Abstract
PURPOSE
Randomized clinical trials (RCTs) have shown progression-free survival (PFS) benefits of metastasis-directed therapy (MDT) without androgen deprivation therapy for oligometastatic castration-sensitive prostate cancer (omCSPC). Most patients with bone metastatic (BM) omCSPC recur with additional bone disease after MDT. We hypothesized the BM-targeting alpha-emitter radium-223 dichloride (Ra223) could target subclinical bone disease and delay progression.
METHODS
This is an investigator-initiated, multicenter, open-label phase II RCT. Eligible men with recurrent omCSPC with ≥one bone metastasis (≤three on conventional imaging and/or ≤five on molecular imaging) were randomly assigned (1:1) to stereotactic ablative radiation (SABR) MDT alone or SABR MDT with Ra223 (six cycles). Primary end point was composite PFS.
RESULTS
From August 9, 2019, to March 2, 2023, 64 patients were randomly assigned, 33 to SABR MDT and 31 to SABR MDT/Ra223 balancing for key covariates. Most SABR MDT/Ra223 patients (87%) received six cycles of Ra223. The median PFS was 11.8 months with SABR MDT and 10.5 months with SABR MDT/Ra223 (adjusted hazard ratio [aHR], 1.42 [95% CI, 0.79 to 2.56]; P = .24). Seven patients (11%) experienced grade 3 treatment-related adverse events (no grade 4 or 5), 2 of 33 (6%) with SABR and 5 of 30 (17%) with SABR MDT/Ra223. Patients with high-risk (HiRi) pathogenic mutations in ATM, BRCA1/2, RB1, or TP53 had worse PFS (HR, 5.95 [95% CI, 1.83 to 19.3]; P = .003). Greater T-cell receptor (TCR) unique productive rearrangements were prognostic for improved PFS independent of the treatment arm (aHR, 0.45 [95% CI, 0.21 to 0.96]; P = .04).
CONCLUSION
Adding Ra223 to SABR MDT in BM omCSPC does not delay progression of disease. We provide evidence for an HiRi mutational signature and TCR repertoire as prognostic biomarkers in omCSPC treated with SABR MDT, highlighting the importance of collecting biological correlates in RCTs for omCSPC.
INTRODUCTION
Metastatic prostate cancer is a significant cause of morbidity and mortality for men worldwide. Improving treatment modalities for metastatic disease remains a critical challenge. For metachronous oligometastatic castration-sensitive prostate cancer (omCSPC), current standard-of-care options include systemic therapy with continuous or intermittent androgen deprivation (with or without intensification using androgen receptor signaling inhibitors) and local metastasis-directed therapy (MDT).
CONTEXT
Key Objective
Does radium-223 dichloride (Ra223) delay disease progression when added to stereotactic ablative radiation metastasis-directed therapy (SABR MDT) in bone oligometastatic castration-sensitive prostate cancer?
Knowledge Generated
In this multicenter phase II randomized clinical trial, addition of Ra223 to SABR MDT versus SABR MDT alone did not delay progression of disease. Correlative molecular analysis suggests that the presence of high-risk (HiRi) pathogenic mutations in ATM, BRCA1/2, RB1, or TP53 and a less diverse T-cell receptor repertoire 3 months post-treatment are both prognostic for worse progression-free survival independent of the treatment arm.
Relevance (J.P.S. Knisely)
Ra-223's osteotropism does not appear to adequately address subclinical disease for this subset of patients with prostate cancer and through inducing lymphocytopenia likely contributes to decreases in T-cell diversity. Evaluation of different systemic approaches to control subclinical disease and exploit T-cell based adaptive immunity in conjunction with body radiosurgery for oligometastatic disease may provide better outcomes, as may further intensification of systemic therapy for those men with HiRi mutations.*
*Relevance section written by JCO Associate Editor Jonathan P.S. Knisely, MD.
Several trials have demonstrated an important role for stereotactic ablative radiotherapy (SABR) MDT in metachronous omCSPC. The phase II SABR-COMET randomized clinical trial (RCT) was the first to show an overall survival (OS) benefit of SABR MDT (21% prostate cancer in the SABR MDT arm).1 The STOMP and ORIOLE phase II RCTs found that SABR MDT improved androgen deprivation therapy (ADT)–free survival and progression-free survival (PFS),2-4 respectively, when compared with observation. The EXTEND phase II RCT showed that addition of SABR MDT to intermittent hormone therapy compared with hormone therapy alone led to improvements in PFS.5 However, responses to SABR MDT for omCSPC remain heterogeneous, and there are few biomarkers to predict patient trajectories.
Analyses of patterns of failure for patients with bone metachronous omCSPC have shown that the majority of patients treated with SABR MDT progress at an osseous location.6-8 Radium-223 dichloride (Ra223) is an alpha-emitting radionuclide that has shown efficacy in targeting bone metastases in metastatic castration-resistant prostate cancer (mCRPC). In the ALSYMPCA trial, Ra223 extended the OS from 11.3 months to 14.9 months compared with placebo.9 Mechanistically, Ra223 binds to regions of bone turnover and delivers short-range high-energy radiation.
Therefore, we hypothesized that addition of Ra223 to SABR MDT might address subclinical osseous disease in patients with omCSPC and improve PFS. We tested this hypothesis in a phase II RCT called RA223 dichloride and SABR versus SABR for oligometastatic prostate cancers (RAVENS).10
We also investigated biomarkers of response including genomics and peripheral T-cell receptor (TCR) sequencing. Targeted profiling of the most variable region of the TCR, which acts as a barcode to identify clonal T cells targeting the same epitope, allows for evaluation of unique TCR productive rearrangements (UPRs). UPRs are believed to reflect immune diversity and the potential of T-cell–based adaptive immunity to recognize a broad portfolio of possible antigens and have been associated with clinical responses across cancer types.5,11,12
METHODS
Study Design and Participants
RAVENS was a multicenter, open-label, phase II RCT at five sites throughout North America. Eligible patients had metachronous omCSPC with ≥one bone metastasis (total ≤three metastases on conventional imaging and/or ≤five on fluciclovine, choline, or piflufolastat F 18–positron emission tomography [PET]/computed tomography [CT]). Lymph node metastases were permitted. Patients had previous definitive treatment for the primary tumor with surgery or radiotherapy, metastatic lesion ≤5 cm (per lesion), prostate specific antigen (PSA) doubling time (PSADT) <15 months, PSA ≥0.5 ng/mL and ≤50 ng/mL, testosterone >50 ng/dL in the 6 months preceding, and Eastern Cooperative Oncology Group 0-2. Previous ADT therapy was permitted for ≤3 years in total, with no ADT 6 months before enrollment. Exclusion criteria included mCRPC, spinal cord compression, and visceral metastases. Patients receiving Ra223 were required to have a complete blood count (CBC) demonstrating absolute neutrophil count ≥1.5 × 109/L, platelet count ≥100 × 109/L, and hemoglobin ≥10 g/dL before first administration.
