Evolving Treatment Strategies Are Reshaping mCRPC Care

The treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) continues to shift as new therapies, earlier intervention strategies and improved molecular understanding reshape patient care, according to Dr. Cora N. Sternberg.

She shared these insights at the 19th Annual New York GU Cancers Congress®, highlighting that clinicians are no longer managing the same disease seen a decade ago. Instead, patients are now entering the mCRPC stage after receiving multiple lines of intensified therapy earlier in their disease course, including androgen receptor pathway inhibitors (ARPIs), PARP inhibitors and radioligand therapy (RLT).

This earlier exposure to potent treatments has improved disease control; however, it has also introduced new challenges. Tumors are adapting more quickly, leading to complex resistance patterns and changes in tumor biology. As a result, optimizing treatment sequencing and selecting the right therapy at the right time has become increasingly important for improving outcomes.

Sternberg is clinical director of the Englander Institute for Precision Medicine, as well as a professor of medicine at Weill Cornell Medicine, Sandra and Edward Meyer Cancer Center, New York-Presbyterian, New York.

Understanding resistance and optimizing sequencing

One of the central challenges in mCRPC management is treatment resistance. AR-driven resistance remains a key mechanism, occurring in approximately 30% to 50% of cases. This resistance can limit the effectiveness of sequential AR-targeted therapies, meaning that switching from one ARPI to another often provides minimal benefit.

Clinical trial data reinforce this point. Studies such as CARD demonstrated improved outcomes with chemotherapy compared with a second ARPI in patients previously treated with AR-targeted therapy. These findings emphasize the importance of diversifying treatment approaches rather than relying on repeated targeting of the same pathway.

Additionally, emerging evidence suggests that some tumors evolve into AR-independent disease. This subtype is often associated with aggressive features, including visceral metastases and lower prostate-specific antigen production. Identifying these changes early may help guide treatment decisions, including the potential use of platinum-based chemotherapy.

The critical role of genomic testing in mCRPC

Genomic testing has become a cornerstone of mCRPC care. Both germline and somatic testing are recommended for all patients, as each provides complementary information that can guide treatment selection.

Approximately 10% to 12% of patients carry inherited mutations, most commonly in BRCA2, which are associated with strong responses to PARP inhibitors. Somatic testing can identify additional actionable mutations that may not be detected through germline analysis alone.

These findings have direct treatment implications. Patients with BRCA1 or BRCA2 mutations often derive the greatest benefit from PARP inhibitors such as olaparib or rucaparib. Other alterations, including ATM or CDK12 mutations, may confer variable or limited benefit, highlighting the importance of personalized treatment planning.

In addition, a small subset of patients with microsatellite instability–high or mismatch repair–deficient tumors may benefit from immunotherapy, further expanding treatment options.

Study methods and patient population considerations

The findings summarized in this discussion are based on data from multiple clinical trials and long-term studies evaluating therapies across different stages of prostate cancer. These include trials assessing ARPIs, PARP inhibitors, chemotherapy and radioligand therapy in both hormone-sensitive and castration-resistant settings.

Patient populations in these studies vary widely, reflecting the diversity of mCRPC. Key factors influencing treatment decisions include prior therapies, disease aggressiveness, sites of metastases and genomic profile. For example, patients with bone-only disease may follow a different treatment path compared with those with visceral metastases.

Importantly, the evolving treatment paradigm means that many patients now reach the mCRPC stage with more heavily pretreated disease, which may impact both treatment tolerance and response.

Radioligand therapy and earlier intervention approaches

Radioligand therapy targeting prostate-specific membrane antigen (PSMA) is emerging as a transformative option in mCRPC. Initially used in later lines of therapy, RLT is now being evaluated and increasingly used earlier in the treatment sequence.

Clinical trials have demonstrated meaningful improvements in progression-free survival and overall survival with agents such as lutetium-177 PSMA-617. These therapies deliver targeted radiation directly to cancer cells, offering a novel mechanism of action that complements existing treatments.

The movement of RLT into earlier treatment settings reflects a broader trend in prostate cancer care: using the most effective therapies sooner to improve long-term outcomes. However, this approach may also contribute to cumulative toxicity and increased biological complexity over time.

Additional findings and future directions

The growing use of combination therapies, including ARPIs paired with PARP inhibitors, has shown promising improvements in progression-free survival, particularly in patients with homologous recombination repair mutations. However, questions remain regarding long-term survival benefits and the potential for increased toxicity.

Beyond currently approved treatments, several novel approaches are under investigation. These include antibody-drug conjugates, bispecific T-cell engagers, and targeted therapies aimed at specific molecular alterations. Early-phase studies suggest response rates ranging from 30% to 50% in selected patient populations.

Despite these advances, significant challenges persist. Clinical trial enrollment remains low, and disparities in access to advanced diagnostics and treatments continue to affect outcomes. For example, prostate cancer mortality is approximately twice as high in Black men, who remain underrepresented in clinical trials.

Looking ahead, the future of mCRPC care will depend on new therapies and improving how existing treatments are used. This includes earlier molecular profiling, dynamic monitoring of disease evolution and ensuring equitable access to care.

References

1. “Prostate Cancer: CRPC Today and Tomorrow–Overcoming Barriers and Advancing Therapeutic Frontiers,” by Dr. Cora N. Sternberg. Presented at: 19th Annual New York GU Cancers Congress®.

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