William K. Kelly, DO, professor of medical oncology and urology, Thomas Jefferson University, and director of the Division of the Solid Tumor Oncology at Sidney Kimmel Cancer Center, discusses results from a phase 1b dose-finding study (NCT03076203) evaluating the combination of radium-223 dichloride (Xofigo) plus niraparib (Zejula) in patients with metastatic castration-resistant prostate cancer (mCRPC).

The primary objective of the trial was to determine the optimal dose of niraparib when combined with radium-223 in patients with mCRPC who have and have not received prior chemotherapy. A total of 30 patients were enrolled on the trial; 15 patients were assigned to the chemotherapy-exposed arm, while the remaining 15 patients were assigned to the chemotherapy-naïve arm. Overall, patients on both arms had an excellent ECOG performance status, says Kelly.

Results showed that the maximum-tolerated dose (MTD) of niraparib was 100 mg daily in the chemotherapy-exposed arm and 200 mg daily in the chemotherapy-naïve arm, says Kelly.

Interestingly, the most clinical activity with the approach was reported in in the chemotherapy-naïve arm, adds Kelly. When looking at the 200-mg dose level in a group of 7 patients who had not received prior chemotherapy, 1 patient had a ≥50% decline in prostate-specific antigen (PSA) at 12 weeks and 5 patients experienced a ≥30% decline in alkaline phosphatase (ALP). Furthermore, 43% of patients on the chemotherapy-naïve arm achieved a ≥50% reduction in ALP. Overall, all 7 patients on this arm experienced a decline in either ALP or PSA, suggesting clinical activity with this approach, concludes Kelly.

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William K. Kelly, DO, discusses results from a phase 1b dose-finding study (NCT03076203) evaluating the combination of radium-223 dichloride (Xofigo) plus niraparib (Zejula) in patients with metastatic castration-resistant prostate cancer.
 


Dr. Kelly on Radium-223 Dichloride and Niraparib in Patients With mCRPC

William Kevin Kelly, DO, professor of medical oncology and urology, Thomas Jefferson University, and director of the Division of the Solid Tumor Oncology at Sidney Kimmel Cancer Center, discusses the rationale for a phase 1b dose-finding study (NCT03076203) evaluating the combination radium-223 dichloride (Xofigo) and niraparib (Zejula) in patients with metastatic castration-resistant prostate cancer (mCRPC).

Studies suggest that PARP1 and PARP2 are key regulators in the androgen receptor signaling pathway, says Kelly. Moreover, the pathway plays a critical role in the transition to advanced CRPC.

Previous research has established the activity of PARP inhibitors in mCRPC and, in some cases, has shown a survival improvement, says Kelly. For example, niraparib demonstrated favorable single-agent activity and safety for patients with mCRPC.

Initial findings from a phase 1b dose-escalation trial presented during the 2020 ASCO Virtual Scientific Program showed that the combination of niraparib and radium-223 was safe in patients with mCRPC.

William Kevin Kelly, DO, discusses the rationale for a phase 1b dose-finding study evaluating the combination radium-223 dichloride and niraparib in patients with metastatic castration-resistant prostate cancer.

Dr. Kelly on the Rationale for Combining Radium-223 and Niraparib in mCRPC

William Kevin Kelly, DO, professor of medical oncology and urology, Thomas Jefferson University, director, Division of the Solid Tumor Oncology, Sidney Kimmel Cancer Center, discusses the evolution of local control in locally advanced prostate cancer.

Physicians are starting to rethink their approach in locally advanced prostate cancer. Patients with locally advanced disease can derive a benefit from local control of the tumor. This hasn’t been the predominant approach in the past, says Kelly, although all other tumor types have maximized its use.

In the past, physicians would shy away from using local control in anyone who had locally advanced disease. Now, there’s a shift toward its use in these patients and even in those with micrometastatic disease. Surgery is now used because it gives optimal local control. Multimodality approaches are also becoming increasingly important in treatment. Physicians are now encouraging the use of multidisciplinary approaches. Prostate cancer is no longer one disease, but many diseases that require the use of these approaches, states Kelly.

Dr. Kelly on the Importance of Local Control in Locally Advanced Prostate Cancer

William Kevin Kelly, DO, professor of medical oncology and urology, Thomas Jefferson University, discusses the possibility of preselecting which castration-resistant prostate cancer (CRPC) patients will be sensitive to chemotherapy or hormone therapy.

Kelly says there are a number of small trials that are looking at androgen levels by using sensitive assays and spectroscopy to determine if there are any residual androgens. Researchers are also looking at the cellular level, to see if the androgen receptor pathway is active by looking at the retinoblastoma gene, which can determine if patients will be sensitive to chemotherapy or other agents.

These tools can be integrated into clinical trials, Kelly says.

William Kevin Kelly, DO

Articles

Dr. Kelly on Radium-223 Dichloride and Niraparib in Patients With mCRPC

Dr. Kelly on the Rationale for Combining Radium-223 and Niraparib in mCRPC

Dr. Kelly on the Importance of Local Control in Locally Advanced Prostate Cancer

Dr. Kelly on Selecting Therapy for Patients with CRPC