The study was approved by the Institutional Review Board at each participating institution (full Protocol, online only). The trial schema was as previously reported.10 The trial is registered with ClinicalTrials.gov (identifier: NCT04037358) and conforms with CONSORT guidelines.
Random Assignment and Blinding
Random assignment was nonblinded 1:1 to Ra223 plus SABR MDT or SABR MDT alone. Random assignment used a minimization algorithm13 with stratification factors: institution, initial treatment (surgery v radiation), previous hormone therapy (yes or no), and PSADT (<6 months v 6-14.9 months).
Procedures
Study treatment and procedures continued until disease progression, unacceptable toxicity, or patient withdrawal. ADT was not permitted on study. Routine physical examination, laboratory testing, and imaging were performed before treatment and at 3-, 6-, and 12-month follow-ups for both arms. Imaging modality was at the discretion of the practicing physician. Additional imaging was performed for PSA progression at the discretion of the provider. Brief pain inventory (short form) and adverse events (Common Terminology Criteria for Adverse Events [CTCAE] version 4.0) were assessed at baseline and at 3, 6, and 12 months. Peripheral blood samples were collected at baseline and 3 months for TCR sequencing via the Adaptive Biotechnology immunoSEQ platform.14
For SABR, patients underwent CT-based simulation with customized immobilization. Additional simulation considerations, target volume delineation, and treatment planning were performed as previously described and detailed in the protocol.3,10 Briefly, clinical tumor volume (CTV) was equal to the gross tumor volume, and the planning target volume was a 3- to 5-mm margin around the CTV. Prescription doses ranged from 28 to 50 Gy in 2-5 fractions. Treatment was delivered with daily image guidance using cone beam CT. Normal tissue constraints were adhered to, following the AAPM Task Group 101 recommendations.15
Ra223 was administered intravenously 55 kBq/kg in 4-week intervals for six total injections. The first injection was given within 2 weeks of starting SABR MDT. Before subsequent Ra223 administrations, assessments included vitals, weight, and CBC. Crossover was not permitted.
Outcomes
The primary end point was PFS. Progression was defined as a ≥25% increase in PSA from nadir (and absolute increase ≥2 ng/mL), requiring confirmation ≥4 weeks later; radiologic progression (on CT/magnetic resonance imaging [MRI] scan: ≥20% enlargement in sum diameter of soft tissue target lesions [RECIST 1.1 criteria] or on bone scan: ≥one new bone lesions); symptomatic progression (worsening disease-related symptoms or new cancer-related complications); and initiation of ADT or death because of any cause. Prespecified secondary outcomes included ADT-free survival and metastasis-free survival (MFS). Bone PFS was analyzed post hoc. MFS was defined as identification of new metastases on conventional imaging.16 For patients with new metastases visualized on molecular imaging (fluciclovine/choline/prostate-specific membrane antigen [PSMA]-PET/CT), lesions needed to have a clear correlate on the CT portion (for soft tissue and nodal disease, meeting size criteria per RECIST 1.1, and for bone lesions, having a clear sclerotic/lytic component). Bone PFS was defined to include progression visualized on conventional and/or molecular imaging. All end points were calculated from the time of random assignment.
DNA and TCR Sequencing
DNA sequencing to assess somatic and germline mutations was performed using Tempus xT and FoundationOne CDx. A previously defined high-risk (HiRi) mutation signature comprised a pathogenic mutation in at least one of these genes: ATM, BRCA1/2, RB1, or TP53.4 TCR-β complementarity-determining region 3 (CDR3) regions in rearranged TCR β-chains were sequenced from peripheral blood using the immunoSEQ assay (Adaptive Biotechnologies, Seattle, WA).14 The CDR3 region was chosen for TCR-seq over CDR1 and CDR2 as it is directly responsible for antigen interaction. UPRs were defined as the number of distinct in-frame CDR3 sequences encoding a functional protein receptor.
Statistical Analysis
A sample size of 64 patients with 38 progression events would provide an 80% power to detect an increase in median PFS from 10 months to 20 months (corresponding to hazard ratio [HR], 0.5) with type I error 0.1, using a one-sided log-rank test.10 The primary analysis cutoff date was April 13, 2024, when the last progression event observed. For patients alive without disease progression, PFS was censored at the time of the last PSA or imaging. Analyses were performed using a modified intention-to-treat approach, in which patients who withdrew consent after random assignment but before commencing study treatment were excluded from all analyses. Comparison of clinical variables used a two-sided Fisher's exact test for categorical variables and Pearson's correlation for continuous variables.
For the primary and secondary survival end points, the Kaplan-Meier method and the log-rank test were used to compare outcomes. Stratified Cox proportional hazards regression was used to estimate adjusted HRs (aHRs) between treatments adjusting for baseline random assignment stratification factors as covariates. Comparisons of progression and presence of new metastases at 12 months were performed using a two-sided Fisher's exact test. Multivariable Cox regression was performed as part of the HiRi mutation analysis to assess for confounding. The maximum CTCAE v4.0 toxicity grade for each adverse event per patient was documented and compared between arms using a two-sided Fisher's exact test.
TCR clonal expansion and contraction were quantified between the baseline and 3-month time points using a published beta-binomial model with Benjamini-Hochberg false discovery correction.17 For external validation, TCR clonal expansion was compared with the ORIOLE trial (ClinicalTrials.gov identifier: NCT0268058),3 which also used the immunoSEQ assay at the same time points, using a two-sided Mann-Whitney U test. Pairwise changes in UPR abundance between baseline and 3 months were compared using a Wilcoxon signed-rank test.
RESULTS
Between August 9, 2019, and March 2, 2023, 64 patients were randomly assigned: 33 (52%) to SABR MDT and 31 (48%) to Ra223 plus SABR MDT (Fig 1). One patient in the Ra223 plus SABR MDT arm withdrew before treatment, resulting in 63 patients in the modified intention-to-treat population. Patient characteristics are presented in Table 1. The median age of the modified intention-to-treat population was 68 years (range, 55-86). The median follow-up was 18.7 months (range, 6.1-53.1). Grade Group (GG) was slightly higher in the SABR MDT arm (21 of 33, 64% for GG >3) compared with Ra223 plus SABR MDT. There were no statistically significant differences in initial imaging approach, initial lesion type (bone only v bone and nodal), total lesion number, bone lesion number, presence of bone lesion outside of the pelvis/spine, and presence of extra-pelvic lymph nodes (Table 1). Details of dose prescriptions are presented in Appendix Table A1 (online only). Eighty-seven percent (26 of 30) of patients in the Ra223 plus SABR MDT arm received the full six planned cycles of Ra223, and four discontinued Ra223 because of disease progression.
