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“This is a moving target, [especially when] patients move from castration sensitive to castration resistant. They have already experienced a lot of treatment.”

Jue Wang, MD, a professor in the Department of Internal Medicine at UT Southwestern Medical Center, discussed the evolving challenges in the management of castration-resistant prostate cancer (CRPC). He emphasized that as patients progress from castration-sensitive disease to CRPC, prior therapies both suppress tumor growth and drive resistance mechanisms, making CRPC a “moving target.”

Historically, treatment has been guided by sequencing strategies, whereby clinicians moved stepwise through available agents. However, with the expansion of life-prolonging therapies—including androgen receptor pathway inhibitors, chemotherapy, PARP inhibitors, radioligand therapy, and immunotherapy—treatment selection has become increasingly complex, Wang said. He noted that cancer care delivery in 2025 can no longer be reduced to replicating clinical trial protocols in a rigid order. Instead, the application of evidence in practice requires careful reinterpretation and reinvention to optimize real-world outcomes.

According to Wang, advances in molecular testing and imaging over the past decade have enabled the development of precise, patient-centered algorithms, rather than a one-size-fits-all approach. For example, molecular profiling can identify patients with DNA repair deficiencies who may benefit from PARP inhibitors, while novel imaging modalities provide improved staging and therapeutic guidance. These tools support the design of individualized strategies that go beyond sequencing to integrate clinical, biologic, and patient-specific factors, he said.

Wang stressed that having a broad menu of therapeutic options does not automatically translate to better patient outcomes. Rather, the effectiveness of treatment depends on aligning therapies with disease biology, treatment history, performance status, and patient preferences. He cautioned against delaying use of active agents until patients are too ill to benefit, underscoring the importance of timely integration of therapies within a precision medicine framework.

Ultimately, Wang concluded that the future of CRPC management lies in combining real-world lessons with precision oncology. While randomized clinical trials establish the foundation of evidence, clinical practice requires flexibility, adaptation, and patient-centered decision-making. The challenge for oncologists is to move beyond rigid sequencing and instead deliver individualized strategies that maximize the benefit of available therapies in this heterogeneous and evolving disease.

Videos

Jue Wang, MD, discusses the evolving challenges in the management of castration-resistant prostate cancer. 

Dr Wang on Evolving Challenges in the Management of CRPC

Dr Wang on Reducing Treatment Discontinuation in Older Patients With mCRPCDr Wang on Reducing Treatment Discontinuation in Older Patients With mCRPC

Dr Wang on Reducing Treatment Discontinuation in Older Patients With mCRPC

Jue Wang, MD, professor in the Department of Internal Medicine and member of the Division of Hematology and Oncology at the University of Texas Southwestern Medical Center, outlined key factors contributing to treatment drop-off in older patients with metastatic castration-resistant prostate cancer (mCRPC), as well as strategies to address this challenge and enhance real-world outcomes.

Wang began by noting that mCRPC primarily affects older adults, requiring management of both advanced malignancy and age-associated comorbidities. The gap between first- and second-line therapy is driven by several factors, he stated. Disease progression is a key contributor, particularly when subsequent treatments have similar mechanisms of action, which can result in cross-resistance and diminished efficacy, Wang shared. Decline in performance status is also common; many patients have undergone prolonged androgen deprivation therapy (ADT) and treatment intensification. Androgen signaling inhibitors maximally suppress testosterone, which can contribute to frailty, sarcopenia, and reduced functional reserve, making it more difficult for patients to tolerate additional therapy as they advance through lines of treatment.

To improve outcomes, care must extend beyond pharmacologic interventions to include a holistic, patient-centered approach, Wang emphasized. This requires integrating an understanding of disease biology, tumor heterogeneity, and resistance mechanisms with proactive supportive care. Anticipating the physical toll of treatment and implementing measures to preserve functional capacity are critical. Interventions may include early involvement of physical therapy, nutritional optimization, symptom management, and psychosocial support, he outlined.

Shared decision-making is also essential, Wang continued. Patients should be empowered with clear information on treatment benefits, risks, and trade-offs, enabling informed choices aligned with their values and goals. Wang concluded by highlighting the importance of multidisciplinary care, noting that at UT Southwestern, advanced nurse practitioners and physician assistants play a central role in treatment planning, toxicity monitoring, and survivorship navigation.

Jue Wang, MD, discusses the challenge of treatment discontinuation in older patients with metastatic castration-resistant prostate cancer.

Jue Wang, MD, professor, Department of Internal Medicine, member, Division of Hematology and Oncology, UT Southwestern Medical Center, discusses how to approach testing for molecular alterations in patients with relapsed or refractory urothelial carcinoma. 

Urothelial cancer is characterized by a high prevalence of genetic mutations; however, progress continues to unfold in the ongoing exploration of these genetic alterations within the framework of molecular and precision medicine, Wang begins. Importantly, agents targeting 

 mutations have received regulatory approval, he explains, adding that tissue testing remains the cornerstone of accurate diagnosis and tailored treatment strategies. Wang emphasizes the importance of early testing and preparedness for the incorporation of targeted therapies.

Moreover, the emergence of liquid biopsies for the assessment of circulating tumor cells has added another dimension to the ability to identify genetic mutations and guide therapeutic decisions in urothelial cancer, Wang emphasizes. In the context of real-world clinical practice, oncologists have harnessed the wealth of existing tissue samples from previous biopsies, he expands. The dynamic nature of cancer, marked by its evolving processes, presents challenges for molecular testing because of variability in sample preparation, isolated DNA, and complex clinical scenarios, he explains. Oncologists’experience in caring for patients with urothelial carcinoma confirms the gradual evolution of molecular events over time, Wang says. 

