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Immune checkpoint inhibitors have shown limited clinical benefit in unselected patients with metastatic prostate cancer. Although androgen deprivation and radiotherapy may influence the tumor immune microenvironment, whether combining these approaches with immune checkpoint blockade can improve treatment outcomes remains uncertain.
The phase II SAABR trial investigated the addition of atezolizumab, an anti–PD-L1 antibody, to androgen receptor pathway inhibition, androgen-deprivation therapy (ADT), and stereotactic body radiotherapy (SBRT) to the prostate in patients with de novo metastatic hormone-sensitive prostate cancer.
The study reported substantial treatment-related toxicity, including three serious adverse events that led to early trial closure, without a clear improvement in clinical outcomes compared with historical controls.
The study, titled “Phase II Study of an Androgen Receptor Pathway Inhibitor + Atezolizumab + Gonadotropin-Releasing Hormone Analog and Stereotactic Body Radiotherapy in Hormone-Sensitive Metastatic Prostate Cancer,” was published in JCO Oncology Advances on October 14, 2026.
The research was conducted by Matthew Dallos, Mark Stein, Israel Deutsch, Catherine Spina, Celine Nguyen, Patrick McCann, Victoria Catharine, Zhigang Zhang, Azusa Okada, Meghan Lloyd, Jan Manarite, Deaglan McHugh, Susan Slovin, Daniel Danila, Wassim Abida, Karen A. Autio, Michael J. Morris, Yingbei Chen, Charles Drake, Dana Rathkopf, and Sean M. McBride.
Why Was the SAABR Trial Conducted?
Prostate cancer is generally considered an immunologically cold tumor, characterized by limited T-cell infiltration and an immunosuppressive tumor microenvironment. These features may contribute to the limited activity of immune checkpoint inhibitors observed in unselected patients with prostate cancer.
Preclinical studies have suggested that radiotherapy may enhance antitumor immune responses through increased antigen presentation, immunogenic cell death, and changes in PD-L1 expression. Androgen deprivation may also promote T-cell infiltration and reduce immune tolerance within prostate tumors. These findings provided the rationale for investigating whether immune checkpoint blockade could become more effective when combined with androgen pathway inhibition and radiotherapy.
The SAABR investigators hypothesized that adding atezolizumab to maximal androgen blockade and prostate SBRT could improve 2-year freedom-from-failure compared with historical results from treatment with abiraterone, a gonadotropin-releasing hormone (GnRH) analog, and SBRT alone.
SAABR Trial Design and Treatment
SAABR (NCT04262154) was a multicenter, single-arm, phase II clinical trial conducted at Memorial Sloan Kettering Cancer Center and Columbia University Medical Center.
The study enrolled patients with biopsy-confirmed, de novo metastatic hormone-sensitive prostate cancer who were eligible for prostate SBRT according to institutional criteria. There were no restrictions on the extent of metastatic disease, and patients were not required to have oligometastatic disease. Up to 3 months of previous ADT was permitted. The treatment regimen combined atezolizumab with hormonal therapy and prostate-directed SBRT. Atezolizumab was administered intravenously at 1,200 mg every 3 weeks, beginning on cycle 1, day 1. An ARPI was introduced on cycle 2, day 1, followed by ADT using a GnRH analog on cycle 3, day 1.
Prostate SBRT was scheduled to begin during cycle 5, with 7.25–7.5 Gy delivered every other day for five fractions. The initial radiation protocol included the prostate and seminal vesicles, although subsequent amendments allowed treatment of the prostate alone. Systemic treatment was planned for up to 2 years or until disease progression, unacceptable toxicity, or withdrawal of consent.
The primary endpoint was freedom-from-failure at 2 years, defined as the absence of biochemical recurrence, radiographic progression, study withdrawal, or death. Patients who discontinued treatment because of toxicity remained evaluable for the primary endpoint. Secondary endpoints included symptomatic skeletal events, prostate cancer–specific survival, and overall survival (OS). Safety was also assessed. The study was originally designed to enroll 42 evaluable patients, but enrollment ended prematurely because of safety concerns.