FIG 1.
CONSORT diagram. Ra223, radium-223; SABR, stereotactic ablative radiation.
TABLE 1.
Patient Characteristics at Baseline
| Patient Characteristic | Overall (N = 63) | SABR (n = 33) | Ra223 + SABR (n = 30) | P |
|---|---|---|---|---|
| Institution, No. (%) | .963 | |||
| Johns Hopkins Hospital, Baltimore, MD | 31 (49.2) | 17 (51.5) | 14 (46.7) | |
| Mayo Clinic, Rochester, MN | 16 (25.4) | 8 (24.2) | 8 (26.7) | |
| Princess Margaret Hospital, Toronto, ON, Canada | 10 (15.9) | 5 (15.2) | 5 (16.7) | |
| University of Miami, Miami, FL | 3 (4.8) | 1 (3.0) | 2 (6.7) | |
| University of Texas Southwestern Medical Center, Dallas, TX | 3 (4.8) | 2 (6.1) | 1 (3.3) | |
| Age, years | .434 | |||
| Median (minimum-maximum) | 68.0 (55.0-86.0) | 69.0 (55.0-84.0) | 66.0 (55.0-86.0) | |
| Grade group, No. (%) | .133 | |||
| 1-3 | 29 (46.0) | 12 (36.4) | 17 (56.7) | |
| 4-5 | 34 (54.0) | 21 (63.6) | 13 (43.3) | |
| Initial treatment, No. (%) | .754 | |||
| Radiation | 12 (19.0) | 7 (21.2) | 5 (16.7) | |
| Surgery | 51 (81.0) | 26 (78.8) | 25 (83.3) | |
| Previous hormone therapy, No. (%) | .794 | |||
| No | 20 (31.7) | 11 (33.3) | 9 (30.0) | |
| Yes | 43 (68.3) | 22 (66.7) | 21 (70.0) | |
| Baseline PSA, ng/mL | .542 | |||
| Mean (SD) | 5.61 (7.06) | 5.08 (5.88) | 6.20 (8.24) | |
| PSADT, months | .258 | |||
| Mean (SD) | 5.16 (3.76) | 5.67 (4.17) | 4.60 (3.22) | |
| Initial imaging type, No. (%) | .624 | |||
| Conventional only | 9 (14.3) | 3 (9.1) | 6 (20.0) | |
| Conventional and PSMA-PET | 17 (27.0) | 8 (24.2) | 9 (30.0) | |
| Conventional and non–PSMA-PET | 17 (27.0) | 9 (27.3) | 8 (26.7) | |
| PSMA-PET only | 14 (22.2) | 9 (27.3) | 5 (16.7) | |
| Non–PSMA-PET only | 6 (9.5) | 4 (12.1) | 2 (6.7) | |
| Initial lesion, No. (%) | .226 | |||
| Bone only | 49 (77.8) | 28 (84.8) | 21 (70.0) | |
| Bone and lymph node | 14 (22.2) | 5 (15.2) | 9 (30.0) | |
| Total lesion number and lesion distribution, No. (%) | ||||
| 1 | ||||
| Bone only | 34 (54.0) | 20 (60.6) | 14 (46.7) | .0864 |
| 2 | 17 (27.0) | 10 (30.3) | 7 (23.3) | |
| Two bones | 7 (21.2) | 3 (10.0) | ||
| One bone, one node | 3 (9.1) | 4 (13.3) | ||
| 3 | 10 (15.9) | 2 (6.1) | 8 (26.7) | |
| Three bones | 0 | 3 (10.0) | ||
| Two bones, one node | 1 (3.0) | 3 (10.0) | ||
| One bone, two nodes | 1 (3.0) | 2 (6.7) | ||
| 4 | 1 (1.6) | 1 (3.0) | 0 | |
| Two bones, two nodes | ||||
| 5 | 1 (1.6) | 0 | 1 (3.3) | |
| Three bones, two nodes | ||||
| Bone lesion number, No. (%) | .112 | |||
| 1 | 44 (69.8) | 24 (72.7) | 20 (66.7) | |
| 2 | 15 (23.8) | 9 (27.3) | 6 (20.0) | |
| 3 | 4 (6.3) | 0 | 4 (13.3) | |
| Bone lesion type, No. (%) | .61 | |||
| No lesion outside pelvis/vertebra | 37 (58.7) | 18 (54.5) | 19 (63.3) | |
| Lesion outside pelvis/vertebra | 26 (41.3) | 15 (45.5) | 11 (36.7) | |
| Extra-pelvic lymph nodes, No. (%) | 1 | |||
| No | 59 (93.7) | 31 (93.9) | 28 (93.3) | |
| Yes | 4 (6.3) | 2 (6.1) | 2 (6.7) |
Abbreviations: PSA, prostate specific antigen; PSADT, PSA doubling time; PSMA-PET, prostate-specific membrane antigen positron emission tomography; Ra223, radium-223 dichloride; SABR, stereotactic ablative radiation; SD, standard deviation.
Follow-up imaging was concordant with initial imaging for most patients, with very few instances of progression detected by PET in the absence of initial PET imaging (Appendix Table A2). The variability in type of imaging obtained was largely driven by individual institutional practices. The primary outcome of composite PFS was not significantly different between the two arms. The median PFS was 10.5 months for Ra223 plus SABR MDT versus 11.8 months for SABR MDT (aHR, 1.42 [95% CI, 0.79 to 2.56]; P = .24; Fig 2A). The secondary end points of MFS (aHR, 1.09 [95% CI, 0.92 to 2.51]; P = .84) and ADT-free survival (aHR, 1.53 [95% CI, 0.65 to 3.41]; P = .30) were also not significantly different (Fig 2B; Appendix Fig A1A). Furthermore, the addition of Ra223 to SABR MDT did not delay bone PFS (Appendix Fig A1B).
FIG 2.
(A) PFS and (B) MFS. MFS, metastasis-free survival; PFS, progression-free survival; Ra223, radium-223 dichloride; SABR, stereotactic ablative radiation.
Grade 3 adverse events were uncommon in both arms, though more frequent in the Ra223 plus SABR MDT arm (Appendix Table A3). There were no grade 4 or 5 toxicities. Seven patients (11%) experienced grade 3 treatment-related adverse events, 2 of 33 (6%) in the SABR MDT arm and 5 of 30 (17%) in the Ra223 plus SABR MDT arm. The most common grade 3 adverse event was lymphopenia (1 of 33 [3%] patients in SABR MDT v 4 of 30 [13%] in Ra223 plus SABR MDT; P = .15). One patient in each arm exhibited a skeletal related event.
