Particularly, disruption of HSP90-mediated protein stabilization sensitizes tumor cells to DNA damage, and in vivo synergism has been reported with the combined use of the HSP90 inhibitor AT13387 and the PARP inhibitor Olaparib, highlighting a promising combination strategy to overcome therapeutic resistance. On the other hand, upregulation of stem cell genes like Oct 4, Sox 2, nanog, aldehyde dehydrogenase 1 (ALDH1), and bone morphogenetic protein (BMP2) has also been observed, supporting the above concepts. Nilutamide is known for its lesser side effects than flutamide but observed with adverse effects like gastrointestinal toxicity and allergic pneumonitis in more than 70% of patients. , Despite adverse effects, nilutamide monotherapy established better activity in hormone-sensitive metastatic PCa. Wassim and group investigated the rate of PSA response in patients with previous androgen ablation failure, reporting that nilutamide has a favorable response rate with 64% reduction in PSA. In general, studies supported the administration of other antiandrogens apart from nilutamide upon a significant increase in newer antiandrogens, without adverse effects, for which its usage frequency has been diminished. Bicalutamide Bicalutamide is a pure antagonist that inhibits the AR selectively, having a half-life of 5–6 days, longer than flutamide and nilutamide. Early receptor binding studies on rat prostate AR revealed the higher affinity of bicalutamide, four times greater than flutamide. In vitro studies on lymph node carcinoma of prostate (LNCaP) cell lines elucidated the effectiveness of antagonism by bicalutamide in mutant prostate cells, too. Adverse effects have been observed including hot flashes, decreased libido and impotence, gynecomastia in 3/4th of the patients. Combined analysis of patients under radiation therapy along with bicalutamide exhibited better activity in early nonmetastatic PCa. In spite of advantages, mutational studies reported that the W742L mutation causes resistance to bicalutamide, due to changes in its rotamer confirmations. Loss of Try-742 causes loss of bulk in the mutated region, where the sulfonyl-linked phenyl region is placed in agonist confirmation unlikely to its natural state, thereby causing resistance. Enzalutamide Enzalutamide, a second-generation AR antagonist, inhibits the proliferation of CRPC cells by inhibiting the translocation of AR to the nucleus. It is shown to exhibit a 5-fold affinity greater than bicalutamide. Adverse effects reported to be hot flashes, fatigue, and back pain more commonly than with bicalutamide. In the STRIVE trial, analysis of 139 men having high-risk non-metastatic PCa and 257 with metastatic PCa resulted in progression-free survival prolonged by enzalutamide than bicalutamide, reducing the risk of death by 76% in patients. A phase III trial, PROSPER, exhibited the efficiency of enzalutamide in improving the survival rate by more than 70 percent. Another trial, PREVAIL, demonstrated a moderate improvement in the survival rate in chemotherapy naïve metastatic patients. About 20–40% of patients develop resistance after administration of enzalutamide in advanced prostate cancer patients. The overall affinity of the drug is affected by changes in the structure of the receptor that involve splice variants and mutations. Studies showed that overactivation of the glucocorticoid receptor (GR) (like AR) can also lead to enzalutamide resistance as part of activation of alternative signaling pathways. Enzalutamide is conferred with agonistic properties due to the F877L mutation and GR induction. H875Y, T878A, and L702H mutations are observed with post- and pre-enzalutamide treatment in 9% of patients, causing resistance. In addition, ARV −7 is also said to confer resistance to enzalutamide due to a lack of LBD, resulting in aggressive disease. Apalutamide Apalutamide is proven to be effective, inhibiting the nuclear translocation of AR, avoiding its interaction with androgen response elements in nonmetastatic prostate cancer patients. It is better than enzalutamide, as it has fewer side effects exhibited along with overall improvement in the survival rate, where 89% patients had more than 50% decrease in PSA levels. The SPARTAN trial proved the efficacy of apalutamide, where the survival rate is moderate. Apalutamide investigated in the TITAN trial, containing around 1052 patients, illustrated radiographic progression-free survival in metastatic PCa cases. About 20–40% of patients develop resistance after administration of abiraterone acetate in advanced prostate cancer patients. An increase in androgen synthesis and mutations in the receptor are the main causes of resistance to apalutamide. Apalutamide has been observed to show agonistic properties due to the F877L mutation and GR induction, like enzalutamide, while a bypass mechanism is also said to cause resistance in CRPC patients. AR variants, ARV-7, have been known to cause resistance due to the lack of LBD in their structures, presenting no space for antiandrogens to act upon, especially in apalutamide. , Patients with metastatic CRPC (mCRPC) treated with abiraterone or enzalutamide who harbor AR-V7-positive circulating tumor cells exhibit significantly shorter progression-free survival compared with AR-V7-negative cases, supporting its role in therapeutic resistance. Accordingly, AR-V7 has emerged as a potential predictive biomarker for identifying patients who are less likely to benefit from next-generation AR-targeted therapies. Darolutamide Darolutamide, a novel nonsteroidal antiandrogen, has a unique chemical structure with an extra tail part that helps in improving its efficacy in treating nonmetastatic prostate cancer patients (2017) and metastatic PCa patients. It binds the receptor with comparatively higher affinity and antagonizes receptor function, thereby inhibiting the growth of cancer cells. Strong recommendation of its usage is due to the reduction in