Presently, the urothelial cancer treatment paradigm is limited to a singular targeted therapy. However, it is essential to consider that when patients experience rapid deterioration, practicalities inherent in the real-world healthcare system, including the necessity of pre-authorization for specific treatments, must be navigated, Wang continues. Therefore, oncologists continue to advocate for patients, particularly those with refractory disease, to receive the opportunity to undergo molecular profiling as an integral component of their care, he says. This proactive approach can be seamlessly integrated into the standard of care, ensuring a more comprehensive understanding of the disease and facilitating the timely application of personalized therapies, ultimately offering potential avenues for improved patient outcomes, Wang concludes.

Jue Wang, MD, discusses how to approach testing for molecular alterations in patients with relapsed or refractory urothelial carcinoma. 


Dr Wang on Testing for Molecular Alterations in Relapsed/Refractory Urothelial Carcinoma

Jue Wang, MD, professor, Department of Internal Medicine, member, Division of Hematology and Oncology, UT Southwestern Medical Center, discusses the importance of personalized treatment approaches in patients with relapsed or refractory urothelial carcinoma.

Relying on a trial-and-error approach isn't effective when treating patients with refractory urothelial carcinoma, Wang begins. With numerous active treatment options available, several factors, including the uniqueness of each patient's condition, guide treatment choices, he says. Community oncologists must identify individual patient characteristics and understand the dynamic nature of the disease, as refractory cancers often display features that deviate from those addressed with standard treatment plans, Wang notes. Overall, oncologists should acknowledge that, in addition to working with patients, they are grappling with the disease itself, Wang emphasizes.

When selecting treatments for patients with refractory diseases, one must consider aging, potential comorbidities, and lingering adverse effects (AEs) and complications from prior treatments, he expands. For instance, patients with diabetes may experience immediate AEs requiring steroid therapy, he explains. Each cancer treatment has its own AE profile, and AEs may overlap when patients transition between therapies, Wang says. Looking ahead, investigators should shift away from rigidly assigning treatments to specific lines of therapy and instead focus on understanding the disease's biology from the outset, Wang says.

Every cancer treatment decision should integrate patients’ disease burden, disease progression, comorbidities, and AEs, and treatment approaches should be personalized for every patient, he notes. Wang emphasizes the importance of disseminating knowledge and carefully evaluating each patient's specific circumstances to determine their suitability for the best available drugs.

There's no one-size-fits-all guide to addressing complex questions regarding treatment decisions for patients with relapsed or refractory disease, Wang continues. Clinical algorithms fall short in defining every clinical scenario, as real-world patients are often far more intricate than those enrolled in clinical trials, he says. To navigate this complexity, the medical community should collaborate to design clinical trials tailored to real-world challenges and utilize resources such as real-world data to address these nuanced questions, Wang concludes.

Jue Wang, MD, discusses the importance of personalized treatment approaches in patients with relapsed or refractory urothelial carcinoma.


Dr Wang on the Importance of Personalized Treatment Approaches in Urothelial Cancer

Jue Wang, MD, professor, Department of Internal Medicine, member, Division of Hematology and Oncology, UT Southwestern Medical Center, discusses the benefits of switch maintenance therapy and individualized treatment strategies in patients with relapsed or refractory urothelial carcinoma.

The standard of care for patients with relapsed/refractory disease has historically been a one-size-fits-all approach because of the limited armamentarium in urothelial cancer Wang says. However, new strategies, such as switch maintenance therapy, have emerged to help prevent disease relapse and improve outcomes in this population, Wang notes.

In the past, patients with urothelial cancer often received a fixed number of cycles of a given treatment regimen, followed by a break in their treatment, Wang explains. However, with this strategy, many patients eventually experience disease progression, a more rapid pace of disease upon relapse, and increased disease burden, according to Wang. Furthermore, frailty and organ dysfunction resulting from disease progression can make these patients ineligible for second or third lines of therapy, Wang emphasizes.

Switch maintenance therapy involves switching a patient from receiving frontline chemotherapy to receiving maintenance immunotherapy before disease progression, rather than giving them a treatment break, Wang says. This treatment strategy is supported by research showing the complementary relationship between chemotherapy and immunotherapy, Wang explains. Although chemotherapy was once considered immunosuppressive, it is now understood that immunotherapy can enhance patients’ immune systems by immunogenically killing cancer cells and releasing neoantigens, Wang notes. Switch maintenance therapy has demonstrated superior survival improvements compared with traditional urothelial cancer treatment approaches, Wang emphasizes.

In the past, patients who were refractory to 1 chemotherapy agent received a different chemotherapy agent, according to Wang. However, this treatment strategy is ineffective because chemotherapy puts therapeutic pressure on highly mutated cancer cells, Wang says. Since patient characteristics vary, a one-size-fits-all approach does not work for all patients, Wang adds.

Now, patients with chemotherapy-refractory disease have individualized treatment options. These includeing monoclonal antibodies, which deliver chemotherapy directly to the cancer cells, and immunotherapy, which targets cancer-related immunosuppression, Wang explains. In addition, targeting the molecular vulnerability of the cancer is effective in certain patient subgroups, and traditional chemotherapy is still an option, Wang concludes. 

Jue Wang, MD

Articles

Dr Wang on Evolving Challenges in the Management of CRPC

Dr Wang on Reducing Treatment Discontinuation in Older Patients With mCRPC

Dr Wang on Testing for Molecular Alterations in Relapsed/Refractory Urothelial Carcinoma

Dr Wang on the Importance of Personalized Treatment Approaches in Urothelial Cancer

Dr Wang on Switch Maintenance Therapy in Urothelial Carcinoma