In total, 26 patients underwent DNA sequencing from prostate biopsy or prostatectomy tissue, and of these, 23 samples were of sufficient quality for variant calling. Of these 23 patients, six had a HiRi pathogenic mutation in ATM, BRCA1/2, RB1, or TP53. The distribution of HiRi and non-HiRi patients was balanced between the treatment arms, with 4 of 12 in the SABR MDT arm versus 2 of 11 in the Ra223 plus SABR MDT arm (P = .64). The presence of an HiRi mutation was associated with worse PFS (HR, 5.95 [95% CI, 1.83 to 19.3]; P = .0030) and MFS (HR, 13.1 [95% CI, 2.46 to 69.6]; P = .0026; Fig 3). On multivariable Cox regression, the presence of HiRi mutation was the only variable to remain significant for PFS (Appendix Table A4). At 12 months, the proportion of patients who developed metastatic disease progression was 6 of 6 (100%) HiRi patients compared with 6 of 17 (35%) non-HiRi patients (P = .014).
FIG 3.
Patients with an HiRi mutational signature have worse (A) PFS and (B) MFS. HiRi, high risk; MFS, metastasis-free survival; PFS, progression-free survival.
TCR sequencing of 7,978,032 T cells was performed across 44 unique patients. High abundance of UPRs at 3 months was associated with improved PFS independent of the random assignment arm (high v low UPR dichotomized at median; aHR, 0.45 [95% CI, 0.21 to 0.96]; P = .040; Fig 4A). The prognostic impact of UPR after SABR MDT alone in the ORIOLE RCT was similar (HR, 0.46 [95% CI, 0.19 to 1.05]; P = .068; Appendix Fig A2). Systemic TCR clonal expansion was observed after both SABR MDT alone and Ra223 plus SABR MDT (Fig 4B). Compared with the observation arm from the ORIOLE RCT, systemic TCR expansion was significantly greater after SABR MDT (P = .009) and Ra223 plus SABR MDT (P = .0007; Fig 4C). Unexpectedly, despite these observations of immune stimulation, UPR abundance decreased significantly at 3 months in the Ra223 plus SABR MDT arm (P = .0002), whereas there was not a significant decrease in the SABR MDT arm (P = .09; Fig 4D).
FIG 4.
TCR sequencing results for patients at baseline and 3 months. (A) UPRs at 3 months are prognostic for PFS. (B) Number of TCR clones showing expansion and contraction between 3 months versus baseline for Ra223 plus SABR MDT and SABR MDT alone arms. Each bar represents an individual patient. (C) Mean clonal expansion fold change for Ra223 plus SABR MDT and SABR MDT alone compared to the observation arm from the ORIOLE trial (3 month versus baseline). (D) UPR abundance at baseline and 3 months for patients with matched data in both arms. MDT, metastasis-directed therapy; PFS, progression-free survival; Ra223; radium-223 dichloride; SABR, stereotactic ablative radiation; TCR, T-cell receptor; UPR, unique TCR productive rearrangement.
DISCUSSION
To our knowledge, this phase II study represents the first RCT of Radium-223 in metastatic castration-sensitive prostate cancer. The results for patients randomly assigned to Ra223 plus SABR MDT compared with SABR MDT did not demonstrate an improvement in the primary end point of PFS. There was no significant difference in MFS, ADT-free survival, and time to new bone metastasis between the arms.
These findings are important in the context of the phase III randomized ALSYMPCA and PEACE-3 trials, which were conducted in patients with mCRPC. ALSYMPCA showed a median OS benefit of 3.6 months (HR, 0.7; P < .001) with Ra223 versus placebo in patients with mCRPC with symptomatic bone metastases and high osseous burden (>85% with more than six metastases).9 More recently, initial results of PEACE-3 demonstrated that addition of Ra223 to enzalutamide as first-line therapy for mCRPC improved the median OS by 7.3 months (HR, 0.69; P = .0031; performed at 80% events).18 The PEACE-3 protocol required ≥four metastases on protocol, with 43% of patients having ≥10 metastases.
Our findings are consistent with pilot single-arm studies of Ra223 in mCSPC.19,20 A study of 10 patients with metachronous mCSPC with significant bone disease burden reported complete PSA response in 50% of patients and partial radiographic response in 30%.20 By contrast, Tosco et al19 found that Ra223 alone resulted in a short PFS of 5.5 months in eight patients with biochemical recurrence and negative staging imaging (by both PSMA-PET and MRI).
Taken altogether, these results suggest that determinants of response to Ra223 may depend on a number of factors, including bone disease burden, ablative treatment to macroscopic disease, hormone therapy use, and metastatic disease biology. Patients in RAVENS had ≤three metastases on conventional imaging or ≤five on molecular imaging (≥one bone lesion), and all patients were given SABR MDT to eradicate macroscopic disease. Therefore, while there is bone tropism for Ra223, the low burden of any additional active microscopic disease (and/or the lack of significant osteoblastic reaction) may be insufficient for Ra223 alone to affect the disease trajectory and clinical outcomes.
More specific targeting of metastatic disease in mCSPC may still be promising, as was shown by the recent phase II UpFrontPSMA RCT of sequential Lu-PSMA-617 and docetaxel versus docetaxel in de novo mCSPC.21 However, synchronous mCSPC has poorer prognosis and more aggressive biology when compared with metachronous mCSPC,22,23 which was the cohort studied in RAVENS. Given that complete consolidation of metastatic disease detectable by molecular imaging decreases the risk of subsequent metastases,3 addressing microscopic metastatic disease in patients with omCSPC remains an important goal. However, this was not achieved with Ra223 in RAVENS.
Several key findings emerged from the correlative analyses. First, the HiRi mutational signature, which was predictive and prognostic in the combined STOMP and ORIOLE RCT meta-analysis,4 also validated independently in RAVENS for PFS and MFS. At 12 months, 100% of patients with an HiRi mutation had developed new metastases compared with 35% of patients without an HiRi mutation. Given that no patients received ADT on trial, this highlights the potential to avoid ADT for a select patient population. These findings do not necessarily preclude a benefit of SABR MDT for patients with an HiRi mutation but also suggest the need for treatment escalation. Use of this HiRi signature is currently being assessed prospectively in the integral biomarker-designed phase II KNIGHTS RCT (ClinicalTrials.gov identifier: NCT06212583) comparing SABR MDT plus 6 months of ADT versus SABR MDT plus 6 months of ADT and niraparib/abiraterone.