the transcriptional activity in mutated variants like F877L and its property of not crossing the blood–brain barrier, reducing the CNS effects like epilepsy, falls, and cognitive impairment. The ARAMIS trial involving 1509 men reported a 31% death reduction and a survival rate of 83% in patients upon darolutamide administration. ARADES and ARAFOR trials reported a >50% to 90% PSA level reduction rate, demonstrating its importance in treating nonmetastatic and metastatic PCa patients. Darolutamide has been elucidated as a potent antagonist having marked activity against F877L, M896T, and M896 V mutants, which confer resistance to enzalutamide and apalutamide. Studies of noncoding RNAs have deciphered the role of LOC730101 (a noncoding RNA) in resistance to darolutamide by modulating changes in the cell cycle gene expression. Hence, detailed characterization of darolutamide resistance, considering every possibility with a more critical study, is necessary for the development of novel darolutamide derivatives. Abiraterone This is a selective inhibitor that blocks the CYP17A1, inhibiting the synthesis of androgens, where CYP17A1 encodes the 17-alpha hydroxylase, which converts hydroxy pregnenolone into DHEA. Any enhanced expression or mutation in CYP17A1 increases DHEA levels, causing a tumor. Phase III trial COU-AA-301 continued to establish the efficacy of abiraterone, where the median overall survival rate is shown to be 14.8 months compared to placebo. On the other hand, LATITUDE and STAMPEDE demonstrated the overall success rate in the usage of abiraterone in metastatic castration-resistant PCa patients. Resistance to abiraterone has been displayed in one-third of patients, where several genes with respect to alternate signaling are activated, producing more DHT, escaping the effects of inhibition. Previous treatment of enzalutamide and abiraterone developed resistance to docetaxel treatment in patients. Research demonstrated the importance of cross-resistance in cancer therapeutics. Notably, resistance between enzalutamide [due to lack of LBD in the receptor] and abiraterone [as it does not require androgen to bind] is caused by the AR variant (AR-V) 7, as both cannot target the variant for the above-mentioned reasons, upon which they primarily act. Aldo-keto reductase family 1 member C3 (AKR1C3) and the ARV7 axis maintain the AR stabilization and its synthesis rate, and constitutive activation of AR leads to emergence of this resistance in patients. , Chemotherapy in Prostate Cancer Comprehensive and effective research on the evolution of disease by inherent genetic mechanisms indicates chemotherapy is the most widely used method, which implements the use of anticancer drugs that inhibit or kill the cancer cells ( Figure ). Mitoxantrone, docetaxel, and cabazitaxel are primarily used chemotherapeutic drugs in PCa treatment. Mitoxantrone is the first FDA-approved drug, a synthetic anthracenedione that intercalates DNA, inhibiting topoisomerase II for suppressing prostate cancer growth in metastatic patients. In a phase III trial, patients who had been exposed to mitoxantrone along with hydrocortisone were observed with less pain, thus having an improved quality of life. In addition, it has been a good choice with mCRPC patients who had prior docetaxel treatment, but there is less benefit with other drugs, making its use even less likely with the increase of more relevant chemo drugs. In the case of castration-resistant cells, docetaxel is the standard therapy. It implements apoptosis by adhering to beta-tubulin that inhibits microtubule depolymerization, suppressing cell division. However, docetaxel resistance has been observed with relapse. P-glycoproteins belong to ABC transporters (ATP binding cassette), which use energy produced by ATP hydrolysis to transport substances across membranes and out of cells. Reportedly, under taxane treatment, docetaxel exhibited resistance 7–8 months postmedian PSA response, where it is triggered with increased drug efflux from tumor cells, by overexpression of these ABC transporters, supporting the cause of resistance with relapse. , Altered epithelial–mesenchymal transition markers are proven to confer resistance to cabazitaxel in advanced tumors. Cabazitaxel is an antineoplastic semisynthetic drug and is aimed at reducing docetaxel resistance. It is an alternative first-line therapy for those candidates who do not respond effectively to docetaxel but not superior to docetaxel, though. This is supported by the phase III FIRSTANA trial which estimated the survival rate to be higher in docetaxel, and the neuronal adverse effects rose in cabazitaxel. Despite drawbacks, docetaxel is still the standard first-line therapy in PCa patients due to characteristics like an improved survival rate and fewer adverse effects except for neuronal toxicity in some cases. 4. Open in a new tab Systemic therapeutic strategies in prostate cancer. The diagram illustrates the major systemic treatment mechanisms in PCa, including chemotherapy, stem-cell-based therapy, PARP inhibition, and PROTACs. Chemotherapy agents such as docetaxel and cabazitaxel act by inhibiting microtubule depolymerization, thereby blocking spindle formation during cell division, while mitoxantrone inhibits DNA replication and induces DNA damage, culminating in apoptosis. Adoptive cell-mediated immunotherapy employs chimeric antigen receptor (CAR)-engineered T cells, which recognize tumor-associated antigens (TAA) on prostate cancer stem cells. Upon antigen binding, CAR-T cells release cytotoxic cytokines, granzymes, and perforins, leading to targeted tumor cell death. PARP inhibitors (e.g., Olaparib, rucaparib) exert their antitumor effect through PARP entrapment on damaged DNA, preventing recruitment of DNA repair factors such as XRCC1, ultimately impairing repair and promoting apoptosis. Finally, PROTAC (proteolysis-targeting chimera) therapy selectively degrades the AR by recruiting E3 ligases