Patient Characteristics
Between July 2020 and April 2023, 28 patients were enrolled and initiated study treatment. The median age was 65 years (interquartile range [IQR], 58–70), and 89% of patients had an Eastern Cooperative Oncology Group performance status of 0. Most patients had bone metastases (82%), while 50% had high-volume disease, defined in the study as at least four metastatic lesions. Gleason scores of 8 or higher were reported in 71% of patients, and the median baseline prostate-specific antigen (PSA) level was 12 ng/mL (IQR, 4–34).
Eight patients (29%) had received ADT before enrollment. Of the 28 enrolled patients, 23 initiated an ARPI, including 20 who received abiraterone and three who received enzalutamide. Five patients discontinued treatment after cycle 1 and did not receive an ARPI. The median duration of atezolizumab treatment was 161 days (range, 1–743), corresponding to a median of eight cycles.
Efficacy Outcomes
At 2 years, 20 of 28 patients (71%) remained failure-free, according to the study’s primary endpoint. Among the eight patients classified as having experienced failure, four developed biochemical recurrence, three experienced radiographic progression, and one withdrew from the study before completing 2 years of follow-up. The Kaplan–Meier estimate of freedom-from-failure at 2 years was 74.8% (95% CI, 60.3%–92.9%). At 4 years, the estimated freedom-from-failure rate was 46.3% (95% CI, 29.3%–72.9%).
Median failure-free survival was 3.4 years, with a reported interval of 3.1 years to not estimable. Regarding PSA response, 20 patients achieved PSA levels below 0.2 ng/mL within 6 months of treatment initiation. No symptomatic skeletal events occurred during the study.
Estimated OS was 96% (95% CI, 90%–100%) at 12 months and 93% (95% CI, 83%–100%) at 24 months. No prostate cancer–specific deaths occurred during the first 12 months. By 24 months, the cumulative incidence of prostate cancer–specific death was 3.9% (95% CI, 0.26%–17%), accounting for competing risks.
Despite these outcomes, the investigators reported that the 2-year freedom-from-failure rate was comparable with historical results, without evidence of a clear clinical improvement from the addition of atezolizumab. As a single-arm trial, SAABR did not include a randomized control group. Therefore, the findings cannot establish the independent contribution of atezolizumab to the observed efficacy outcomes.
Safety Findings: Serious Toxicity Led to Early Trial Closure
Safety emerged as the principal concern during the SAABR trial. Treatment-related adverse events occurred in 96% of patients, including grade ≥3 events in 46%. Three serious treatment-related adverse events prompted early study closure: two grade 4 colonic perforations and one grade 5 hemophagocytic lymphohistiocytosis (HLH).
The two colonic perforations occurred after seven and nine doses of atezolizumab, respectively. Both events developed within 2 months following SBRT and after initiation of androgen receptor pathway inhibition. The perforations occurred close to or within the sigmoid colon, where radiation dose overlap was presumed. Both affected patients had a history of diverticulosis and had experienced diarrhea approximately 2 months before radiotherapy.
Following these events, the investigators amended the protocol to remove abiraterone/prednisone as an ARPI option because of concern that prednisone might contribute to gastrointestinal toxicity. Enzalutamide was subsequently used, and a history of diverticulosis was added to the exclusion criteria.
No additional bowel perforations occurred after the protocol amendment. The investigators discussed several possible mechanisms contributing to gastrointestinal toxicity, including immune-mediated inflammation, radiation exposure to nearby bowel, and the potential effects of concurrent corticosteroid treatment. However, the precise mechanism responsible for the perforations could not be determined.
The third serious event was a fatal case of HLH, which occurred after a single dose of atezolizumab, before the patient received ARPI, ADT, or SBRT. HLH is a rare but severe immune-related adverse event that has been reported with PD-1/PD-L1 inhibitors. The affected patient had no known history of autoimmune disease or infection that could have predisposed them to this complication. After these three serious treatment-related events, the trial met its predefined stopping criteria and was closed to further enrollment.
Of the 28 enrolled patients, five completed 2 years of treatment, while 23 discontinued treatment earlier because of adverse events, physician decisions, withdrawal, progressive disease, or death. All 28 patients were ultimately taken off study, including 17 following sponsor-initiated study termination.
