Despite recent advances, advanced prostate cancer remains a morbid disease. Next-generation androgen receptor pathway inhibitors, PARP inhibitors, and radiopharmaceuticals, such as Lutetium-177Lu-PSMA-617, have revolutionized the field, and newer therapies attempt to build on these successes. In this article, the authors detail treatments on the horizon for advanced prostate cancer-including novel hormonal therapies and targeted agents, new radiopharmaceuticals, and the introduction of immune therapies.

Patients can develop metastatic castrate resistant prostate cancer either by developing resistance to hormone therapies after presenting with metastatic disease at diagnosis or developing metastatic disease after all curative intent and hormonal therapies in non-metastatic setting.

Prostate cancer progression is largely driven by androgen receptor signaling. While androgen deprivation therapy remains a cornerstone of treatment, it imposes a selective pressure that ultimately leads to the emergence of a castration-resistant phenotype, driven by a range of adaptive molecular mechanisms. In recent years, significant advances have been made in understanding its complex biology, making it a critical focus of ongoing research. The application of multi-omics approaches has played a pivotal role in uncovering the molecular underpinnings of this disease, offering deeper insights into its heterogeneity and resistance mechanisms.

Systemic therapy intensification has improved outcomes for patients with de novo metastatic prostate cancer. Retrospective studies highlighted the benefits of radiotherapy to the local tumor, prompting prospective evaluation via the HORRAD, STAMPEDE, and PEACE-1 trials. While the HORRAD trial suggested a trend toward improved survival, the STAMPEDE trial demonstrated a statistically significant overall survival benefit in patients with lower-risk or lower-volume disease. The PEACE-1 trial investigated local radiotherapy in the era of intensified systemic therapy. Benefits including improved radiographic progression-free survival, castrate resistance-free survival, and genitourinary side effects make local radiotherapy a valuable therapy for subgroups of patients.

Cytoreductive radical prostatectomy (CRP) involves removing the primary tumor in men with de novo metastatic prostate cancer, particularly those with resectable primary, good response to systemic therapy, and good performance status. Emerging evidence suggests CRP may reduce tumor burden, enhance systemic therapy efficacy, and improve survival in select patients. Robot-assisted approaches are increasingly favored for their lower complication rates. CRP can better prevent local complications than radiotherapy but carries higher risks of incontinence and erectile dysfunction. CRP has been shown to be safe in early trials, and is currently being investigated in larger randomized studies to confirm its potential benefits.

De novo metastatic prostate cancer represents a biologically and clinically distinct subset of metastatic hormone-sensitive prostate cancer characterized by aggressive disease behavior and poor survival outcomes. Although androgen deprivation therapy (ADT) has long been the cornerstone of systemic management, recent advances transformed the treatment paradigm toward intensified combination regimens. The addition of docetaxel or androgen-receptor-pathway inhibitors such as abiraterone, enzalutamide, apalutamide, or darolutamide to ADT has demonstrated significant improvements in survival. More recently, triplet strategies combining ADT, docetaxel, and either abiraterone or darolutamide have produced further survival gains without excess toxicity. Molecular insights have advanced precision-based approaches.

Biochemical recurrence of prostate cancer represents a heterogeneous clinical state ranging from indolent disease to aggressive metastatic progression. Standard definitions include a prostate-specific antigen (PSA) 0.2 ng/mL or greater post-prostatectomy or a rise of 2 ng/mL above nadir following radiation therapy. Risk stratification incorporating PSA doubling time, Gleason grade, surgical pathology, and advanced imaging, particularly prostate-specific membrane antigen (PSMA) PET, guides clinical decision-making by distinguishing local from systemic recurrence. This review highlights definitions, risk stratification, the role of PSMA PET imaging, and management strategies ranging from observation to local salvage, systemic therapy, and emerging metastasis-directed approaches.

Clinical lymph node positive prostate cancer refers to prostate adenocarcinoma with metastasis to regional lymph nodes detected prior to definitive therapy. This is an aggressive cancer with varying presentations and prognosis. Thorough diagnostic imaging is key to establishing this stage of cancer, carefully distinguishing it from distant metastatic disease. The mainstay of therapy is multimodal treatment, typically surgery + radiation + hormone therapy or radiation therapy + hormone therapy. Treatment individualization is important, both surgery and radiation-based strategies can be effective when appropriately combined with androgen deprivation therapy.

High-risk localized prostate cancer (HR-PCa) presents a substantial risk of recurrence and progression despite definitive local treatment. This article evaluates the evolving role of neoadjuvant and adjuvant therapies, including androgen deprivation therapy, second-generation androgen receptor pathway inhibitors, and chemotherapy. While neoadjuvant strategies improve pathologic responses, survival benefits remain unproven. Adjuvant therapy is increasingly individualized, with early salvage radiotherapy favored over routine adjuvant radiotherapy based on recent trial data. Ongoing studies, molecular profiling, and advanced imaging aim to refine patient selection and personalize treatment, balancing oncologic control with quality of life in the management of HR-PCa.

Modern radiotherapy for high-risk prostate cancer offers fewer treatments, selectively higher doses, elective pelvic nodal treatment, and the potential for intensification of androgen-deprivation therapy as well. There are active studies to better intensify or deintensify radiotherapy and androgen deprivation therapy based on novel genomic risk stratification tools.

The role of pelvic lymph node dissection (PLND) at the time of radical prostatectomy for clinically localized prostate cancer has remained controversial. While providing the most accurate staging for prostate cancer, the data regarding the therapeutic benefits of a PLND is inconclusive. In this article, we summarize the different PLND templates as well as the data both for and against performing a PLND. Finally, we outline future directions in selecting patients for PLND, and propose a theory on how pelvic lymph nodes may play a vital role in developing novel immunotherapy regimens.

High-risk prostate cancer (HRPCa) is a heterogeneous disease with variable presentations and outcomes. While radiotherapy with androgen deprivation therapy was historically favored, radical prostatectomy (RP) is now increasingly employed as a primary treatment. Emerging evidence supports RP as an effective option in select patients, potentially avoiding the adverse effects of combined therapy. Advances in imaging and surgical techniques allow for more personalized surgical care in HRPCa, thereby reducing RP morbidity without compromising oncologic control. Ongoing trials are evaluating the role of RP within a multimodal therapy approach and will provide data on the optimal treatment of HRPCa.

This narrative review explores the emerging role of locoregional therapy (LRT) in metastatic prostate cancer, highlighting evidence from randomized trials and observational studies. LRT, including prostate radiotherapy, radical prostatectomy, and ablation, may benefit select patients, particularly those with low-volume or oligometastatic disease. Advanced imaging integration such as prostate-specific membrane antigen positron emission tomography and evolving risk stratification systems supports more tailored approaches. While early outcomes are promising, prospective studies are needed to define LRT's optimal use in modern metastatic prostate cancer management. The treatment paradigm for metastatic prostate cancer continues to evolve with the integration of novel systemic therapy agents.