to the AR-ligand complex, inducing ubiquitination and subsequent proteasomal degradation and thus suppressing AR-dependent transcription and tumor progression. Combination Therapies in Prostate Cancer A substantial body of clinical trial evidence supports the efficacy of combination therapies in overcoming several of the existing limitations and adverse effects associated with prostate cancer treatment. Over the past 15 years, numerous clinical trials have been conducted, and the major studies have been summarized here using information sourced primarily from ClinicalTrials.gov and CanSAR.ai. A minimal level of analysis has also been incorporated to support clarity and improve readability for the audience ( Tables and ). To enhance the visibility and interpretability of the collected data sets, the information was processed using Python with the pandas library, and histogram-based visual representations were generated through matplotlib. These are presented in Figures and . 3. Combination Therapies for Prostate Cancer Patients. clinical trial ID drug and combinations year of study no. of Patients outcomes NCT04523207 Apalutamide+ ADT +Relugolix 2020–2024 108 Confirmed biochemical recurrence-free rate along with maintenance of testosterone levels <50 ng/dL NCT04207255 Opaganib+ Abiraterone +Enzalutamide 2019–2024 69 Stable disease without metastasis NCT03085095 Relugolix and Leuprolide acetate 2017–2022 930 Relugolix exhibited a more than 50% PSA reduction rate and testosterone levels observed <50 ng/dL compared to leuprolide NCT03016312 Enzalutamide and Atezolizumab +Enzalutamide 2017–2024 759 Enzalutamide alone is more efficient NCT02918968 Enzalutamide+ ADT and Flutamide+ ADT 2016–2021 206 Enzalutamide+ ADT is better with 90% reduced PSA rate than the flutamide combination NCT02485691 Cabazitaxel, Abiraterone, Enzalutamide 2015–2022 255 Cabazitaxel is more efficient than abiraterone or enzalutamide NCT02217566 Abiraterone acetate 2014–2020 46 Abiraterone acetate showed a 50% decrease in PSA levels NCT02058706 Enzalutamide, Bicalutamide 2014–2020 71 Enzalutamide exhibited a PSA response rate higher NCT01875250 Enzalutamide without ADT 2013–2020 38 Improved survival rate up to more than 50% NCT01717053 Abiraterone acetate + Prednisone 2014–2021 37 AA with Prednisone, better PSA improvement observed NCT01715285 Abiraterone acetate + Prednisone 2013–2022 1209 Improved survival rate up to more than 50% NCT01664923 Enzalutamide, bicalutamide 2012–2018 396 Enzalutamide is effective NCT01393730 Abiraterone+ dutasteride 2011–2017 40 Reduction of 60% of the PSA level NCT01288911 Enzalutamide, bicalutamide 2011–2017 375 Lower metastasis seen NCT01023061 Abiraterone+ EBRT 2010–2015 24 Abiraterone aid is better for a more survival outcome NCT00884273 Degarelix, Goserelin 2009–2011 182 Degarelix showed improved outcomes NCT00814788 Bicalutamide+Everolimus 2008–2016 24 Bicalutamide in combination reduced adverse effects, improving survival NCT00460031 Ketoconazole +Lenalidomide 2006–2010 34 Better outcomes seen than with hormone therapy NCT01429064 Darolutamide 2011–2015 76 Highly safe, avoiding adverse effects NCT02200614 Darolutamide 2014–2021 1509 Highly safe, avoiding adverse effects Mori et al., 2020 Apalutamide+ Enzalutamide +Darolutamide 2020 4117 Darolutamide is highly effective with lower side effects, while APA + enzalutamide is highly effective in reducing PSA levels, both reasonably improving survival rates in patients George et al., 2023 Darolutamide, Apalutamide, Enzalutamide 2023 828 A higher survival rate is observed by darolutamide than by apalutamide and enzalutamide Open in a new tab 4. Ongoing Clinical Trials on Individual and Combination Therapies in Prostate Cancer Patients. clinical trial ID type of study year of study number of Patients NCT06060587 ADT + Abiraterone + ADT + Docetaxel +Abiraterone 2023–2030 150 NCT05999968 Abemaciclib+Darolutamide 2024–2026 10 NCT05968599 Enzalutamide+Abiraterone 2023–2024 2800 NCT05617885 Darolutamide+Abemaciclib 2023–2026 09 NCT05605964 MACE study Relugolix, Leuprolide acetate 2023–2024 2250 NCT05457257 Olaparib vs Enzalutamide/Abiraterone 2022–2025 43 NCT05348577 Capivasertib+ Docetaxel 2022–2026 1017 NCT05171816 Olaparib+Abiraterone 2021–2026 108 NCT05171387 Darolutamide+ ADT 2021–2025 78 NCT04926181 Apalutamide+Cetrilimab 2022–2025 02 NCT04821622 Talazoparib +Enzalutamide 2021–2027 599 NCT04703920 Talazoparib +Belinostat 2021–2024 26 NCT04577833 Niraparib+ Abiraterone acetate 2020–2025 136 NCT04557059 Apalutamide+ Radiotherapy and LHRH agonist (PRIMORDIUM) 2020–2029 694 NCT04497844 Niraparib+Abiraterone acetate and Prednisone vs Abiraterone acetate 2020–2027 696 NCT04493853 Capivasertib+Abiraterone 2020–2027 1012 NCT04484818 Darolutamide+ ADT vs ADT postsurgery (ERADICATE) 2021–2028 27 NCT04477512 Cabozantinib+ Abiraterone + nivolumab (CABIOS) 2021–2025 18 NCT04298983 Abemaciclib+ ADT 2021–2026 09 NCT04253262 Copansilib+Rucaparib 2020–2027 13 NCT04191096 Pembrolizumab + Enzalutamide + ADT vs Enzalutamide+ ADT 2020–2026 1251 NCT04108208 Apalutamide vs placebo 2019–2026 75 NCT04076059 Enzalutamide+ ADT vs ADT 2019–2028 180 NCT04019327 Talazoparib + Temozolomide 2019–2027 16 NCT03934840 Carboplatin, Cabazitaxel, Abiraterone (CASCARA) 2019–2025 22 NCT03834493 Pembrolizumab +Enzalutamide vs Enzalutamide + Placebo 2019–2024 1244 NCT03821792 Abiraterone acetate + Prednisone +Apalutamide 2019–2026 60 NCT03787680 ATR and Olaparib (TRAP) 2019–2027 49 NCT03748641 Niraparib+Abiraterone acetate + Prednisone vs Abiraterone acetate + Prednisone 2019–2027 765 NCT03732820 Olaparib+Abiraterone 2018–2024 895 NCT03706365 Abiraterone acetate + Prednisone and Abemaciclib (CYCLONE 2) 2018–2026 350 NCT03674814 Enzalutamide+Relacorilant 2018–2026 35 NCT03442556 Docetaxel + Carboplatin +Rucaparib 2018–2025 18 NCT03431350 Niraparib+Abiraterone acetate (QUEST) 2018–2024 136 NCT0335197 Talazoparib +Enzalutamide vs Enzalutamide (TALAPRO-2) 2017–2025 1054 NCT03360721 