Second, increased TCR repertoire diversity was associated with outcomes after SABR MDT, with greater UPR abundance at 3 months associating with improved PFS. This finding was supported by data from the separate ORIOLE RCT. Interestingly, while there was evidence of systemic TCR clonal expansion after either Ra223 plus SABR MDT or SABR MDT, the addition of Ra223 to SABR MDT did not appear to meaningfully increase the probability of TCR expansion. Moreover, the total number of UPRs in the TCR repertoire were significantly decreased after 3 months of Ra223 plus SABR MDT but not after SABR MDT alone, suggesting that Ra223 may lead to additional cytotoxicity of circulating T cells. Bone marrow suppression has been a documented side effect of Ra223.20,24 Taken together, these exploratory findings raise the hypothesis that in low-volume bone disease, the ability of SABR MDT to induce immunogenic cell death and clinically relevant T-cell activation may be partly counteracted by an immunosuppressive impact of Ra223. The higher rates of lymphopenia in the Ra223 plus SABR MDT arm support this hypothesis.
This study was open-label. Treatment and follow-up also occurred during the COVID-19 pandemic, leading to assessment biases associated with telemedicine encounters. This study was conducted before routine use of molecular imaging (including fluciclovine-, choline-, and PSMA-PET) to corroborate disease burden detected on conventional imaging, and molecular imaging was not mandated on the trial. However, patterns of follow-up imaging were consistent per institution because of stratification and hence were balanced in the treatment arms. The study size is small and limits the prognostic correlates observed.
In conclusion, to our knowledge, RAVENS demonstrates for the first time that addition of Ra223 to SABR MDT in a castration-sensitive low-volume bone-metastatic state does not delay progression of disease. We also provide evidence for the HiRi mutational signature and TCR repertoire diversity as prognostic biomarkers in omCSPC treated with SABR MDT. SABR MDT alone for omCSPC affords PFS benefits, but the emergence of additional bone metastases remains a challenge.
ACKNOWLEDGMENT
We acknowledge James Huang, Dana Kaplin, the Department of Radiation Oncology and Molecular Radiation Sciences, and Johns Hopkins University School of Medicine.
APPENDIX
FIG A1.
ADT-free survival and bone PFS. ADT, androgen deprivation therapy; PFS, progression-free survival; Ra223, radium-223 dichloride; SABR, stereotactic ablative radiation.
FIG A2.
Association between UPRs at 3 months and PFS for patients in the ORIOLE trial. PFS, progression-free survival; UPR, unique T-cell receptor productive rearrangement.
TABLE A1.
Doses to Bone and Nodal Lesions for SABR and Ra223/SABR Arms
| Fraction | Prescription | Lesions Treated, No. |
|---|---|---|
| Bone lesions | ||
| SABR | ||
| 2 | 14 Gy × 2 | 1 |
| 3 | 10 Gy × 3 | 14 |
| 12 Gy × 3 | 5 | |
| 9 Gy × 3 | 5 | |
| 11 Gy × 3 | 2 | |
| 8 Gy × 3 | 1 | |
| 9.5 Gy × 3 | 1 | |
| 5 | 7 Gy × 5 | 6 |
| 6 Gy × 5 | 4 | |
| 6.5 Gy × 5 | 1 | |
| 8 Gy × 5 | 1 | |
| 9 Gy × 5 | 1 | |
| Ra223 + SABR | ||
| 3 | 10 Gy × 3 | 16 |
| 8 Gy × 3 | 4 | |
| 7 Gy × 3 | 2 | |
| 9 Gy × 3 | 2 | |
| 7.5 Gy × 3 | 1 | |
| 8.5 Gy × 3 | 1 | |
| 9.25 Gy × 3 | 1 | |
| 9.5 Gy × 3 | 1 | |
| 5 | 7 Gy × 5 | 7 |
| 6 Gy × 5 | 5 | |
| 8 Gy × 5 | 2 | |
| 10 Gy × 5 | 1 | |
| 5 Gy × 5 | 1 | |
| Nodal lesions | ||
| SABR | 2 | |
| 3 | 10 Gy × 3 | 4 |
| 5 | 7 Gy × 5 | 1 |
| 6 Gy × 5 | ||
| Ra223 + SABR | ||
| 3 | 10 Gy × 3 | 5 |
| 5 | 7 Gy × 5 | 5 |
| 6 Gy × 5 | 1 | |
| 7.25 Gy × 5 | 1 |
Abbreviations: Ra223, radium-223 dichloride; SABR, stereotactic ablative radiation.
TABLE A2.
Details of Follow-Up Imaging Compared With Initial Imaging for Patients at the Time of Progression
| Follow-Up Imaging v Initial Imaging | Overall (n = 49), No. (%) | SABR (n = 23), No. (%) | Ra223 + SABR (n = 26), No. (%) |
|---|---|---|---|
| Concordant | |||
| Conventional | 4 (8.2) | 1 (4.3) | 3 (11.5) |
| Non–PSMA-PET | 7 (14.3) | 3 (13.0) | 4 (15.4) |
| PSMA-PET | 18 (36.7) | 10 (43.5) | 8 (30.8) |
| Discordant | |||
| Conventional only initial → progression on PET | 3 (6.1) | 1 (4.3) | 2 (7.7) |
| PET initial → progression without PETa | 11 (22.4) | 5 (21.7) | 6 (23) |
| Non–PSMA-PET initial → progression on PSMA-PET | 3 (6.1) | 1 (4.3) | 2 (7.7) |
| PSMA-PET initial → progression on non–PSMA-PET | 2 (4.1) | 1 (4.3) | 1 (3.8) |
| No imaging on progression | 1 (2.0) | 1 (4.3)b | 0 |
Abbreviations: PSA, prostate specific antigen; PSMA-PET, prostate-specific membrane antigen positron emission tomography; Ra223, radium-223 dichloride; SABR, stereotactic ablative radiation.
Patients progressed by PSA (n = 5) or by conventional imaging (n = 6) at institutions in which the practice pattern was to obtain conventional imaging and PSA in accordance with the protocol.
The patient was documented to have progressed and started on systemic therapy at an outside institution. However, no records of follow-up imaging were provided from the outside institution before his death.
TABLE A3.
