Daniel J. George, MD, professor of medicine and surgery, and member, Duke Cancer Institute, discusses the changing treatment landscape in prostate cancer.

Within the past decade, hormonal therapy, particularly androgen deprivation therapy, has been the focus of treatment for patients with metastatic prostate cancer. Over the past few years, that landscape has changed, with data showing the clinical benefit of docetaxel, abiraterone acetate (Zytiga), apalutamide (Erleada), and enzalutamide (Xtandi) upfront in the metastatic hormone-sensitive setting.

These findings have opened the door to explore additional cytotoxic approaches with radiopharmaceuticals, such as radium-223 dichloride (Xofigo), docetaxel, and cabazitaxel, or other targeted approaches, such as prostate-specific membrane antigen (PSMA)—directed therapy in the post-androgen receptor and -chemotherapy settings. Some of these approaches could end up being used in the curative setting, which would result in a paradigm shift in the advanced setting, concludes George.

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Daniel J. George, MD, discusses the changing treatment landscape in prostate cancer.

Dr. George on the Changing Treatment Landscape in Prostate Cancer

Daniel J. George, MD, professor of medicine and surgery, member, Duke Cancer Institute, discusses investigational agents downstream of the androgen receptor (AR) in advanced prostate cancer.

There is still a lot of work that needs to be done in order to understand how to pair agents downstream of the AR with other treatments, says George. However, such combinations could obviate the need for a sequential approach, he adds. Several novel mechanisms of action are under investigation, including transcription factors, such as EZH2 and DNA-dependent protein kinase catalytic subunits, agents which could modulate resistance to the AR. In addition, PARP inhibitors are under evaluation in selected patient populations.

Investigators are also evaluating novel ways to target the AR besides just the ligand domain, says George. Additional therapeutic classes under investigation include immunotherapy and PSMA-targeted strategies, such as bispecific antibodies and radiopharmaceuticals.

Daniel J. George, MD, discusses investigational agents downstream of the androgen receptor in advanced prostate cancer.

Dr. George on Investigational Agents Downstream of the Androgen Receptor in Prostate Cancer

Daniel J. George, MD, professor of medicine and surgery, member, Duke Cancer Institute, discusses the use of radium-223 dichloride (Xofigo) in prostate cancer.

Radium-223 operates through a novel mechanism and has shown a reduction in the risk of progression or death of approximately 30% versus placebo in patients with metastatic castrate-resistant prostate cancer. Although the drug has shown a benefit in overall survival in a historically difficult-to-treat patient population, it has not been shown to affect prostate-specific antigen response or imaging response. As such, it has been difficult to employ in practice, says George.

Moreover, data from the phase III ERA-223 trial, which were presented at the 2018 ESMO Congress, pointed to the added complication of risk of fractures. In the trial, chemotherapy-naïve patients with mCRPC received abiraterone acetate (Zytiga), prednisone, and radium-223, or abiraterone and prednisone alone. Patients who received radium-223 had a higher rate of fractures than those who received abiraterone and prednisone alone. This was a new finding, says George, suggesting a potentially toxic synergy between abiraterone, prednisone, and radium-223 in a less heavily pretreated patient population. Now, there is a warning against the use of radium-223 in combination with abiraterone. However, because bone metastases lead to increased risk of mortality, George states that radium-223 can be used as monotherapy to lessen the burden of metastatic disease.

Dr. George on the Use of Radium-223 in Prostate Cancer

Daniel J. George, MD, professor of Medicine and Surgery, member, Duke Cancer Institute, discusses the promise of PARP inhibitors in prostate cancer.

PARP inhibitors hold a lot of promise in patients with homologous recombination deficiency (HRD), particularly those who harbor alterations in 

. Other HRD alterations that may be important include 

, although the data in this space are less clear, says George.

Some of these mutations are seen at the germline level; therefore, screening patients with metastatic disease for these alterations is recommended. More importantly are tests that can detect somatic alterations, adds George. Although these tests are encouraged, they are not always feasible. In addition to tumor biopsies, cell-free DNA may be another way to assess the biology of a patient’s tumor.

PARP inhibitors are likely to have a role in the treatment of patients with HRD, whether as single agents or in combination, says George. The question is whether they will play a role in patients without HRD. Synthetic lethality may be a way of enabling this, either with radiation or immunotherapy. Trials are ongoing and, if positive, may broaden the accessibility of these agents.

Dr. George on Promise of PARP Inhibitors in Prostate Cancer

Daniel J. George, MD, professor of Medicine and Surgery, member, Duke Cancer Institute, discusses next steps for research in renal cell carcinoma (RCC).

In the next 5 years or so, as more emphasis is placed on treating patients in the adjuvant setting, the rate of cure may increase, explains George. Additionally, greater focus has to be dedicated to exploring curative approaches for patients with oligometastatic disease, and to understanding how definitive approaches and immunotherapeutic strategies can be incorporated into that setting. For patients with intermediate- and high-risk disease, achieving a complete response will become the focus of treatment as well as determining the appropriate sequence of therapy that will delay disease progression. These are all important questions that need to be addressed, says George.

In addition, more focus needs to be paid to patients with less common cancers such as nonclear cell cancers. In that setting, physicians need to understand when 

 is the standard for papillary cancers, and if it is, how immunotherapy can be incorporated into treatment. Moreover, what distinguishes nonclear cancers from clear cell cancers besides 

There are other immunologic targets in RCC that should be adopted in the frontline setting as that is where the greatest effects will happen, George concludes.

Dr. George Discusses Next Steps in RCC

Daniel J. George, MD, professor of Medicine and Surgery, member, Duke Cancer Institute, discusses the impact of immunotherapy on TKIs in renal cell carcinoma (RCC).