Abiraterone acetate + Prednisone +Apalutamide 2018–2025 07 NCT03338790 Nivolumab + Docetaxel + Rucaparib +Enzalutamide 2017–2024 292 NCT03246347 ADT + Docetaxel +Enzalutamide 2017–2028 40 NCT03012321 Abiraterone/Prednisone, Olaparib, or Abiraterone/Prednisone +Olaparib 2017–2021 70 NCT02807805 Abiraterone Acetate, Niclosamide, and Prednisone 2016–2024 37 NCT02522715 Enzalutamide+Cabazitaxel 2015–2015 37 NCT02339168 Enzalutamide+Metformin hydrochloride 2016–2025 24 NCT02319837 Enzalutamide+ Leuprolide (EMBARK) 2014–2026 1068 NCT02020070 Ipilimumab + Degarelix + Prostatectomy 2013–2025 16 NCT01952223 Cabazitaxel+ Radiotherapy 2013–2041 761 NCT00667069 Triptorelin+ Radiotherapy 2008–2025 424 NCT00430183 Docetaxel + Leuprolide/Goserelin 2017–2030 788 Open in a new tab 5. Open in a new tab Clinical trial data on combination therapies in prostate cancer. Histogram depicting clinical trials on combination therapies for prostate cancer from 2006 to 2024. The graph illustrates the number of trials conducted over time and the total number of patients enrolled at specific intervals, highlighting a peak trend. 6. Open in a new tab Ongoing clinical trials data on combination therapies in prostate cancer. Histogram depicting ongoing clinical trials collected from PubMed, ClinicalTrials.gov, and CanSar.ai. The graph illustrates the total number of patients enrolled in clinical trials over time, showing a peak curve corresponding to the different drug combinations. The trend is projected to continue until 2041. Early phase 1 studies demonstrated that abiraterone in combination with prednisone helps to reduce adverse effects such as fluid retention and hypertension, and this regimen is now widely applied in the treatment of mCRPC and metastatic castration sensitive prostate cancer (mCSPC). , Clinical trials conducted between 2013 and 2023 ( Tables and and Figures and ) evaluated the therapeutic value of this combination and showed more than 50 percent reduction in PSA levels and improved overall survival in a total of 1246 patients. One of the major studies in this field is the STAMPEDE trial. STAMPEDE is a large multi-arm and multistage clinical platform study designed to test several treatment combinations alongside standard ADT in prostate cancer. In this trial, 1917 patients treated with ADT along with abiraterone and prednisone exhibited more than 80 six percent survival over three years, establishing abiraterone-based therapy as a preferred first-line option for patients with metastatic prostate cancer. Another influential trial is the ENZAMET study. ENZAMET is an international phase 3 randomized trial that evaluates the benefit of adding enzalutamide to ADT in men with metastatic prostate cancer. The study demonstrated more than 80 percent survival in patients receiving this combination. This is supported by another study involving 206 patients between 2016 and 2021, where PSA levels were reduced by more than 90 percent ( NCT02918968 ). A clinical investigation using a novel regimen consisting of opaganib, abiraterone, and enzalutamide reported stable disease without progression or metastasis, even though no improvement was detected in other clinical parameters ( NCT04207255 ) ( Figure ). Comparative trials have also clarified the advantage of specific AR signaling inhibitors. For example, two clinical studies ( NCT01664923 ; NCT01288911 ) showed that enzalutamide provides better outcomes than bicalutamide in 411 patients, including greater suppression of testosterone levels, fewer adverse effects, and a lower rate of disease progression. Chemotherapy with cabazitaxel demonstrated superior efficacy compared to abiraterone and enzalutamide in the study registered as NCT02485691 . A broader evaluation of trials involving more than 5702 patients from 2011 to 2021 showed that darolutamide is both effective and safer, as it produces fewer adverse reactions compared to several other AR signaling inhibitors. At the same time, combinations involving apalutamide and enzalutamide appear to promote an even greater improvement in survival compared to darolutamide, although further detailed investigation is required to validate this observation ( Figure ). Several additional trials are ongoing and are expected to provide deeper insights into the therapeutic potential of combination strategies for prostate cancer in the near future ( Table , Figure ). Emerging Therapeutics in PCa Adoptive Cell Therapy Conventional therapies like chemotherapy deplete a large portion of cells in the tumor, but residual prostate stem cells (PSCs) continue to be a problem. PSCs develop in the absence of androgen and are considered to be responsible for rapid development despite androgen ablation. These stem cells divide into both androgen-dependent and independent cells, observed in CRPC, thereby exhibiting a heterogeneous phenotype. Various stem cell-targeting therapies have been developed to limit cancer progression ( Figure ). Adoptive cell therapies, such as CAR-modified T-cell therapy, represent an immune cell-based approach in which genetically engineered T lymphocytes are directed against tumor-associated antigens expressed on cancer stem cells. Recent studies have demonstrated robust expression of prostate stem cell antigen (PSCA) and PSMA, which are leveraged as key therapeutic targets in metastatic CRPC (mCRPC). Using xenograft and syngeneic tumor models, PSCA-CAR T-cell therapy has shown high efficacy with improved therapeutic responses. CD133 is the targeted biomarker of CSC, and phase I trials have given prominent results for metastatic malignancy. In addition, B7–H3-expressed prostate cancer stem cells are treated with anti-B7–H3 CAR T-cell constructs mediating cytolysis in different in vitro-based assays. EpCAM-CAR treatment has also proved to be efficient in killing the cancer cells, but toxicity and adverse pulmonary effects resulted in prevention of its further evaluation. Immunotherapy Immunotherapy has