Treatment-Related AEs
| Treatment-Related AE | SABR, No. | Ra223 + SABR, No. | ||||
|---|---|---|---|---|---|---|
| Grade 1-2 | Grade 3 | Total | Grade 1-2 | Grade 3 | Total | |
| Abdominal pain | 1 | 0 | 1 | 0 | 0 | 0 |
| Anemia | 6 | 0 | 6 | 16 | 0 | 16 |
| Anorexia | 1 | 0 | 1 | 3 | 0 | 3 |
| Bloating | 1 | 0 | 1 | 0 | 0 | 0 |
| Blood in stool | 1 | 0 | 1 | 0 | 0 | 0 |
| Constipation | 4 | 0 | 4 | 2 | 0 | 2 |
| Diarrhea | 2 | 0 | 2 | 8 | 0 | 8 |
| Esophagitis | 1 | 0 | 1 | 0 | 0 | 0 |
| Fatigue | 6 | 1 | 7 | 13 | 0 | 13 |
| Fracture (L ischium—nondisplaced) | 1 | 0 | 1 | 0 | 0 | 0 |
| Insomnia | 1 | 1 | 2 | 0 | 0 | 0 |
| Lymphocyte count decreased | 8 | 1 | 9 | 19 | 4 | 23 |
| Musculoskeletal pain | 7 | 0 | 7 | 4 | 1 | 5 |
| Nausea | 1 | 0 | 1 | 5 | 0 | 5 |
| Neck pain | 1 | 0 | 1 | 0 | 0 | 0 |
| Urinary frequency | 2 | 0 | 2 | 1 | 0 | 1 |
| Urinary incontinence | 1 | 0 | 1 | 1 | 0 | 1 |
| Weight loss | 2 | 0 | 2 | 1 | 0 | 1 |
| Anxiety | 0 | 0 | 0 | 2 | 0 | 2 |
| Bruising | 0 | 0 | 0 | 1 | 0 | 1 |
| Decreased appetite | 0 | 0 | 0 | 1 | 0 | 1 |
| Dehydration | 0 | 0 | 0 | 1 | 0 | 1 |
| Dysgeusia | 0 | 0 | 0 | 1 | 0 | 1 |
| Erectile dysfunction | 0 | 0 | 0 | 1 | 0 | 1 |
| Generalized muscle weakness | 0 | 0 | 0 | 1 | 0 | 1 |
| Hemorrhoids | 0 | 0 | 0 | 1 | 0 | 1 |
| Hyperkalemia | 0 | 0 | 0 | 1 | 0 | 1 |
| Loose bowel movement | 0 | 0 | 0 | 1 | 0 | 1 |
| Compression fracture T-12 | 0 | 0 | 0 | 1 | 0 | 1 |
| Neutrophil count decreased | 0 | 0 | 0 | 4 | 0 | 4 |
| Platelet count decreased | 0 | 0 | 0 | 9 | 0 | 9 |
| Urinary urgency | 0 | 0 | 0 | 1 | 0 | 1 |
| Any adverse eventa | 19 | 2 | 21 | 22 | 5 | 27 |
Abbreviations: AEs, adverse events; Ra223, radium-223 dichloride; SABR, stereotactic ablative radiation.
Number of patients whose worst AE was grade 1-2, 3 and total.
TABLE A4.
Multivariable Cox Regression for PFS for Patients With HiRi Mutation
| Variable | HR | Lower 95% CI | Upper 95% CI | P |
|---|---|---|---|---|
| HiRi mutation | 9.24 | 2.41 | 35.40 | .001 |
| No. of lesions | 1.39 | 0.65 | 2.97 | .397 |
| No. of bone lesions | 1.13 | 0.34 | 3.68 | .845 |
| Baseline PSA | 1.07 | 0.99 | 1.16 | .073 |
| Grade group | 1.01 | 0.60 | 1.70 | .959 |
| PSADT | 0.93 | 0.78 | 1.10 | .396 |
Abbreviations: HiRi, high-risk; HR, hazard ratio; PFS, progression-free survival; PSA, prostate specific antigen; PSADT, PSA doubling time.
Alexander D. Sherry
Employment: MD Anderson Cancer Center
Honoraria: Sermo
Philip Sutera
Stock and Other Ownership Interests: Pfizer, Merck, Catalent (I)
Ryan M. Phillips
Travel, Accommodations, Expenses: Novartis
Uncompensated Relationships: Veracyte
Curtiland Deville
Consulting or Advisory Role: Blue Earth Diagnostics, AstraZeneca
Theodore L. DeWeese
Employment: Johns Hopkins Medicine
Leadership: Johns Hopkins Medicine
Stock and Other Ownership Interests: Digital Harmonic
Patents, Royalties, Other Intellectual Property: Patent pending on computer algorithm in radiation therapy planning
Daniel Y. Song
Honoraria: Lantheus Medical Imaging
Consulting or Advisory Role: Isoray, BioProtect
Research Funding: Candel Therapeutics, BioProtect, Lantheus Medical Imaging
Travel, Accommodations, Expenses: Lantheus Medical Imaging
Robert F. Hobbs
Consulting or Advisory Role: Advanced Accelerator Applications/Novartis, Varian Medical Systems, Vivos Therapeutics, Boston Scientific, Mirion Technologies
Patents, Royalties, Other Intellectual Property: IP for RAPID (Radiopharmaceutical Imaging and Dosimetry) LLT
Other Relationship: American Association of Physicists in Medicine
Sara A. Dudley
Leadership: Belay Diagnostics (I)
Stock and Other Ownership Interests: Belay Diagnostics (I)
Consulting or Advisory Role: Belay Diagnostics (I)
Travel, Accommodations, Expenses: Belay Diagnostics (I)
Emmanuel S. Antonarakis
Consulting or Advisory Role: Sanofi, Janssen Biotech, Merck, AstraZeneca, Lilly, Bayer (Inst), Amgen, Blue Earth Diagnostics, Curium Pharma, Foundation Medicine, Tempus, AIkido Pharma, Z-Alpha, AADi, Corcept Therapeutics, Hookipa Pharma, Menarini Silicon Biosystems, Pfizer, Tango Therapeutics
Research Funding: Astellas Pharma (Inst), Bayer (Inst), Bristol Myers Squibb (Inst), Macrogenics (Inst), Merck (Inst), Orion Health (Inst)
Patents, Royalties, Other Intellectual Property: Co-inventor of a biomarker technology that has been licensed to Qiagen
Catherine H. Marshall
Honoraria: Tempus
Consulting or Advisory Role: McGraw-Hill Education, Dendreon, Bayer, Obseva
Research Funding: AstraZeneca (Inst)
Patents, Royalties, Other Intellectual Property: McGraw Hill—textbook royalties
Travel, Accommodations, Expenses: Bayer
Samuel Denmeade
Research Funding: Astellas Pharma (Inst), Bayer
Channing J. Paller
Consulting or Advisory Role: Dendreon, Omnitura, Exelixis, AstraZeneca, Janssen Oncology, Pfizer, Bayer
Research Funding: Lilly (Inst)
Travel, Accommodations, Expenses: Bayer
Michael A. Carducci
Honoraria: Remedica
Consulting or Advisory Role: Pfizer, Acrivon Therapeutics, AstraZeneca
Research Funding: Pfizer (Inst), Arcus Biosciences (Inst), Merck (Inst), Celgene/Bristol Myers Squibb (Inst)
Kenneth J. Pienta
Stock and Other Ownership Interests: CUE Biopharma, PEEL Therapeutics, Kreftect, Inc
Consulting or Advisory Role: CUE Biopharma
Research Funding: Progenics
Travel, Accommodations, Expenses: CUE Biopharma
James L. Leenstra
Employment: Mayo Clinic
Leadership: Northfield Hospital
Stock and Other Ownership Interests: ROM Tech
Travel, Accommodations, Expenses: Alliance for Clinical Trials in Oncology
Sean S. Park
Employment: Mayo Clinic Cancer Center
Stock and Other Ownership Interests: Natera, Guardant Health
Patents, Royalties, Other Intellectual Property: Nanotics—royalty (Inst)
