Ra223 plus SABR does not delay progression of oligometastatic HSPC

The addition of radium-223 (Ra223, Xofigo) to stereotactic ablative radiotherapy (SABR) did not delay disease progression for patients with bone-metastatic oligometastatic hormone-sensitive prostate cancer (HSPC), according to data presented at the 2024 American Society for Radiation Oncology Annual Meeting in Washington, DC.¹

In her presentation of the phase 2 RAVENS study (NCT04037358), Ana Kiess, MD, PhD, noted that the ORIOLE (NCT02680587) and STOMP (NCT01558427) trials demonstrated the benefit of treatment with SABR in patients with oligometastatic HSPC.^2,3

Recently, the combination of enzalutamide (Xtandi) plus radium-223 (Ra223, Xofigo) for the treatment of metastatic castration-resistant prostate cancer with bone metastases was found to be both safe and associated with significantly improved radiological progression-free survival.⁴

For the current study, Kiess said she and her co-investigators hypothesized that “the addition of Ra223 to SABR for bone-metastatic oligometastatic hormone-sensitive prostate cancer may delay progression of disease.”

The study was non-blinded and multicenter. Patients were eligible for the study if they had metachronous hormone-sensitive oligometastatic prostate cancer, 3 or fewer lesions by conventional imaging or 5 or fewer lesions by PET (prostate-specific membrane antigen or choline) with at least 1 bone lesion and no visceral lesions, prostate-specific antigen (PSA) doubling time of less than 15 months and PSA level of between 0.5 ng/dL and 50 ng/dL, and no more than 3 years of prior androgen deprivation therapy (ADT) ending more than 6 months prior to the study.

Sixty-four patients were randomly assigned 1:1 to receive either SABR (33 patients) or SABR/Ra223 (31 patients). One patient withdrew prior to treatment. The primary end point was composite PFS, which was “either PSA progression by PCWG2, or conventional radiologic progression or symptomatic progression or ADT initiation,” Kiess said. Secondary end points included ADT-free survival, metastasis-free survival, overall survival, patterns of progression, toxicity and quality of life, and several molecular studies. In the SABR/Ra223 arm, 26 (87%) patients received all 6 planned treatments of Ra223. Median follow-up was 18.7 months.

Ana Kiess, MD, PhD

“The arms were well balanced in terms of the stratification variables as well as grade group and PSA,” said Kiess, associate professor of Radiation Oncology and Molecular Radiation Sciences at Johns Hopkins University, Baltimore, Maryland.

Kiess reported that there was no difference seen with composite PFS between the 2 arms. Median PFS was 11.8 months in the SABR arm vs 10.5 months in the SABR/Ra223 arm (HR, 1.37; 95% CI: 0.78-2.39, P = .27).

“We also did not see a difference in conventional metastasis-free survival or ADT-free survival,” Kiess said.

When discussing why Ra223 was not effective, Kiess said the investigators believed it was due to Ra223’s mechanism of action, “with radium-223 most likely to be effective in the setting of bone turnover with bone lesions not eradicated by SABR.”

Regarding safety, 7 patients had grade 3 toxicities, which were mostly lymphopenia in patients in the SABR/Ra223.

“In conclusion, the addition of radium-223 to SABR metastasis-directed therapy in low-volume bone-metastatic hormone-sensitive prostate cancer does not delay progression of disease in the RAVENS study. Due to the mechanism of action, radium-223 is likely most effective in higher volume disease with bone lesions that are not eradicated by SABR, but other radiopharmaceuticals that are molecularly targeted may still show benefit in this disease setting. We did find that SABR [metastasis-directed therapy] induces a systemic adaptive immune response, and we have highlighted 2 important novel prognostic biomarkers in this setting, including the high-risk tumor genomic signature and unique productive T-cell receptor rearrangements,” Kiess said.

REFERENCES

1. Tran PT, Sherry AD, Bazyar S, et al. Outcomes of RAdium-223 and SABR vs. SABR for oligomEtastatic prostate caNcerS - the RAVENS Phase II randomized trial. Presented at: Presented at: 2024 American Society for Radiation Oncology Annual Meeting. September 29-October 2, 2024. Washington, DC. Abstract LBA10. https://astro2024.eventscribe.net/agenda.asp?startdate=10/1/2024&enddate=10/1/2024&BCFO=M&pfp=Browse%20by%20Day&fa=&fb=&fc=&fd=

2. Phillips R, Shi WY, Deek M, et al. Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer: The ORIOLE phase 2 randomized clinical trial. JAMA Oncol. 2020;6(5):650-659. doi:10.1001/jamaoncol.2020.0147

3. Ost P, Reynders D, Decaestecker K, et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II trial. J Clin Oncol. 2018;36(5):446-453. doi:10.1200/JCO.2017.75.4853

4. Gillessen S, Choudhury A, Saad F, et al. A randomized multicenter open label phase III trial comparing enzalutamide vs a combination of radium-223 (Ra223) and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic castration-resistant prostate cancer (mCRPC): First results of EORTC-GUCG 1333/PEACE-3. Presented at: 2024 European Society for Medical Oncology Annual Congress. September 13-17, 2024. Barcelona, Spain. Abstract LBA1. https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/session/calendar?q=LBA1