been a promising treatment strategy for most of the cancers. In general, PCa tumors are characterized as ‘cold’ due to lower expression of PD-L1 (transmembrane protein on T-cells), hindering the effect of current immunotherapy. Several methods were known to show modest improvements in the outcome of survival in patients. Primarily, methods include direct monoclonal antibody delivery, which has the capacity for binding tumor-specific antigens in cancer cells, ICI’s (immune checkpoint inhibitors), cytokines (as adjuvants), bispecific T-cell engaging antibodies (BiTE’s), and adoptive cell transfer (ACT). Sipuleucel-T has been the first immunotherapeutic agent in treatment of mCRPC with demonstrated progression-free survival, wherein it targets prostatic acid phosphatase antigen, eliciting an immune response. In addition, DCVAC and GVAX are vaccines that are proven to be beneficial for metastatic PCa patients. However, due to limited and moderate response, immune checkpoint inhibitors (ICIs) like Ipilimumab, Pembrolizumab, Tremelimumab, and Nivolumab are used as immunotherapeutic agents, prone to cure disease more effectively. , They inhibit the immune checkpoint receptors (which prevent activation of T-cells), thereby preventing inactivation of T-cells and reducing tumor immune evasion. Most of the clinical trials showed a reduction of more than 50% PSA by deploying this mechanism by regulating checkpoints like programmed cell death (PD-1), PDL1, and CTLA-4. Nevertheless, most patients are resistant to ICIs due to a highly complex tumor immune microenvironment (TIME) and very low PDL1 expression, which demands more robust and specific methods. Research by Wu and group reported excellent PSA response in patients with noticeable biallelic CDK12 mutation, on treatment with the anti-PD1 antibody. Biallelic inactivation of CDK12 is associated with a distinct genomic instability phenotype characterized by CDK12-specific focal tandem duplications (6.3% out of 28%), which drive the differential expression of oncogenic drivers such as CCND1 and CDK4, thereby promoting cell-cycle dysregulation. In prostate cancer, CDK12 alterations represent one of the most frequent DNA repair gene aberrations and have emerged as a promising predictive biomarker alongside mismatch repair deficiency for treatment response to immune checkpoint blockade. Importantly, these molecular features provide a strong biological rationale for combinatorial therapeutic strategies integrating immune checkpoint inhibition with CDK4/6 inhibitors in CDK12-mutated tumors, a concept currently being explored in clinical trials. , Beyond immune checkpoint inhibitors and vaccine-based approaches, adoptive cell therapy (ACT) has emerged as a novel immunotherapeutic strategy utilizing genetically engineered CAR-T cells targeting prostate-specific antigens, with improved survival outcomes reported. Also, bispecific T-cell engagers (BiTEs) have shown encouraging trends in overall survival in multiple clinical trials ,, Pasotuxizumab, an anti-CD3/anti-PSMA BiTE, demonstrated over 50% PSA reduction in early trials; however, its clinical utility was limited by reduced shelf life. Subsequent efforts have explored BiTEs targeting alternative tumor-associated antigens such as PSCA, KLK2, STEAP1, and DLL3, though many trials have reported limited efficacy and significant adverse effects. Despite notable success in hematological malignancies, CAR-T and BiTE therapies have shown limited efficacy in prostate cancer due to an immune-cold tumor microenvironment characterized by low T-cell infiltration, reduced mutational burden, and altered cytokine signaling. − Additional challenges include off-target toxicity, antigen heterogeneity, and impaired T-cell trafficking in solid tumors such as prostate cancer. , RNA Technology Studies on m RNA expression and its signaling, for protein construction, have been widely considered, which led to the discovery of new methods to counteract any adverse effects in protein expression. Hence, targeting mRNA has been proven to be efficient in controlling PCa, where antisense oligonucleotide technology involves the use of synthetic single-stranded deoxyribonucleotides targeting the mRNA of target genes, resulting in RNase H cleavage and blocking protein synthesis in prostate cells. Profound effects are observed in xenograft models of prostate cancer. Another notable approach dealt with the use of small interfering RNA delivery to the AR, thereby blocking the protein expression in cancer cells. In addition to nullifying disease progression to a certain extent, several noncoding RNAs and long noncoding RNAs (lncRNAs) are known to play a role as distinct molecular biomarkers in cancer. Advances in high-throughput sequencing and sensitive transcriptomic technologies have revealed that the total number of identified lncRNAs now exceeds that of the protein-coding genes. These transcripts are predominantly synthesized by RNA polymerase II and frequently undergo post-transcriptional modifications, including capping, splicing, and polyadenylation. lncRNAs exhibit diverse subcellular localizations, being detected within the nucleus, nucleolus, cytoplasm, and mitochondria, reflecting their broad regulatory functions. , Mechanistically, lncRNAs regulate gene expression through multiple modes, including acting as competing endogenous RNAs for miRNAs, interacting with transcription factors to modulate their activity, and influencing chromatin architecture. , Notably, PCA3 has achieved clinical application as a urinary biomarker for prostate cancer detection and was approved by the FDA in 2012. Increasing evidence links lncRNA dysregulation to the pathogenesis of human diseases, including cancer, thereby positioning them as promising diagnostic and prognostic biomarkers as well as therapeutic targets. In prostate cancer, lncRNAs such as prostate cancer antigen 3 (PCA3), second chromosome locus associated with prostate-1 (SChLAP1), and