Immunotherapies are a compliment to the field, says George. For patients with intermediate- and high-risk metastatic disease, combination immunotherapy with nivolumab (Opdivo) and ipilimumab (Yervoy) has been extremely valuable. Unfortunately, most patients who are treated with immunotherapy experience progression. The use of TKIs following immunotherapy has shown success in combating progression, adds George. Commonly used TKIs include pazopanib (Votrient), cabozantinib (Cabometyx), axitinib (Inlyta), lenvatinib (Lenvima), and everolimus (Afinitor).

For patients with good-risk disease, a single-agent, sequential approach is recommended, says George. In this space, immunotherapy has not been shown to be superior to sunitinib (Sutent) monotherapy. As such, VEGF TKIs are still the frontline treatment option in that setting. Though, providers are beginning to see more combinations of immunotherapy with VEGF TKIs emerge. To date, positive results from the JAVELIN Renal 101 study and the KEYNOTE-426 study suggest that there is a role for combining these agents in the frontline setting.

Daniel J. George, MD, professor of medicine and surgery, member, Duke Cancer Institute, discusses the impact of immunotherapy on TKIs in renal cell carcinoma (RCC).

Dr. George on the Impact of Immunotherapy on TKIs in RCC

Daniel J. George, MD, professor of Medicine and Surgery, member, Duke Cancer Institute, discusses the importance of dosing TKIs properly in patients with renal cell carcinoma (RCC).

Although the S-TRAC trial showed the benefit of adjuvant therapy with sunitinib (Sutent) in patients with high-risk stage III disease, there has not been as much of an uptake due to prior negative studies. For example, the ASSURE study looked at sunitinib, sorafenib (Nexavar), and placebo in the adjuvant setting, and demonstrated no difference in disease-free survival (DFS). However, many patients were dose-reduced to as low as 25 mg of sunitinib, says George. More than halfway into the study, the dose protocol was reduced from 50 mg to 37.5 mg, which most likely resulted in decreased efficacy, he adds.

In the PROTECT study, investigators had to change the initial adjuvant dose of pazopanib (Votrient) from 800 mg to 600 mg halfway through due to tolerance. In patients who started at 800 mg, investigators noted a statically significant improvement in DFS similar to what was observed in S-TRAC. However, in the patients who had the dose reduction from the beginning, the benefit was not determined to be statistically significant.

Therefore, dose matters when it comes to the adjuvant setting, says George. The issue is that a higher dose also results in added toxicity. Learning how to balance that is key, he adds. Identifying patients who have an ECOG performance status of 0 following surgery is important in finding that balance, as is counseling patients on tolerability and being proactive with dose interruptions, rather than dose reductions. If this approach is adopted, there are patients who will be able to benefit and tolerate TKIs in the adjuvant setting.

Dr. George on Dosing TKIs in RCC

Daniel J. George, MD, professor of Medicine and Surgery, member, Duke Cancer Institute, discusses sequential therapy in metastatic prostate cancer.

For patients with metastatic hormone-sensitive prostate cancer, physicians are combining docetaxel-based therapies or secondary hormonal therapies, says George. Moving forward, there may be an opportunity to combine both of those agents together, especially in patients with high-volume, extensive-stage disease.

For patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on agents such as abiraterone acetate (Zytiga) or enzalutamide (Xtandi), physicians are faced with selecting the optimal second-line therapy. Prognostic factors and tumor burden are 2 big components that must be considered, says George. Within this population, there are patients with a high tumor burden who are going undetected, and, as a result, are not receiving therapy that is aggressive enough. Mild progression of symptoms is still progression, he adds. Following progression on frontline therapy, the median survival of a patient with mCRPC is 18 months. By being cognizant of these changes, physicians can take a more proactive approach and try to maintain a patient’s performance status at 0 or 1 for as long as possible.

Dr. George on Sequential Therapy in Metastatic Prostate Cancer

Daniel J. George, MD, professor of Medicine and Surgery, member, Duke Cancer Institute, discusses concerns with immune-related adverse events (irAEs) in renal cell carcinoma (RCC).

Anytime immunotherapy is used, there is a risk for side effects that are potentially long lasting, as immunotherapy tends to stay in the body a long time, explains George. When toxicities do present as a result of treatment, they can be slow to resolve. Potential toxicities include rashes, pneumonitis, and colitis. Although rare, they may require a prolonged use of steroids, he explains.

More often than not, treatment is halted until irAEs resolve to grade 1 or less; as such, these events may cause a significant delay in subsequent treatment, says George. However, that does not necessarily equate to a greater likelihood of disease progression. The potential for irAEs has not been a deterrent for the majority of patients, says George, although it does require proactive management to prevent high-grade complications from happening.

Dr. George on Concerns With Immune-Related Adverse Events in RCC

Daniel J. George, MD, professor of Medicine and Surgery, member, Duke Cancer Institute, discusses sequencing in renal cell carcinoma (RCC).

There are many factors to consider when selecting and sequencing therapy, one of which is risk status. Good-risk patients tend to have a manageable tumor burden and live a long time, says George. However, many good-risk, low-volume patients can get by with active surveillance. Intermediate risk comprises the largest risk category of RCC patients at about 60%, explains George. Physicians should take a proactive approach for these patients, as they can be unpredictable. Typically, an immunotherapy-based regimen is a suitable treatment option.

Treatment for patients with poor-risk disease depends on tolerability, states George. Many patients may require palliation, and drugs such as cabozantinib (Cabometyx) can result in very quick responses, which can be helpful. Some patients may have an overwhelming burden of disease, in which case palliation and supportive care take precedence.

Daniel J. George, MD

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