In the evolving landscape of prostate cancer treatment, hormone-sensitive prostate cancer (HSPC) has traditionally been managed with androgen-deprivation therapy (ADT) as a monotherapy. For decades, ADT was the cornerstone of systemic therapy, exploiting the tumor’s dependence on androgens for growth and survival. However, recent advances in our understanding of the molecular and biological heterogeneity of prostate cancer have prompted a paradigm shift. Clinicians now increasingly employ intensified multimodal strategies that extend beyond ADT alone to optimize therapeutic outcomes. This shift is propelled by clinical trials demonstrating survival benefits from combining ADT with other systemic and localized treatments, signaling a new era of personalized treatment in HSPC.
At the crux of this therapeutic intensification is the integration of androgen receptor pathway inhibitors (ARPIs), chemotherapeutic agents like docetaxel, and targeted radiotherapy. ARPIs such as enzalutamide, apalutamide, and darolutamide disrupt androgen signaling at various junctures, effectively incapacitating tumor growth pathways that remain active despite castration levels of testosterone. Meanwhile, docetaxel, a microtubule inhibitor, enhances cytotoxicity when paired with ADT. Radiotherapy directed at primary prostate tumors or metastatic sites adds a locoregional dimension to systemic treatment. This multifaceted approach harnesses biologic vulnerabilities and strategically attacks prostate cancer on multiple fronts, thereby improving progression-free and overall survival metrics, especially among select patient cohorts.
The classification of hormone-sensitive prostate cancer hinges fundamentally on the clinical history and disease burden at presentation. Patients fall into two principal categories: those with localized prostate cancer treated definitively before systemic features evolve, and those diagnosed de novo with metastatic disease. Further stratification relies on imaging assessments that delineate the extent and anatomical distribution of metastases. Conventional modalities like computed tomography (CT) and whole-body bone scintigraphy have been the mainstay. However, these methods possess inherent limitations, notably in resolution and sensitivity for microscopic or low-volume metastatic involvement. Consequently, clinical decision-making based solely on traditional imaging can underestimate disease extent, potentially leading to suboptimal treatment choices.
Enter prostate-specific membrane antigen (PSMA) positron emission tomography (PET), a transformative imaging technology that substantially redefines the detection landscape in prostate cancer. PSMA PET provides exquisite sensitivity and spatial resolution, enabling visualization of metastatic deposits that evade standard imaging detection thresholds. This leap in diagnostic capability allows for earlier identification of metastatic disease, uncovering previously unrecognized patient subsets with low-volume metastases or oligometastatic states. Such fine-grained biological and anatomical insight offers unprecedented opportunities to tailor systemic and local therapeutic strategies to the individual patient’s disease phenotype, fostering truly personalized treatment intensification.
Nonetheless, the clinical utility of incorporating PSMA PET into routine staging and treatment algorithms remains an active area of investigation and debate. On one hand, detecting micrometastatic spread can prompt incorporation of docetaxel into ADT plus ARPI regimens, conferring a survival advantage in certain groups. On the other, patients with minimal disease burden discerned only on PSMA PET may derive limited incremental benefit from adding chemotherapy, exposing them unnecessarily to toxicity. The challenge lies in calibrating treatment intensity commensurate to the biological aggressiveness and visibility of metastases on advanced imaging, ensuring that the added treatment burden is justified by clinical gains.
Personalized management of non-metastatic hormone-sensitive prostate cancer (nmHSPC) now incorporates novel strategies that balance aggressive therapy with quality of life considerations. Radiotherapy directed at the primary tumor in conjunction with systemic therapy has emerged as a critical intervention, especially in patients with high-risk localized disease. Recent evidence indicates that delivering definitive radiotherapy can improve metastasis-free survival and potentially overall survival. Additionally, ARPIs augment treatment efficacy in nmHSPC by suppressing androgen receptor signaling more robustly than ADT alone, delaying progression to metastatic castration-resistant prostate cancer.
In the metastatic hormone-sensitive prostate cancer (mHSPC) setting, risk and volume stratification profoundly influence treatment selection. High-volume metastatic disease, characterized by extensive visceral or bone involvement, benefits disproportionately from intensified regimens including docetaxel combined with ADT and an ARPI. Conversely, patients with low-volume disease may be spared the toxicities of chemotherapy without compromising outcomes, relying instead on combination ADT and ARPI approaches. This nuanced tailoring of therapy underscores the importance of accurate disease characterization via comprehensive imaging and clinical evaluation.
Recent therapeutic developments are expanding the armamentarium for mHSPC beyond established agents. AKT inhibitors, which target a critical node in the PI3K/AKT/mTOR pathway frequently dysregulated in prostate cancer, show promise in early-phase trials, particularly for tumors harboring pathway alterations. Parallelly, radioligand therapies employing novel isotopes conjugated to PSMA ligands allow targeted delivery of cytotoxic radiation directly to prostate cancer cells, potentially improving control with reduced systemic side effects. Poly ADP-ribose polymerase (PARP) inhibitors, initially developed for homologous recombination repair-deficient tumors, are being evaluated in mHSPC settings to exploit DNA repair vulnerabilities early in disease evolution.
As the therapeutic complexity escalates, mitigation of toxicity assumes critical importance in long-term management. Strategies to reduce adverse effects span from optimized dosing schedules, the judicious use of growth factor support with chemotherapy, to vigilant monitoring of cardiovascular, metabolic, and neurocognitive domains affected by prolonged androgen suppression. Emerging data underscore the necessity of multidisciplinary care teams, integrating oncology, urology, radiation therapy, and supportive care specialists to individualize treatment and preserve patient quality of life.
Moreover, the heterogeneity of prostate cancer biology embedded in genomic, transcriptomic, and microenvironmental factors calls for integration of molecular profiling into clinical algorithms. Attempts to incorporate biomarkers predictive of response to ARPIs, chemotherapy, and targeted agents are underway, aiming to refine patient selection further. Personalized medicine in HSPC thus rests on a triad of improved imaging diagnostics, comprehensive clinical and molecular risk stratification, and the availability of diverse therapeutic modalities.
This transformative approach reshapes not only treatment paradigms but also patient expectations and survivorship frameworks. Patients previously relegated to ADT monotherapy now anticipate more aggressive yet personalized regimens that offer hope for prolonged disease control. At the same time, balancing intensity with tolerability necessitates shared decision-making, with clinicians guiding patients through increasingly complex benefit-risk landscapes.
In conclusion, the management of hormone-sensitive prostate cancer is experiencing a renaissance driven by intensified treatment strategies grounded in profound biological insights and cutting-edge diagnostic tools. The deployment of androgen receptor pathway inhibitors, chemotherapy, and targeted radiotherapy, individually or in combination, marks a decisive departure from traditional monotherapy approaches. Novel agents targeting molecular pathways and employing innovative delivery mechanisms promise further improvements in outcomes. The advent of PSMA PET imaging illuminates metastatic spread with unprecedented precision, enabling more nuanced treatment selection. Together, these advancements empower clinicians to personalize and intensify therapy, aiming to optimize survival and maintain quality of life for patients navigating the evolving landscape of hormone-sensitive prostate cancer.
Subject of Research: Hormone-sensitive prostate cancer and personalized treatment intensification strategies
Article Title: Personalized intensification of treatment for hormone-sensitive prostate cancer
Article References:
Cilento, M.A., Butler, L.M., Emmett, L. et al. Personalized intensification of treatment for hormone-sensitive prostate cancer. Nat Rev Clin Oncol (2025). https://doi.org/10.1038/s41571-025-01100-3
Image Credits: AI Generated