prostate cancer-associated transcript-1 (PCAT1) are robust biomarkers owing to their cancer-specific and differential expression patterns. The inherent stability of circulating lncRNAs in biological fluids such as serum, urine, and cerebrospinal fluid further enhances their clinical utility. Beyond lncRNAs, circulating cell-free miRNAs display tissue-specific expression and are frequently deregulated in tumors. miR-21, miR-221, miR-1290, and miR-375 have been associated with advanced stages of prostate cancer. Furthermore, therapeutic modulation of RNA biology is emerging as a viable strategy; for instance, zotatifin, a small-molecule inhibitor of eIF4A, has demonstrated significant suppression of AR expression in both wild-type and splice-variant AR-driven prostate cancer models through structural remodeling of 5′-UTRs. Complementing this, recent RNA-sequencing studies identified robust expression of the lncRNA PRCAT71 in both primary and metastatic prostate cancer tissues, where it stabilizes AR mRNA via recruitment of the KHSRP protein, highlighting its diagnostic and therapeutic relevance. Despite significant progress, clinical translation of RNA-based biomarkers and therapeutics remains challenged by inefficient intracellular delivery, immune activation, and off-target effects, underscoring the need for continued technological refinement. Currently, several biomarkers like microarray and single-molecule molecular inversion probe (smMIP) have been discovered to be transcriptomic platforms for identifying expression levels of different genes within using array chips. PARP Inhibitors Damage to DNA in cancer cells may be due to production of reactive oxygen species, radiation exposure, or chemotherapy. Notably, a high frequency of mutations is visible in DNA repair genes like BRCA1 and BRCA2, which causes activation of other repair mechanisms, entering PARylation into the picture. To date, six major DNA damage repair (DDR) pathways have been identified that collectively address single-strand breaks (SSBs) and double-strand breaks (DSBs) arising from diverse genotoxic insults. Among these, homologous recombination (HR) and nonhomologous end joining (NHEJ) represent the two principal mechanisms for DSB repair. HR is an error-free pathway that predominantly operates during the S and G2 phases of the cell cycle, facilitated by the availability of a sister chromatid as a repair template. In contrast, NHEJ is an error-prone but rapid repair process that functions throughout the cell cycle, with predominant activity in the G1 phase and exclusion during mitosis. Beyond the canonical NHEJ machinery, including Ku70/Ku80, DNA-PKcs, Artemis, DNA polymerases λ/μ, DNA ligase IV-XRCC4, and XLFseveral newly identified proteins have been implicated in pathway regulation, such as PAXX, MRI/CYREN, TARDBP (TDP-43), IFFO1, ERCC6L2, and RNase H2. Notably, MRI/CYREN exhibits a dual regulatory role by promoting NHEJ during the G1 phase while suppressing the pathway in the S and G2 phases, thereby ensuring appropriate pathway choice across the cell cycle. Genetic aberrations affecting key components of HR and other DDR pathways, frequently observed in prostate cancer, particularly involving BRCA1 and BRCA2, shift cellular reliance toward alternative repair mechanisms, notably PARP-mediated SSB repair. This compensatory dependency provides the mechanistic basis for synthetic lethality, wherein pharmacological inhibition of PARP results in accumulation of unrepaired DNA damage, replication fork collapse, and tumor-selective apoptosis ( Figure ). Clinically evaluated PARP inhibitors such as Olaparib, rucaparib, talazoparib, and veliparib have demonstrated efficacy in mCRPC. , Beyond catalytic inhibition of poly­(ADP-ribosyl)­ation, PARP inhibitors exert cytotoxic effects by stabilizing PARP–DNA complexes at sites of DNA damage, thereby impairing DNA replication fork progression and repair processes. This mechanism, known as PARP trapping, is now recognized as a critical determinant of the antitumor efficacy of PARP inhibitors and explains the differential magnitude of cytotoxicity observed among individual agents. Among clinically evaluated PARP inhibitors, Olaparib, niraparib, and rucaparib demonstrate markedly stronger PARP-trapping activity, approximately 100-fold greater than veliparib, which primarily functions as a catalytic inhibitor with relatively weak trapping capacity. This differential trapping efficiency provides a mechanistic basis for the enhanced therapeutic efficacy of selected PARP inhibitors in metastatic CRPC (mCRPC), particularly in tumors harboring defects in HR repair pathways. In patients with HR gene mutation, Olaparib was effective after administration with enzalutamide or abiraterone, where a randomized clinical trial-III exhibited the efficacy of Olaparib-treated patients higher than control patients with only hormone therapy. On the other side, Rucaparib is proven to be 54% more effective in patients who have been treated initially with hormone therapy and chemo-taxane-based therapies. Both of these PARP inhibitors are currently under study for treating hormone-sensitive metastatic patients. Most promisingly, talazoparib is found to strongly inhibit the DNA repair enzymes as well as accumulate the adhesion of PARP1 onto DNA, trapping replication and resulting in cell death. The double-blind PROPEL trial showed the combination of Olaparib with abiraterone to be the first-line PARPi treatment in mCRPC. Veliparib has recently gained attention due to progression of survival in mCRPC patients, in combination with abiraterone and prednisone. Regardless, resistance to the above has led to the investigation of combination therapies of (PARP inhibitors) PARPi, with more antiandrogens, which are yet to be proven in clinical trials. Research on DNA repair led to identification of amplified in liver cancer (ALC) 1, a chromatin remodeler, which is involved in mobilization of PARP1, where