Ask AI
Back Back
Emerging Strategies in mCRPC
Emerging Therapeutic Strategies and Biomarker-Driven Care in mCRPC

Released: May 12, 2026

Alicia K. Morgans
Alicia K. Morgans, MD, MPH, FASCO
Charles J. Ryan
Charles J. Ryan, MD
Activity Information

Activity

Progress
1
Course Completed
Continue
Key Takeaways
  • Combination therapy with PARP inhibitors and ARPI is associated with hematologic adverse events, such as anemia, which require careful monitoring and management.
  • Radioligand therapy with 177Lu-PSMA-617 is a standard of care in patients with mCRPC and PSMA-positive disease who had previously received an ARPI.
  • Real-world data indicate that fewer than 60% of patients with mCRPC undergo germline and somatic testing, which are essential components of optimal patient care.

Metastatic castration-resistant prostate cancer (mCRPC) represents a biologically complex and heterogeneous disease that remains incurable despite an expanding array of therapeutic options. The transition to castration resistance reflects adaptive tumor biology, including persistent androgen receptor (AR) signaling, defects in DNA repair pathways, and activation of alternative growth and survival mechanisms. Understanding these pathways has been critical to the development of novel therapeutic strategies. In this commentary, Alicia K. Morgans, MD, MPH, FASCO, and Charles J. Ryan, MD, review the rapidly evolving treatment landscape of mCRPC, highlighting the biological rationale, clinical evidence, and importance of biomarker-driven strategies and equitable access in advancing precision oncology.

Biological Rationale and Mechanisms of Novel Therapies in mCRPC

Alicia K. Morgans, MD, MPH, FASCO:
One of the most important advances in precision oncology for mCRPC is the use of PARP inhibitors, which exploit deficiencies in homologous recombination repair (HRR). The PARP enzyme repairs single-strand DNA breaks, and inhibition of PARP leads to the accumulation of DNA damage that results in double-strand breaks. In tumor cells harboring BRCA1 or BRCA2 mutations, these double-strand breaks cannot be effectively repaired, leading to cell death through a process known as synthetic lethality. This biologic vulnerability provides a strong rationale for targeting HRR-deficient tumors with PARP inhibitors.

There is also strong rationale for combining a PARP inhibitor with an androgen receptor pathway inhibitor (ARPI). AR signaling regulates DNA repair pathways, and inhibition of AR signaling may induce a state of relative HRR deficiency, thereby increasing tumor sensitivity to PARP inhibition. Conversely, PARP inhibition may suppress AR-driven transcriptional programs and resistance mechanisms. This bidirectional interaction creates a synergistic therapeutic opportunity that has been validated in multiple clinical trials.

Radioligand therapy represents another major innovation in mCRPC treatment. These agents, such as lutetium-177–labeled PSMA-617 (177Lu-PSMA-617), deliver targeted radiation directly to tumor cells expressing prostate-specific membrane antigen (PSMA). The physical properties of the radioactive payload influence therapeutic effect, with β emitters providing moderate tissue penetration and α emitters delivering highly potent, localized energy with minimal spread. This approach allows for selective tumor targeting while minimizing damage to surrounding normal tissues.

Beyond these established mechanisms, several emerging pathways are being actively investigated. The PI3K/AKT/mTOR signaling pathway is frequently dysregulated in prostate cancer, particularly in the setting of PTEN loss, and inhibitors such as capivasertib are designed to counteract this activation. Epigenetic modulation through EZH2 inhibition represents another strategy, as it has the potential to reprogram tumor cells and enhance sensitivity to AR-directed therapies. Additional approaches include upstream steroidogenesis inhibition with CYP11A1 inhibitors and proteolysis-targeting chimeras (PROTACs) that degrade the AR protein directly, thereby overcoming resistance mechanisms associated with AR overexpression or mutation.

Evaluating Clinical Data for Novel Therapeutic Strategies

Charles J. Ryan, MD:
Recent phase III clinical trials have significantly advanced the treatment landscape for mCRPC, particularly in the context of combination therapies and biomarker-driven approaches. Trials evaluating PARP inhibitor combinations have demonstrated meaningful improvements in clinical outcomes. For example, the PROpel trial showed that the addition of olaparib to abiraterone improved radiographic progression-free survival (rPFS) even in an unselected population, and TALAPRO-2 demonstrated improvements in both rPFS and overall survival with the addition of talazoparib to enzalutamide. The MAGNITUDE trial further clarified that the greatest benefit from PARP inhibition occurs in patients with HRR mutations, particularly those with BRCA1 or BRCA2 alterations. These combination strategies are associated with increased toxicity, most notably hematologic adverse events such as anemia, which require careful monitoring and management. Nevertheless, the magnitude of benefit observed in appropriately selected patients supports their integration into clinical practice.

