1003 - Initial Results of a Phase 2 Trial of Stereotactic Body Radiation Therapy, Hormone/Androgen Deprivation Therapy and Radium 223 Dichloride for Oligometastatic Castrate Sensitive Prostate Cancer (SHARP)

S. V. Dandapani¹, C. Hao¹, C. J. Ladbury¹, J. Y. C. Wong¹, Y. R. Li¹, J. R. Liu¹, S. M. Glaser¹, P. Lee², P. M. Mandelin³, S. K. Pal⁴, M. Alcantara³, M. Kortylewski⁵, P. Frankel⁶, C. Ruel³, A. Chehrazi-Raffle³, Y. Lyou³, J. Liu⁷, J. Simpson⁷, T. B. Dorff⁴, and P. Twardowski⁸; ¹Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, ²Department of Radiation Oncology, Lennar Foundation Comprehensive Cancer Center, City of Hope National Medical Center, Irvine, CA, ³City of Hope, Duarte, CA, ⁴Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, ⁵Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA, ⁶Department of Information Sciences, City of Hope National Medical Center, Duarte, CA, ⁷Clinical Trials Office, City of Hope National Medical Center, Duarte, CA, ⁸John Wayne Cancer Institute, Santa Monica, CA

Purpose/Objective(s): While radium 223 dichloride (Ra-223) has been approved for metastatic castrate resistant prostate cancer, there is limited prospective data regarding its use in metastatic castrate-sensitive prostate cancer (mCSPC). We conducted a single-center open-label phase II clinical trial investigating Ra-223 combined with 36 weeks androgen deprivation therapy (ADT) and stereotactic body radiation therapy (SBRT) for patients with oligometastatic (=5 metastases) CSPC (NCT03361735, SHARP trial). The primary objective was time to treatment failure (TTF), and secondary objectives included assessing toxicities, progression-free survival (PFS), and overall survival (OS). Materials/

Methods: ADT (degarelix [n=4], relugolix [n=2], or leuprolide [n=19]) was administered starting at least 4 weeks prior to SBRT and continued for 36 weeks. SBRT was 27 Gy in 3 fractions to bone metastases. De novo patients also received definitive radiation therapy to their prostate primary +/- pelvic lymph nodes. Patients received 6 infusions of Ra-223 at a dose of 55 kBq/kg, with one infusion every 28 days. The first infusion was ~1 month after the first SBRT fraction. Blood samples for correlative studies were collected throughout treatment.
Results: 25 patients were enrolled between August 2018 and July 2023, including 6 de novo and 19 oligoprogressive mCSPC patients. Median Gleason score was 7 (range 6-9). Median number of metastases was 2 bone metastases (range 1-5). 21 patients completed study therapy. Median follow-up was 31.7 months (95% confidence interval [CI] 28.4, 44.1). Median TTF was 19.0 (13.1, not reached [NR]) months in all patients, 34.3 (2.8, NR) months in de novo patients and 17.7 (12.4, NR) months in oligoprogressive patients. 1-year OS was 95.5% (95%CI 71.9%, 99.3%) in all patients, 100% in de novo patients and 94% (95% CI 63%, 99%) in oligoprogressive patients. 1-year PFS was 82.1% (59.1%, 92.9%) in all patients, 83% (95% CI 27%, 98%) in de novo patients and 81% (95% CI 53%, 94%) in oligoprogressive patients. 4 de novo patients were free from progression at the 2-year interval. Grade 3 toxicities at least possibly related to protocol therapy included lymphopenia (n=8), hypertension (n=6), neutropenia (n=2), anemia (n=1), leukopenia (n=1), fracture (n=1), syncope (n=1), and cholecystitis (n=1). No grade 4+ toxicities occurred. 5 patients developed fractures (grade 1, n=2 (imaging only); grade 2, n=2; grade 3, n=1). IL-8 significantly increased from baseline to the end of treatment (p=0.04) and a reduction in proinflammatory IL-1ß and TNFa from baseline was observed.
Conclusion: Ra-223 combined with SBRT to oligometastases and 36 weeks ADT in mCSPC is well-tolerated and results in favorable OS and PFS compared to historical controls. Longer follow-up is necessary to assess if the early use of Ra-223 delays development of new bone metastases.