autoPARylation of ALC1 releases PARP1 from chromatin, causing DNA repair, while a deficiency in ALC1 causes cell death. Conventional PARP inhibitors work on stalled PARP that is stably fixed on DNA and carry out repair process, where PARP interaction with ALC1 promotes accessibility of chromatin to the DNA repair effectors like X-ray repair cross complementing protein (XRCC) 1. In contrast, when ALC1 is overexpressed in tumor cells, PARP is removed at higher rate, repairing cells, which promote resistance to PARP inhibitors. PROTACs PROTAC is a novel proteolytic targeted chimera technology that chemically knockdown transcription factors at the level of protein ( Figure ). It employs ubiquitin mediated protein degradation system, where one end of the chimera is connected to the target protein and the other end is for the E3 ubiquitin ligase, both joined by a linker. , This unique structural setup slims down the space between the target protein and the intracellular ubiquitin ligase to form a chimeric polymer, which leads to the ubiquitination of the target protein and chemically degrades the AR protein through hydrolysis. In 2018, Professor Crew and his group designed AR targeting chimera (ARCC)-4 that can degrade 95% of AR in cells of PCa, significantly inhibiting mutants as well. Mouse xenograft model studies have also proven the efficacy of AR degrader (ARD)-69, another PROTAC to reduce the level of AR proteins in CRPC patients. ARD-61 is said to overcome resistance to antihormone therapies, which inhibits AR levels in addition to enzalutamide resistance inhibition. Neklesa and group reported the significant inhibition of AR-dependent cell proliferation and selective mutant AR degradation by ARV-110 at low nanomolar concentrations of its administration. An exceptional study by Xiang and group promoted the discovery of ARD-2585, which degraded the AR protein by >80%, inhibiting tumor growth in lymph node carcinoma of prostate (LNCaP) and vertebral metastasis of prostate (VCaP) cell lines despite the presence of double mutations and splice variants in them. Beyond AR-targeting PROTACs, several non-AR degraders have been developed against overexpressed oncogenic proteins in prostate cancer. Raina et al. reported ARV-771, a BET-targeting PROTAC, which induced apoptosis across multiple prostate cancer cell lines. Similarly, WWL0245, a dual BET/PLK1 degrader, demonstrated potent antiproliferative activity with reduced BRD4 and c-Myc expression. Zhou et al. further reported selective CDK2 degradation using AT-7519 and FN-1501, inducing cell cycle arrest in PC3 cells. Despite these promising findings, translational challenges persist, including high molecular weight, limited oral bioavailability, dependence on E3 ligase expression, and variable clinical responses observed in trials. In recent times, artificial intelligence has significantly boosted drug discovery in recent years. One refined example is a study by Bohan and group: the Rosetta AI system for peptide PROTAC drug design has been implemented for the AR-V7 variant, which targeted the DNA-binding domain AR (DBD) and reportedly promoted the AR degradation. Targeting of AR-V7 by PROTAC technology needs hour, as it facilitates degradation of AR, counteracting the drawbacks of antiandrogen resistance caused by these variants. Nanomedicine Nanotechnology has become an emerging and promising treatment strategy in prostate cancer. Usage of nanomedicine emerged due to drawbacks in site-specific interactions, drug resistance, and side effects, duly observed in conventional systems. Size, charge, surface hydrophilicity of the nanoparticle (NP), etc. are modulated for enhancing drug solubility and promoting its half-life, which forms the basis for nanomedicine. Nanoparticle-based drug delivery systems have demonstrated reduced systemic toxicity and enhanced antitumor efficacy in prostate cancer. Liposomes, gold nanoparticles, quantum dots, silica nanoparticles, and carbon nanotubes have all shown improved tumor targeting. For instance, PLGA and TP-GQD nanoparticles combined with bicalutamide or enzalutamide enhanced therapeutic efficacy while reducing adverse effects. Cisplatin-loaded PLGA-mPEG nanoparticles exhibited superior anticancer activity compared to free cisplatin in LNCaP cells, while PEGylated lipid nanoparticles carrying docetaxel improved drug stability and bioavailability. Nanomicelle–quercetin complexes further demonstrated enhanced tumor accumulation and lower IC 50 values. Consequently, doxorubicin, paclitaxel, and vincristine sulfate, used in prostate and other cancers, inhibit tumor cells through various mechanisms like inhibiting DNA and RNA synthesis and reducing spindle formation and cell mitosis. PSMA-bound gold nanoparticles with gadolinium are found to be efficient in higher binding affinity to tumor cells and result in better inhibition of prostate cancer. Research illustrated the importance of nanomaterial-based biosensors for the detection of prostate cancer biomarkers like PSA-targeted biosensors and sarcosine oxidase-targeted biosensors, improving detection methods in a precise and faster manner. Nevertheless, despite promising preclinical outcomes, clinical translation remains constrained by interpatient variability, scalability, and regulatory complexity Conclusion and Future Perspectives Over decades of intensive research, the AR has emerged as the central and indispensable regulator of transcriptional programs in prostate cancer, forming the cornerstone for multiple therapeutic strategies in metastatic CRPC (mCRPC). Historically, metastatic disease was managed primarily through ADT and surgical castration, both of which, despite initial efficacy, are noncurative, with inevitable disease relapse. This clinical reality shifted the therapeutic paradigm from targeting circulating androgens to directly inhibiting AR itself. Over the past two decades ( Figure ), selective blockade of AR domains using next-generation