RAdium-223 and SABR Versus SABR for Oligometastatic Prostate Cancers

The metastatic capacity of prostate cancer (PCa) behaves along a spectrum of disease that contains an oligometastatic state where metastases are limited in number and location. The importance of local consolidation of all tumor deposits in oligometastatic disease to forestall further metastatic dissemination is now backed by small randomized studies. Our previous Baltimore ORIOLE randomized trial of stereotactic ablative radiation (SABR) alone, highly focused, high-dose radiation, versus observation in oligometastatic PCa final data demonstrate a progression-free survival (PFS) benefit of SABR alone. The patterns of failure from our ORIOLE trial in combination with prior data suggest one dominant mode of failure is from microscopic disease particularly those with bone-tropic biology. These are important early clinical data suggesting the existence of an oligometastatic state and the importance of local therapies in the management of these patients. Radiopharmaceutical therapy (RPT) approaches have not been applied in the oligometastatic space and thus the opportunity to target micrometastatic disease in conjunction with local consolidation of macroscopic disease with SABR has the potential to provide a curative paradigm for patients with oligometastatic PCa. We introduce the successor trial to ORIOLE called RAVENS that is a phase II randomized trial of SABR +/- the bone metastasis seeking RPT Xofigo in men with oligometastatic PCa. We hypothesize macroscopic prostate tumors support the growth of and help nurture future distant metastases and this process can be impacted most by total, macro- and microscopic, tumor consolidation. In addition, we hypothesize that circulating biomarkers can identify men with oligometastasis that benefit the most from SABR and RPT.

• Radium-223 (Drug): Radium-223 plus SABR will be within two weeks.
• stereotactic ablative radiotherapy (SABR) (Radiation): SABR 1-5 fractions

Primary outcomes

• Progression-free Survival [Up to 24 months]: Time to progression in men who have oligometastatic prostate cancer after therapy. Progression is defined by PCWG2 criteria as follows: >=25% increase in PSA from nadir (and by >=2ng/mL), and/or clinical/radiographic progression (clinical progression = symptomatic progression, worsening of disease-related symptoms or new cancer-related complications; radiographic progression on CT scan defined by RECIST 1.1 criteria: >=20% enlargement in sum diameter of soft-tissue target lesions; or on bone scan >=1 new bone lesions), initiation of ADT or death due to any cause, whichever occurs first.

Secondary outcomes

• Toxicity as Assessed by Number of Participants Who Experience Adverse Events Grade 3 or Greater (CTCAE v4.0) [Up to 24 months]: Adverse events grade 3 or higher (defined by CTCAE v4.0) measured as treatment related events in either SABR or SABR and Radium-223 arms.
• Rate of Local Control at 12 Months [Up to 12 months]: Percentage of participants achieving local control at 12 months
• Time to Locoregional Progression [12 months]: Time from starting treatment until local and/or regional relapse is documented
• Time to Distant Progression [Up to 24 months]: Time from starting treatment until distant relapse is documented
• Metastasis-Free Survival [Up to 24 months]: Time from treatment start to the time of a newly documented tumor metastasis by CT and/or bone scan. Subjects who do not progress will be censored at the time of the last contact.
• Androgen-deprivation Therapy (ADT)-Free Survival [Up to 24 months]: Time from randomization until initiation of androgen-deprivation therapy (ADT). ADT Free Survival (ADT-FS) is defined as the time from starting treatment to the time of initiation of palliative ADT.
• Quality of Life as Assessed by Pain Severity and Pain Interference Score With Imputations Using the Brief Pain Inventory [Baseline, Day 360]: The brief pain inventory assesses the severity of pain, location of pain, amount of pain over the last 24 hours, and impact of pain on daily functions. Scores for the 4 pain severity items and 7 pain interference items range from 0-10, where 10 is the worst pain or pain that completely interferes with described activity and 0 is the least pain or does not interfere with described activity. The mean of these scores is used to measure pain severity and pain interference.
• Change in Quality of Life as Assessed by Pain Severity and Pain Interference With Imputations Using the Brief Pain Inventory [Baseline, Day 360]: The brief pain inventory assesses the severity of pain, location of pain, amount of pain over the last 24 hours, and impact of pain on daily functions. Scores for the 4 pain severity items and 7 pain interference items range from 0-10, where 10 is the worst pain or pain that completely interferes with described activity and 0 is the least pain or does not interfere with described activity. The mean of these scores is used to measure pain severity and pain interference.
• Time to New Metastatsis [12 months]: Time to New Metastasis (TNM) is defined as the time from starting treatment to the time of a new documented tumor metastasis by CT and/or bone scan. Subjects who do not progress will be censored at the time of the last contact.
• Duration of Response [12 Months]: Response will be defined as evidence of CR, PR, or stable disease. The duration of response will be measured from the start of treatment until the criteria for progression are met

Sex: Male, ages: 18 Years to 100 Years

Inclusion Criteria:

* Patient must have at least one and up to three asymptomatic metastatic tumor(s) of the bone or soft tissue (with at least one bone metastasis) develop within the past 6-months that are ≤ 5.0 cm or <250 cm3
* Patient must have had their primary tumor treated with surgery and/or radiation.
* Histologic confirmation of malignancy (primary or metastatic tumor).
* PSADT <15 months. PSA doubling time (PSADT) will be calculated using as many PSA values that are available from time of relapse (PSA > 0.2). To calculate PSADT, the Memorial Sloan Kettering Cancer Center Prostate Cancer Prediction Tool will be used. It can be found at the following web site: https://www.mskcc.org/nomograms/prostate/psa-doubling-time.
* Patient may have had prior systemic therapy and/or ADT associated with treatment of their primary prostate cancer. Patient may have had ADT associated with salvage radiation therapy (to the primary prostate cancer or pelvis is allowed).
* PSA > 0.5 but <50.
* Testosterone > 125 ng/dL.
* Patient must be ≥ 18 years of age.
* Patient must have a life expectancy ≥ 12 months.
* Patient must have an ECOG performance status ≤ 2.
* Patient must have normal organ and marrow function as defined as:

Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL.

