What’s New in 2025 for Metastatic Prostate Cancer?

Established First-Line Treatments for Metastatic Prostate Cancer

Androgen Deprivation and Androgen Receptor Pathway Inhibitors (ARPIs)

A key first-line approach for metastatic prostate cancer, particularly in the castration-sensitive setting (mCSPC), involves androgen deprivation therapy (ADT) combined with ARPIs. Recent approvals have broadened the available ARPI options:

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

Chemotherapy Integration

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

Bone Health Management

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

Use of Xtandi (Enzalutamide) in Metastatic Prostate Cancer

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

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

Ongoing clinical trials are investigating combinations like enzalutamide with EPI-7386 to overcome resistance (UroToday).

Although studies are exploring 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 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 minimize exposure to healthy tissues (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 longer radiographic progression-free survival (11.6 months with Pluvicto vs. 5.6 months with ARPI switch alone).
  • The VISION trial showed increased 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:Typical side effects include fatigue, dry mouth, nausea, anemia, and bone marrow suppression. Close monitoring with blood tests is advised to manage hematologic and renal effects. Symptom management can help reduce side effects (OncoDaily).
• Administration:Administered intravenously every 6 weeks for up to 6 cycles or until disease progression or unacceptable toxicity. Treatment must be given at specialized centers compliant with radiation safety standards (OncoDaily).
• Research on Combination Strategies:Early studies presented at the 2024 ESMO Congress have examined combining Lu-177 PSMA therapy with immune-modulating agents such as pembrolizumab and enzalutamide, though these remain experimental.

Additional Therapeutics and Investigational Agents

• EPI-7386 combined with enzalutamide is under clinical assessment 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 explore optimal sequencing and combination strategies.

Managing the Primary Tumor in Metastatic Disease

In metastatic prostate cancer, local control of the primary tumor might provide benefits:

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

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

Neoadjuvant Enzalutamide Prior to Prostatectomy

As of 2025, limited evidence and no established guidelines exist regarding using neoadjuvant enzalutamide before prostatectomy in metastatic prostate cancer. This remains an area for clinical research.

Imaging and Biomarkers Guiding Treatment

• PSMA PET imaging is increasingly utilized for detailed detection of metastatic lesions, aiding selection for PSMA-targeted therapies such as Pluvicto.
• Genetic testing for mutations in DNA repair genes (e.g., BRCA1/2) guides the use of PARP inhibitors.

These diagnostic tools support personalized treatment plans based on individual patient factors (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 discuss coverage and assistance options with their healthcare providers and insurers.
• Bone-targeted drugs like denosumab and bisphosphonates are usually accessible and insured.

Patients are encouraged to consult their oncology team to discuss treatment choices, including financial considerations.

Conclusion

In 2025, treatment options for metastatic prostate cancer in the United States include established therapies—like ADT combined with ARPIs such as Xtandi—and new targeted radioligand therapy like Pluvicto (Lu-177 PSMA-617). FDA approval of Pluvicto for earlier treatment lines adds an option supported by clinical trial data demonstrating benefits in progression-free and overall survival. Advances in imaging, biomarker testing, and combination therapies continue to guide personalized care. Although investigational approaches including pembrolizumab combinations remain under evaluation, current treatments provide a broad range of options tailored to individual patient needs.

Sources

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

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