Radioligand therapy has also demonstrated substantial clinical benefit. The phase III VISION trial demonstrated improvements in both overall survival and rPFS when 177Lu-PSMA-617 was added to standard of care in patients with mCRPC who had previously received an ARPI and taxane chemotherapy. More recent data from the phase III PSMAfore trial have expanded the use of this therapy to earlier in the disease course, specifically in patients who have progressed on an ARPI but have not yet received taxane chemotherapy. Additional studies such as ECLIPSE suggest that this therapeutic approach may have broader applicability across different radioligand constructs. Radium-223, an α-emitting radiopharmaceutical, has also experienced renewed interest, particularly in combination strategies. The phase III PEACE-3 trial demonstrated improved rPFS when radium-223 was added to enzalutamide, provided that patients received appropriate bone-protective agents to mitigate fracture risk. This highlights the importance of supportive care measures in optimizing treatment outcomes.

AKT inhibitors such as capivasertib have shown promising results in PTEN-deficient patient populations, and EZH2 inhibitors like mevrometostat have demonstrated encouraging early-phase activity in combination with AR-directed therapy. CYP11A1 inhibitors offer a more comprehensive suppression of androgen synthesis compared with existing agents, and PROTAC-based therapies represent a novel approach to targeting the AR. Together, these data underscore the rapid evolution of the mCRPC treatment landscape and the importance of ongoing clinical investigations.

Identifying Patients for Clinical Trials and Precision Therapy

Alicia K. Morgans, MD, MPH, FASCO:
Effective implementation of novel therapies in mCRPC requires careful patient selection, guided by both clinical and molecular characteristics. Germline and somatic testing are essential components of this process, as they enable identification of actionable alterations such as HRR mutations. However, real-world data indicate that fewer than 60% of patients with mCRPC undergo such testing, and even among those who are identified as eligible for targeted therapies, substantial proportions do not receive them. This gap highlights a critical area for improvement in clinical practice.

Matching patients to appropriate therapies requires integration of biomarker data with clinical context. Patients with BRCA1 or BRCA2 mutations are prime candidates for PARP inhibitor therapy, whereas those with PSMA-positive disease may benefit from radioligand therapy. Other molecular features, such as PTEN loss or AR mutations, may guide enrollment in clinical trials investigating targeted agents. In addition, patients with neuroendocrine differentiation may be candidates for therapies targeting specific antigens such as DLL3.

Clinical trial enrollment should be considered at all stages of mCRPC management, rather than being reserved for late-line therapy. Trials are evaluating novel agents in earlier disease settings, including pretaxane populations, with the goal of improving outcomes and potentially delaying the need for chemotherapy. This shift underscores the importance of maintaining awareness of available trials and proactively discussing these options with patients.

Advancing Equity and Access in mCRPC Clinical Trials

Charles J. Ryan, MD:
Addressing disparities in prostate cancer outcomes, particularly among Black men and other underserved populations, is a priority. Ensuring equitable access to advanced diagnostics and novel therapies is essential to improving outcomes. Barriers to equitable care include underuse of genomic testing, limited awareness of clinical trials, logistical challenges such as transportation and financial burden, and historical mistrust of the healthcare system. Overcoming these barriers requires a multifaceted approach that includes standardizing testing practices, integrating clinical trial discussions into routine care, and expanding access through community-based partnerships and decentralized trial models.

Efforts to improve equity must also emphasize culturally competent communication and patient education, ensuring that all patients have the opportunity to make informed decisions about their care. As the therapeutic landscape continues to evolve, it is imperative that advances in treatment are accessible to all patients, regardless of socioeconomic or demographic factors.

Conclusions

Alicia K. Morgans, MD, MPH, FASCO:
The management of mCRPC is undergoing a period of rapid transformation, driven by advances in our understanding of tumor biology and the development of novel therapeutic strategies. PARP inhibitors, radioligand therapies, and emerging targeted agents offer new opportunities for personalized treatment, particularly when guided by biomarker-driven approaches. However, the successful integration of these therapies into clinical practice depends on widespread adoption of genomic testing, thoughtful patient selection, and proactive clinical trial enrollment. Equally important is the commitment to ensuring equitable access to these innovations, so that all patients can benefit from the progress being made in the field.

Your Thoughts
How are you currently integrating biomarker testing and emerging targeted therapies into your treatment strategy for patients with mCRPC?

Continue

Poll

1.

How often are you testing your patients with prostate cancer for HRR mutations?

Submit