NMCRPC Treatments: Innovations in Prostate Cancer Care

Prostate cancer that is non-metastatic but resistant to hormone therapy presents a treatment challenge. Advances in medical research have led to more effective strategies for managing this stage of the disease, improving patient outcomes and quality of life.

Recent innovations are expanding options beyond conventional approaches, offering targeted therapies that address resistance mechanisms.

Androgen Suppression Protocols

Managing non-metastatic castration-resistant prostate cancer (NMCRPC) requires a nuanced approach to androgen suppression, as traditional androgen deprivation therapy (ADT) alone is insufficient. While ADT remains the foundation, resistance mechanisms necessitate more refined strategies to suppress androgen receptor (AR) signaling effectively. The persistence of intratumoral androgen synthesis and AR amplification underscores the need for suppression protocols that go beyond standard luteinizing hormone-releasing hormone (LHRH) agonists or antagonists.

One approach combines LHRH antagonists, such as degarelix or relugolix, with second-generation AR-targeting agents for deeper testosterone suppression. Unlike LHRH agonists, which initially cause a testosterone surge before suppression, antagonists provide a more immediate reduction, potentially slowing disease progression more effectively. Clinical trials, such as the HERO study, have demonstrated that relugolix achieves sustained testosterone suppression below 20 ng/dL in 96.7% of patients, compared to 88.8% with leuprolide, highlighting its potential advantage.

Intermittent androgen deprivation (IAD) has also been explored as a strategy to delay resistance while minimizing side effects. While more commonly studied in metastatic settings, its role in NMCRPC remains less defined. Some research suggests that periodic withdrawal of ADT may help preserve quality of life without significantly compromising disease control, but this approach requires careful monitoring of prostate-specific antigen (PSA) kinetics and radiographic progression. The optimal timing and patient selection criteria for IAD in NMCRPC continue to be studied.

Next-Generation Receptor Inhibitors

As NMCRPC progresses despite androgen deprivation, next-generation AR inhibitors—enzalutamide, apalutamide, and darolutamide—have become a cornerstone of treatment. These agents block AR signaling by preventing nuclear translocation, inhibiting DNA binding, and reducing transcriptional activity. Unlike first-generation antiandrogens, which can exhibit partial agonist effects, these newer compounds provide more complete inhibition, reducing the likelihood of adaptive resistance.

Enzalutamide, a potent AR inhibitor, has demonstrated significant efficacy. The PROSPER trial showed it extended metastasis-free survival (MFS) by a median of 36.6 months compared to 14.7 months with placebo. However, its central nervous system penetration may increase the risk of seizures and cognitive impairment, particularly in older patients.

Apalutamide, evaluated in the SPARTAN trial, extended MFS to 40.5 months versus 16.2 months with placebo. With slightly lower blood-brain barrier penetration than enzalutamide, it may reduce central nervous system-related side effects, making it a preferred option for patients at higher risk of neurocognitive decline. However, it is associated with a higher incidence of rash and hypothyroidism, necessitating close monitoring.

Darolutamide, assessed in the ARAMIS trial, demonstrated an MFS of 40.4 months compared to 18.4 months with placebo. Its limited blood-brain barrier penetration significantly reduces the risk of seizures and cognitive effects, making it suitable for patients with neurological conditions or concerns about cognitive function. Additionally, darolutamide appears to have a more favorable cardiovascular safety profile, with a lower incidence of hypertension and ischemic events.

Radiotherapy Options

Radiotherapy plays a distinct role in NMCRPC, particularly when local progression threatens quality of life or symptom control. While systemic therapies aim to curb disease spread, targeted radiation addresses resistant tumor cells within the prostate or surrounding tissues. The challenge is maximizing tumor control while minimizing toxicity, leading to advancements in both delivery techniques and fractionation schedules.

Stereotactic body radiotherapy (SBRT) has emerged as a promising modality due to its ability to deliver high-dose radiation with sub-millimeter precision. Unlike conventional external beam radiation therapy (EBRT), which requires multiple weeks of treatment, SBRT condenses therapy into just a few sessions, reducing treatment burden. The HYPO-RT-PC trial demonstrated that ultra-hypofractionated regimens achieve comparable tumor control to conventional fractionation while maintaining similar rates of late toxicity.

Beyond primary prostate-directed therapy, radiotherapy is also being explored for oligoprogressive disease in NMCRPC. When isolated lesions develop resistance to systemic treatment, metastasis-directed therapy (MDT) using SBRT can delay the need for additional systemic escalation. The STOMP trial, which investigated MDT in oligorecurrent prostate cancer, found that targeted radiation could extend androgen deprivation therapy (ADT)-free survival by a median of 21 months. While NMCRPC differs from oligorecurrent disease, these findings suggest precise radiation targeting may prolong disease control in select patients.

Immunotherapy Approaches

Harnessing the immune system to target NMCRPC presents unique challenges, as the disease often has a low tumor mutational burden and an immunosuppressive tumor microenvironment. Unlike cancers that respond well to immune checkpoint blockade, prostate cancer has shown limited sensitivity to conventional immunotherapies, necessitating alternative strategies to enhance immune recognition.

Sipuleucel-T, an autologous dendritic cell vaccine, remains the most extensively studied immunotherapy for prostate cancer. By priming antigen-presenting cells with prostatic acid phosphatase (PAP) fused to granulocyte-macrophage colony-stimulating factor (GM-CSF), this therapy stimulates a targeted immune response. Clinical trials have shown that sipuleucel-T extends overall survival by a median of 4.1 months in metastatic settings, raising interest in its potential for NMCRPC. However, logistical challenges, such as the need for leukapheresis and individualized manufacturing, have limited widespread adoption.

To overcome tumor immune evasion, novel combination approaches are being explored. Therapeutic cancer vaccines, such as PROSTVAC, aim to amplify immune activation by delivering engineered viral vectors expressing PSA and costimulatory molecules. While initial trials showed promise, subsequent phase III studies failed to demonstrate a survival benefit, underscoring the complexity of immune modulation in prostate cancer. Researchers are now investigating whether combining vaccines with immune checkpoint inhibitors, such as anti-PD-1 or anti-CTLA-4 agents, can enhance efficacy by reversing T-cell exhaustion.