* Patient must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

* No more than 3 years of ADT is allowed, with the most recent ADT treatment having occurred greater than 6 months prior to enrollment.
* PSMA-PET/MRI or PSMA-PET/CT scan within the past 6 months with results that demonstrate more disease lesions than baseline CT/Bone Scan
* Castration-resistant prostate cancer (CRPC).
* Spinal cord compression or impending spinal cord compression.
* Suspected pulmonary and/or liver metastases (greater >10 mm in largest axis).
* Patient receiving any other investigational agents.
* Patient receiving abiraterone and prednisone.
* Patient is participating in a concurrent treatment protocol.
* Serum creatinine > 3 times the upper limit of normal.
* Total bilirubin > 3 times the upper limit of normal.
* Liver Transaminases > 5-times the upper limit of normal.
* Unable to lie flat during or tolerate PET/MRI, PET/CT or SBRT.
* Prior salvage treatment to the primary prostate cancer or pelvis is allowed.
* Refusal to sign informed consent.

Participant flow

Outcome results

• Progression-free Survival (Primary), Median, Months: Radium-223 and SABR 10.5 (7.30 to 12.40); SABR 11.8 (6.67 to 21.2)
• Toxicity as Assessed by Number of Participants Who Experience Adverse Events Grade 3 or Greater (CTCAE v4.0) (Secondary), Count of participants, Participants: Radium-223 and SABR 5; SABR 3
• Rate of Local Control at 12 Months (Secondary), Mean, percentage of participants: Radium-223 and SABR 0.794 (0.628 to 1); SABR 0.908 (0.793 to 1)
• Time to Locoregional Progression (Secondary)
• Time to Distant Progression (Secondary), Median, Months: Radium-223 and SABR 11.9 (8.6 to 15.1); SABR 12.1 (9.1 to NA)
• Metastasis-Free Survival (Secondary), Median, Months: Radium-223 and SABR 12.3 (11.9 to NA); SABR 19.4 (8.22 to NA)
• Androgen-deprivation Therapy (ADT)-Free Survival (Secondary), Median, Months: Radium-223 and SABR 16.2 (12.3 to NA); SABR 19.2 (12.0 to NA)
• Quality of Life as Assessed by Pain Severity and Pain Interference Score With Imputations Using the Brief Pain Inventory (Secondary), Mean, score on a scale: Radium-223 and SABR 0.31 (0.06 to 0.56); SABR 0.39 (0.01 to 0.77)
• Change in Quality of Life as Assessed by Pain Severity and Pain Interference With Imputations Using the Brief Pain Inventory (Secondary), Mean, score on a scale: Radium-223 and SABR 0.34 (-0.07 to 0.74); SABR -0.01 (-0.13 to 0.11)
• Time to New Metastatsis (Secondary), Median, Months: Radium-223 and SABR 11.9 (8.6 to 15.1); SABR 12.0 (8.2 to NA)
• Duration of Response (Secondary), Median, Months: Radium-223 and SABR 10.5 (7.3 to 12.4); SABR 11.8 (6.7 to 21.2)

Adverse events

Time frame: From the time of enrollment to 1 year or until progression of disease (up to 2 years)

Other adverse events by term

Limitations and caveats: Treatment and follow-up occurred during the COVID-19 pandemic, leading to assessment biases associated with telemedicine encounters. This study was conducted before routine use of molecular imaging (not mandated) to corroborate disease burden detected on conventional imaging. The study size is small and limits the prognostic correlates observed.

• Results publication: Wang JH, Sherry AD, Bazyar S, Sutera P, Radwan N, Phillips RM, Deek MP, Lu J, Dipasquale S, Deville C, DeWeese TL, Song DY, Wang H, Hobbs RF, Malek R, Dudley SA, Greco SC, Antonarakis ES, Marshall CH, Denmeade S, Paller CJ, Carducci MA, Pienta KJ, Oz OK, Ramotar M, Leenstra JL, Park SS, Abramowitz MC, Desai N, Berlin A, Stish BJ, Tang C, Tran PT, Kiess AP. Outcomes of Radium-223 and Stereotactic Ablative Radiotherapy Versus Stereotactic Ablative Radiotherapy for Oligometastatic Prostate Cancers: The RAVENS Phase II Randomized Trial. J Clin Oncol. 2025 Jun 20;43(18):2059-2068. doi: 10.1200/JCO-25-00131. Epub 2025 May 7. PMID 40334149
• Results publication: Hasan H, Deek MP, Phillips R, Hobbs RF, Malek R, Radwan N, Kiess AP, Dipasquale S, Huang J, Caldwell T, Leitzel J, Wendler D, Wang H, Thompson E, Powell J, Dudley S, Deville C, Greco SC, Song DY, DeWeese TL, Gorin MA, Rowe SP, Denmeade S, Markowski M, Antonarakis ES, Carducci MA, Eisenberger MA, Pomper MG, Pienta KJ, Paller CJ, Tran PT. A phase II randomized trial of RAdium-223 dichloride and SABR Versus SABR for oligomEtastatic prostate caNcerS (RAVENS). BMC Cancer. 2020 Jun 1;20(1):492. doi: 10.1186/s12885-020-07000-2. PMID 32487038

• Study Protocol and Statistical Analysis Plan (PDF, 2025-02-07)

• Ana Kiess, M.D., Principal investigator, Johns Hopkins SKCCC