antiandrogens has successfully suppressed transcriptional activity in extratesticular tissues such as the prostate. Nevertheless, the emergence of resistance mechanismsincluding point mutations, ligand-binding domain alterations, and constitutively active splice variants such as AR-V7has significantly undermined the durability of these approaches. In this perspective, we have consolidated and critically examined the full spectrum of therapeutic modalities employed to date ( Figure ), with a particular emphasis on contemporary innovations addressing treatment resistance. Notably, combination regimens incorporating AR signaling inhibitors (ARSIs) and other targeted agents have shown promise in delaying progression, but their optimal integration into standard-of-care protocols remains an open challenge. Moving forward, a more granular understanding of the molecular circuitry underpinning AR resistance, particularly the interplay between AR-driven transcription and compensatory signaling pathways, will be essential. Large-scale clinical trials evaluating rationally designed combination therapies, including proteolysis-targeting chimeras (PROTACs) and next-generation ARSIs, hold the potential to redefine therapeutic sequencing. Additionally, comparative structural analysis of full-length AR and its splice variants, followed by computational docking with candidate ligands, can accelerate the identification of novel high-affinity inhibitors and allosteric modulators. Beyond direct AR targeting, emerging technologies offer complementary avenues for intervention. Nanomedicine-based delivery systems, coupled with mutation-specific biosensors, could enhance therapeutic precision while minimizing systemic toxicity. Furthermore, the integration of AI and ML into prostate cancer research is revolutionizing diagnostics, prognostication, and drug development. Advanced AI architectures, such as artificial neural networks, can be harnessed to predict resistance-associated mutations, stratify patients for personalized therapy, and even optimize drug design pipelines. In conclusion, the trajectory of prostate cancer research is steering toward highly individualized, technology-enabled treatment ecosystems. By uniting molecularly informed AR targeting, cutting-edge computational modeling, nanotechnology-driven delivery, and molecular docking-powered clinical decision-making, the next decade holds the promise of transforming mCRPC from a largely incurable condition into a manageable chronic disease, if not achieving functional cures for select patient subgroups. Acknowledgments Financial support from the SRM University–AP to P.K. [Seed Grant No: SRMAP/URG/SEED/2024-25/042] and financial support from KL University to K.S. [Seed Grant No: KLEF/SRG/2025-26 ODD SEM/BT/003] are gratefully acknowledged. G.S.V.S.R.R. and A.K. thank the SRM University–AP for PhD fellowships. We also acknowledge the HPCC facilities at the SRM University–AP supercomputer centre. D.P. thanks the SERB, Government of India, for support under the SURE project [No. SUR/2022/004576]. Glossary Abbreviations AR Androgen receptor ADT Androgen deprivation therapy AI Artificial intelligence ML Machine learning PARP Poly­(ADP-ribose) polymerase PROTAC Proteolysis-targeting chimera PCa Prostate cancer AJCC American Joint Committee on Cancer ATM Ataxia telangiectasia mutated BRCA1 Breast cancer gene 1 PSA Prostate-specific antigen MRI Magnetic resonance imaging TNM Tumor node metastasis EBRT External beam radiation therapy siRNA Small interfering RNA CTLA-4 Cytotoxic t-lymphocyte associated protein-4 PD-L1 Programmed death ligand −1 MCRPC Metastatic castration-resistant prostate cancer GLOBOCAN Global Cancer Observatory ECIS European Cancer Information System LSTM Long short-term memory GAN Generative adversarial network RMSE Root mean square MAE Mean absolute error LH Luteinizing hormone FSH Follicle-stimulating hormone ER Endoplasmic reticulum T Testosterone DHT Dihydrotestosterone TMPRSS2 Transmembrane serine protease 2 HSP Heat-shock proteins CRPC Castration-resistant prostate cancer ARSI Androgen receptor signaling inhibitors LHRH Luteinizing hormone-releasing hormone GnRH Gonadotropin-releasing hormone CYP17A1 Cytochrome P450 17A1 mTOR mechanistic target of rapamycin Akt Serine/Threonine kinase ALDH1 Aldehyde dehydrogenase 1 BMP2 Bone morphogenetic protein 2 LNCaP Lymph node carcinoma of the prostate GR Glucocorticoid receptor ARV Androgen receptor variant LBD Ligand-binding domain AKR1C3 Aldo-keto reductase family 1 member C3 EMT Epithelial-mesenchymal transition MCSPC Metastatic castration sensitive prostate cancer PSC Prostate stem cell CAR Chimeric antigen receptor CSC Cancer stem cell EpCAM Epithelial cell adhesion molecule BITES Bi specific T-cell engager ACT Adoptive cell transfer ICI Immune checkpoint inhibitors TIME Tumor immune microenvironment CDK12 Cyclin-dependent kinase PCA Prostate cancer antigen miRNA Micro-RNA SchLAP Second chromosome locus associated with the prostate PCAT Prostate cancer-associated transcript SmMIP Single-molecule molecular inversion probe ARCC Androgen receptor targeting chimeras ARD Androgen receptor degrader ALC Amplified in liver cancer XRCC X-ray repair cross-complementing protein VCaP Vertebrate metastasis of the prostate DBD DNA-binding domain ARD Androgen receptor degrader PSMA Prostate-specific membrane antigen TAA Tumor-associated antigen HSP Heat-shock protein PSCA Prostate cell antigen CCND1 Cyclin D1 PAXX Paralog of XRCC4 and XLF CYREN Cell cycle regulator of non-homologous end joining TARDBP TAR DNA-binding protein IFFO1 Intermediate filament family orphan 1 ERCC6L2 Excision repair cross-complementation group 6-like 2 BET Bromodomain and extraterminal domain BRD Bromo domain-containing protein PLK1 Polo-like kinase 1 PLGA-mPEG Poly­( d , l -lactide- co -glycolide)–methoxy poly­(ethylene glycol) Conceptualization: GSVSRR, KS, and PK. 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