Matthew C. Abramowtiz
Employment: University of Miami Hospitals and Clinics
Consulting or Advisory Role: Varian Medical Systems
Research Funding: Varian Medical Systems (Inst)
Travel, Accommodations, Expenses: IBA
Neil Desai
Consulting or Advisory Role: Boston Scientific, Telix Pharmaceuticals, Novartis
Speakers' Bureau: Ultimate Medical Academy
Research Funding: Boston Scientific (Inst), Telix Pharmaceuticals (Inst), Reflexion Medical (Inst)
Travel, Accommodations, Expenses: Bayer
Uncompensated Relationships: Bayer
Open Payments Link: https://openpaymentsdata.cms.gov/physician/1620445
Alejandro Berlin
Consulting or Advisory Role: AbbVie, Ferring, Astellas Pharma
Research Funding: AbbVie
Bradley J. Stish
Employment: Mayo Clinic
Honoraria: Kansas Society of Clinical Oncology
Research Funding: Varian Medical Systems (Inst)
Chad Tang
Employment: MD Anderson Cancer Center
Consulting or Advisory Role: Siemens Healthineers, Lantheus Medical Imaging, Boston Scientific, Telix Pharmaceuticals, MOLLI Surgical, Elekta
Research Funding: Noxopharm (Inst), Myriad Genetics (Inst)
Patents, Royalties, Other Intellectual Property: I have a patent on the utilization of a monoclonal antibody and we license this for use. We receive royalties <$1,000 per year on this license
Travel, Accommodations, Expenses: Vision RT
Other Relationship: Wolters Kluwer, Osler Institute
Phuoc T. Tran
Honoraria: Reflexion Medical
Consulting or Advisory Role: Astellas Pharma, Regeneron, GenomeDx, Reflexion Medical, Dendreon, Noxopharm, Janssen, Myovant Sciences, AstraZeneca, Bayer Health, Lantheus Medical Imaging
Research Funding: Astellas Pharma (Inst), Reflexion Medical (Inst), Bayer Health (Inst)
Patents, Royalties, Other Intellectual Property: Compounds and Methods of Use in Ablative Radiotherapy. Patent filed on 3/9/2012. PCT/US2012/028475. PCT/WO/2012/122471
Travel, Accommodations, Expenses: Reflexion Medical
Ana P. Kiess
Research Funding: Advanced Accelerator Applications/Novartis (Inst), Merck (Inst), Bayer (Inst), Novartis Pharmaceuticals UK Ltd, Lantheus Medical Imaging (Inst)
Travel, Accommodations, Expenses: Novartis
Uncompensated Relationships: POINT Biopharma, Novartis
No other potential conflicts of interest were reported.
DISCLAIMER
The funding bodies had no role in the design or execution of the study; data collection, management, analysis, or interpretation of the data; and preparation, review, or approval of the manuscript.
PRIOR PRESENTATION
Presented at the American Society for Radiation Oncology annual meeting, October 1, 2024, Washington, DC.
SUPPORT
Supported by Bayer HealthCare, Anonymous Donor, Movember Foundation-Distinguished Gentleman's Ride-Prostate Cancer Foundation, the NIH/NCI (U54CA273956, P01CA272222, SBIR 75N91019C00040), and DoD (W81XWH-21-1-0296).
CLINICAL TRIAL INFORMATION
NCT04037358 (RAVENS)
J.H.W. and A.D.S. contributed equally. P.T.T. and A.P.K. are senior authors.
DATA SHARING STATEMENT
A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO-25-00131. Requests for specific analyses or data, including access to deidentified individual participant data collected during the trial, will be considered by the RAVENS lead investigators after publication of the manuscript for researchers who provide a methodologically sound proposal. Proposals should be directed to the corresponding authors (phuoc.tran@umm.edu and akiess1@jhmi.edu) to gain access. Data requestors will need to sign a data access agreement.
AUTHOR CONTRIBUTIONS
Conception and design: Matthew P. Deek, Hao Wang, Reem Malek, Emmanuel S. Antonarakis, Channing J. Paller, Michael A. Carducci, Phuoc T. Tran, Ana P. Kiess
Financial support: Alejandro Berlin, Phuoc T. Tran, Ana P. Kiess
Administrative support: Alejandro Berlin, Phuoc T. Tran, Ana P. Kiess
Provision of study materials or patients: Ryan M. Phillips, Shirl Dipasquale, Curtiland Deville, Emmanuel S. Antonarakis, Samuel Denmeade, Channing J. Paller, Michael A. Carducci, Orhan K. Oz, James L. Leenstra, Neil Desai, Alejandro Berlin, Bradley J. Stish, Phuoc T. Tran, Ana P. Kiess
Collection and assembly of data: Jarey H. Wang, Alexander D. Sherry, Noura Radwan, Ryan M. Phillips, Matthew P. Deek, Shirl Dipasquale, Curtiland Deville, Daniel Y. Song, Robert F. Hobbs, Reem Malek, Emmanuel S. Antonarakis, Catherine H. Marshall, Channing J. Paller, Michael A. Carducci, Orhan K. Oz, Matthew Ramotar, James L. Leenstra, Sean S. Park, Matthew C. Abramowitz, Neil Desai, Alejandro Berlin, Bradley J. Stish, Phuoc T. Tran, Ana P. Kiess
Data analysis and interpretation: Jarey H. Wang, Alexander D. Sherry, Soha Bazyar, Philip Sutera, Ryan M. Phillips, Matthew P. Deek, Jiayun Lu, Curtiland Deville, Theodore L. DeWeese, Daniel Y. Song, Hao Wang, Sara A. Dudley, Stephen C. Greco, Catherine H. Marshall, Samuel Denmeade, Channing J. Paller, Michael A. Carducci, Kenneth J. Pienta, Orhan K. Oz, Matthew Ramotar, Matthew C. Abramowitz, Alejandro Berlin, Bradley J. Stish, Chad Tang, Phuoc T. Tran, Ana P. Kiess
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Outcomes of Radium-223 and Stereotactic Ablative Radiotherapy Versus Stereotactic Ablative Radiotherapy for Oligometastatic Prostate Cancers: The RAVENS Phase II Randomized Trial
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Alexander D. Sherry
Employment: MD Anderson Cancer Center
Honoraria: Sermo
Philip Sutera
Stock and Other Ownership Interests: Pfizer, Merck, Catalent (I)
Ryan M. Phillips
Travel, Accommodations, Expenses: Novartis
Uncompensated Relationships: Veracyte
Curtiland Deville
Consulting or Advisory Role: Blue Earth Diagnostics, AstraZeneca
Theodore L. DeWeese
Employment: Johns Hopkins Medicine