Molecular Findings and Exploratory Biomarker Analysis
The investigators also explored potential associations between genomic alterations and clinical outcomes. MSK-IMPACT sequencing was performed in 23 patients with adequate diagnostic tumor tissue.
The most frequently identified genomic alterations were TP53 mutations (43%), FOXA1 mutations (17%), and PTEN mutations (13%). TMPRSS2:ERG fusions were identified in 26% of sequenced tumors. Homologous recombination repair (HRR) gene alterations involving ATM, BARD1, BRCA1, or BRCA2 were identified in four patients (17%).
Among patients with HRR alterations, one of four (25%) remained failure-free at 2 years, compared with 15 of 19 patients (79%) without HRR alterations (P = 0.07). Although the results showed a numerical difference, the association did not reach conventional statistical significance. The small number of patients also limits interpretation.
For patients with TP53 and/or PTEN mutations, the 2-year freedom-from-failure rate was 73% (8/11), compared with 67% (8/12) among those without these mutations (P = 1.0).
Mean tumor mutational burden was 3.1 mutations/Mb (range, 0–21.0). One patient had high tumor mutational burden, defined as at least 10 mutations/Mb, and this tumor was also microsatellite instability–high. These exploratory findings did not establish a predictive biomarker for benefit from the atezolizumab-containing regimen.
What Do the SAABR Findings Mean for Prostate Cancer Treatment?
The SAABR results raise concerns about combining immune checkpoint blockade with intensive androgen pathway inhibition and prostate-directed SBRT in patients with de novo metastatic hormone-sensitive prostate cancer. Although the study was based on a biological rationale for combining immunotherapy with radiotherapy and hormonal treatment, the observed freedom-from-failure outcomes did not demonstrate a clear improvement over historical results.
The investigators noted that these findings were consistent with other negative studies of immune checkpoint blockade in prostate cancer. In metastatic hormone-sensitive disease, the phase III KEYNOTE-991 trial evaluating pembrolizumab with enzalutamide and ADT was stopped for futility. Similarly, the KEYNOTE-921 and KEYNOTE-641 studies failed to demonstrate clinical benefit from pembrolizumab-containing combinations in metastatic androgen pathway modulation–resistant prostate cancer.
The SAABR findings suggest that adding PD-L1 blockade to hormonal therapy and prostate SBRT may not provide additional clinical benefit in an unselected population. The safety findings also warrant particular attention. The occurrence of two severe colonic perforations in a cohort of only 28 patients raised concerns about the tolerability of combining immunotherapy with pelvic radiotherapy and hormonal treatment. However, several limitations should be considered.
The single-arm design relied on historical comparisons rather than a concurrent randomized control group. Early termination reduced the planned sample size and limited the precision of outcome estimates. The study also included patients with both low- and high-volume metastatic disease, while the choice of ARPI changed during the trial. These factors complicate interpretation of the efficacy and safety findings.
The investigators emphasized the need for careful patient selection, radiation planning that minimizes bowel exposure, and close safety monitoring in future trials involving immunotherapy and pelvic radiotherapy.
They also highlighted the need for predictive biomarkers and treatment strategies directed at specific mechanisms of immune resistance. Additional exploratory analyses of biopsy specimens collected during the trial are ongoing.
Conclusion
The phase II SAABR trial evaluated atezolizumab combined with androgen receptor pathway inhibition, ADT, and prostate SBRT in patients with de novo metastatic hormone-sensitive prostate cancer. At 2 years, 71% of patients remained failure-free, but no clear clinical benefit was identified compared with historical controls.
The combination was associated with substantial toxicity, including two grade 4 colonic perforations and one fatal case of hemophagocytic lymphohistiocytosis, leading to early trial closure. Although the study’s single-arm design and premature termination limit definitive conclusions regarding comparative efficacy, the findings raise significant safety concerns about this treatment strategy.
The investigators concluded that future studies should prioritize approaches targeting specific mechanisms of immune resistance, biomarker-based patient selection, and careful evaluation of toxicity when combining immune checkpoint inhibitors with pelvic radiotherapy.
