What’s New in 2025 for Metastatic Prostate Cancer? Breakthroughs That Could Change Your Treatment Options

Established First-Line Treatments for Metastatic Prostate Cancer

Androgen Deprivation and Androgen Receptor Pathway Inhibitors (ARPIs)

A primary first-line treatment for metastatic prostate cancer, especially in the castration-sensitive setting (mCSPC), involves androgen deprivation therapy (ADT) combined with ARPIs. Recent approvals have expanded the available ARPIs:

• Enzalutamide (Xtandi) is approved for metastatic prostate cancer, including both metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC). Clinical studies report benefits such as improved overall survival and patient quality of life. Research continues on combining enzalutamide with additional agents to address treatment resistance (UroToday, Medscape).
• Abiraterone acetate plus prednisone is another ARPI regimen used with ADT as frontline therapy in metastatic prostate cancer.
• Darolutamide, FDA-approved in June 2025 (used with ADT), has shown radiologic progression-free survival benefits with a side effect profile including fatigue, based on clinical trial data (Medscape).

Chemotherapy Integration

• Docetaxel chemotherapy is an option for certain patients, especially those who are fit and have high-volume disease or limited response to hormonal therapies. It can be used upfront with ADT or after disease progression (UroToday).
• Cabazitaxel may be considered for mCRPC patients progressing after docetaxel.

Bone Health Management

• Bone-protective agents such as bisphosphonates or denosumab are often used to reduce fracture risk associated with bone metastases and ADT.

Use of Xtandi (Enzalutamide) in Metastatic Prostate Cancer

Enzalutamide inhibits androgen receptor activation, which can slow prostate cancer growth. It is approved for:

• First-line therapy in metastatic castration-sensitive and castration-resistant prostate cancer.
• Use alone or combined with ADT in approved indications.

Ongoing clinical trials are evaluating combinations such as enzalutamide with EPI-7386, aiming to address treatment resistance (UroToday).

While research is exploring the use of pembrolizumab (an immune checkpoint inhibitor) combined with enzalutamide, this combination is not an approved or standard treatment for prostate cancer as of 2025.

Emerging and New Treatments for Metastatic Prostate Cancer

Pluvicto (Lutetium Lu 177 PSMA-617) Radioligand Therapy

Pluvicto is a targeted radioligand therapy approved by the FDA in March 2025 for use in certain patients with metastatic castration-resistant prostate cancer who have progressed after androgen receptor pathway inhibitors but before chemotherapy.

• Mechanism: Pluvicto delivers targeted beta radiation to prostate-specific membrane antigen (PSMA) expressing prostate cancer cells, aiming to limit exposure to healthy tissue (OncoDaily).
• Indications:
  • Initially approved for mCRPC patients after ARPI and chemotherapy.
  • Expanded in 2025 to patients progressing after one ARPI but not yet treated with chemotherapy.
• Clinical Trial Data:
  • The PSMAfore phase 3 trial reported increased radiographic progression-free survival (11.6 months with Pluvicto vs. 5.6 months with ARPI switch alone).
  • The VISION trial noted longer overall survival (15.3 months vs. 11.3 months) and higher prostate-specific antigen (PSA) response rates in patients with more advanced disease.
• Safety Considerations:Common side effects include fatigue, dry mouth, nausea, anemia, and bone marrow suppression. Close monitoring via blood tests is recommended for managing hematologic and renal effects. Symptom management strategies can help mitigate side effects (OncoDaily).
• Administration:Administered intravenously every 6 weeks for up to 6 cycles or until disease progression or toxicity. Treatment requires administration at specialized centers compliant with radiation safety protocols (OncoDaily).
• Research on Combination Strategies:Preliminary studies presented at the 2024 ESMO Congress have investigated combining Lu-177 PSMA therapy with immune-modulating agents, such as pembrolizumab and enzalutamide, but these remain investigational.

Additional Therapeutics and Investigational Agents

• EPI-7386 combined with enzalutamide is under clinical evaluation for its potential to overcome resistance by targeting different androgen receptor domains (UroToday).
• PARP inhibitors (e.g., olaparib) are approved for mCRPC patients with specific genetic mutations (e.g., BRCA1/2, ATM).

Ongoing clinical trials continue to investigate optimal sequencing and combination approaches.

Managing the Primary Tumor in Metastatic Disease

In metastatic prostate cancer, local control of the primary tumor may offer benefits:

• External beam radiation therapy (EBRT) combined with ADT is often used to manage locally advanced tumors and may improve progression-free survival.
• Brachytherapy might augment EBRT in selected cases.

Treatment decisions are individualized based on disease characteristics and patient risk factors (Medscape).

Neoadjuvant Enzalutamide Prior to Prostatectomy

As of 2025, there is limited evidence and no established recommendations regarding the use of neoadjuvant enzalutamide before prostatectomy in metastatic prostate cancer. This remains an area of clinical research.

Imaging and Biomarkers Guiding Treatment

• PSMA PET imaging is increasingly employed for detailed detection of metastatic lesions, supporting selection for PSMA-targeted therapies like Pluvicto.
• Genetic testing for mutations in DNA repair genes (e.g., BRCA1/2) helps guide the use of PARP inhibitors.

These diagnostic tools support tailored treatment plans based on individual patient characteristics (Medscape).

Cost and Accessibility Considerations

• Oral agents such as enzalutamide and abiraterone are commonly prescribed and generally covered by insurance within the United States.
• Pluvicto is administered at specialized centers with nuclear medicine expertise; its costs may be higher, and patients should consult with their healthcare providers and insurance representatives about coverage and assistance options.
• Bone-targeted agents like denosumab and bisphosphonates are typically accessible and covered by insurance.

Patients are encouraged to discuss treatment options, including financial aspects, with their oncology care team.

In 2025, treatment options for metastatic prostate cancer in the United States include established therapies—such as ADT combined with ARPIs like Xtandi—and new targeted radioligand therapy like Pluvicto (Lu-177 PSMA-617). FDA approval of Pluvicto for earlier treatment lines provides an additional option with clinical trial evidence supporting benefits in progression-free and overall survival. Advances in imaging, biomarker testing, and combination strategies continue to inform personalized care. While investigational approaches including pembrolizumab combinations remain under study, current therapies offer a range of options based on individual patient factors.

Sources

• UroToday - mCRPC Treatment
• Medscape - Metastatic and Advanced Prostate Cancer
• OncoDaily - Pluvicto (177Lu-PSMA-617)

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