Leadership: Johns Hopkins Medicine
Stock and Other Ownership Interests: Digital Harmonic
Patents, Royalties, Other Intellectual Property: Patent pending on computer algorithm in radiation therapy planning
Daniel Y. Song
Honoraria: Lantheus Medical Imaging
Consulting or Advisory Role: Isoray, BioProtect
Research Funding: Candel Therapeutics, BioProtect, Lantheus Medical Imaging
Travel, Accommodations, Expenses: Lantheus Medical Imaging
Robert F. Hobbs
Consulting or Advisory Role: Advanced Accelerator Applications/Novartis, Varian Medical Systems, Vivos Therapeutics, Boston Scientific, Mirion Technologies
Patents, Royalties, Other Intellectual Property: IP for RAPID (Radiopharmaceutical Imaging and Dosimetry) LLT
Other Relationship: American Association of Physicists in Medicine
Sara A. Dudley
Leadership: Belay Diagnostics (I)
Stock and Other Ownership Interests: Belay Diagnostics (I)
Consulting or Advisory Role: Belay Diagnostics (I)
Travel, Accommodations, Expenses: Belay Diagnostics (I)
Emmanuel S. Antonarakis
Consulting or Advisory Role: Sanofi, Janssen Biotech, Merck, AstraZeneca, Lilly, Bayer (Inst), Amgen, Blue Earth Diagnostics, Curium Pharma, Foundation Medicine, Tempus, AIkido Pharma, Z-Alpha, AADi, Corcept Therapeutics, Hookipa Pharma, Menarini Silicon Biosystems, Pfizer, Tango Therapeutics
Research Funding: Astellas Pharma (Inst), Bayer (Inst), Bristol Myers Squibb (Inst), Macrogenics (Inst), Merck (Inst), Orion Health (Inst)
Patents, Royalties, Other Intellectual Property: Co-inventor of a biomarker technology that has been licensed to Qiagen
Catherine H. Marshall
Honoraria: Tempus
Consulting or Advisory Role: McGraw-Hill Education, Dendreon, Bayer, Obseva
Research Funding: AstraZeneca (Inst)
Patents, Royalties, Other Intellectual Property: McGraw Hill—textbook royalties
Travel, Accommodations, Expenses: Bayer
Samuel Denmeade
Research Funding: Astellas Pharma (Inst), Bayer
Channing J. Paller
Consulting or Advisory Role: Dendreon, Omnitura, Exelixis, AstraZeneca, Janssen Oncology, Pfizer, Bayer
Research Funding: Lilly (Inst)
Travel, Accommodations, Expenses: Bayer
Michael A. Carducci
Honoraria: Remedica
Consulting or Advisory Role: Pfizer, Acrivon Therapeutics, AstraZeneca
Research Funding: Pfizer (Inst), Arcus Biosciences (Inst), Merck (Inst), Celgene/Bristol Myers Squibb (Inst)
Kenneth J. Pienta
Stock and Other Ownership Interests: CUE Biopharma, PEEL Therapeutics, Kreftect, Inc
Consulting or Advisory Role: CUE Biopharma
Research Funding: Progenics
Travel, Accommodations, Expenses: CUE Biopharma
James L. Leenstra
Employment: Mayo Clinic
Leadership: Northfield Hospital
Stock and Other Ownership Interests: ROM Tech
Travel, Accommodations, Expenses: Alliance for Clinical Trials in Oncology
Sean S. Park
Employment: Mayo Clinic Cancer Center
Stock and Other Ownership Interests: Natera, Guardant Health
Patents, Royalties, Other Intellectual Property: Nanotics—royalty (Inst)
Matthew C. Abramowtiz
Employment: University of Miami Hospitals and Clinics
Consulting or Advisory Role: Varian Medical Systems
Research Funding: Varian Medical Systems (Inst)
Travel, Accommodations, Expenses: IBA
Neil Desai
Consulting or Advisory Role: Boston Scientific, Telix Pharmaceuticals, Novartis
Speakers' Bureau: Ultimate Medical Academy
Research Funding: Boston Scientific (Inst), Telix Pharmaceuticals (Inst), Reflexion Medical (Inst)
Travel, Accommodations, Expenses: Bayer
Uncompensated Relationships: Bayer
Open Payments Link: https://openpaymentsdata.cms.gov/physician/1620445
Alejandro Berlin
Consulting or Advisory Role: AbbVie, Ferring, Astellas Pharma
Research Funding: AbbVie
Bradley J. Stish
Employment: Mayo Clinic
Honoraria: Kansas Society of Clinical Oncology
Research Funding: Varian Medical Systems (Inst)
Chad Tang
Employment: MD Anderson Cancer Center
Consulting or Advisory Role: Siemens Healthineers, Lantheus Medical Imaging, Boston Scientific, Telix Pharmaceuticals, MOLLI Surgical, Elekta
Research Funding: Noxopharm (Inst), Myriad Genetics (Inst)
Patents, Royalties, Other Intellectual Property: I have a patent on the utilization of a monoclonal antibody and we license this for use. We receive royalties <$1,000 per year on this license
Travel, Accommodations, Expenses: Vision RT
Other Relationship: Wolters Kluwer, Osler Institute
Phuoc T. Tran
Honoraria: Reflexion Medical
Consulting or Advisory Role: Astellas Pharma, Regeneron, GenomeDx, Reflexion Medical, Dendreon, Noxopharm, Janssen, Myovant Sciences, AstraZeneca, Bayer Health, Lantheus Medical Imaging
Research Funding: Astellas Pharma (Inst), Reflexion Medical (Inst), Bayer Health (Inst)
Patents, Royalties, Other Intellectual Property: Compounds and Methods of Use in Ablative Radiotherapy. Patent filed on 3/9/2012. PCT/US2012/028475. PCT/WO/2012/122471
Travel, Accommodations, Expenses: Reflexion Medical
Ana P. Kiess
Research Funding: Advanced Accelerator Applications/Novartis (Inst), Merck (Inst), Bayer (Inst), Novartis Pharmaceuticals UK Ltd, Lantheus Medical Imaging (Inst)
Travel, Accommodations, Expenses: Novartis
Uncompensated Relationships: POINT Biopharma, Novartis
No other potential conflicts of interest were reported.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO-25-00131. Requests for specific analyses or data, including access to deidentified individual participant data collected during the trial, will be considered by the RAVENS lead investigators after publication of the manuscript for researchers who provide a methodologically sound proposal. Proposals should be directed to the corresponding authors (phuoc.tran@umm.edu and akiess1@jhmi.edu) to gain access. Data requestors will need to sign a data access agreement.