Is it time to say “shorter, safer, and smarter”?—interpreting early toxicity data from the PACE-C non-inferiority trial

Radiotherapy remains a cornerstone curative modality for prostate cancer, although its delivery has evolved considerably over recent decades (1). Advances in radiation technology have facilitated the adoption of hypofractionated external beam regimens, allowing higher doses per fraction over shorter treatment durations without compromising tumor control or substantially increasing toxicity (2). Fewer treatment sessions improve patient convenience, reduce travel burden, and enhance access to care—particularly in resource-constrained settings—while also optimizing utilization of radiotherapy infrastructure (3,4).

PACE-C is a randomized, open-label, phase III non-inferiority trial enrolling 1,208 men across 53 institutions in the United Kingdom, the Republic of Ireland, and New Zealand. Eligible participants were adults (≥18 years) with biopsy-proven intermediate- or high-risk prostate adenocarcinoma [clinical stage T1–T3a, Gleason score 7–8, prostate-specific antigen (PSA) 10–30 ng/mL]. Patients were allocated in a 1:1 ratio to either moderately hypofractionated radiotherapy (MHRT) (60 Gy in 20 fractions over four weeks) or ultrahypofractionated radiotherapy (UHRT) (36.25 Gy delivered in five fractions administered daily or on alternate days over 1–2 weeks). In the UHRT arm, a dose of 40 Gy was prescribed to the prostate and proximal seminal vesicles. All participants were scheduled to receive six months of androgen deprivation therapy (ADT), initiated prior to radiotherapy (5).

While follow-up for the primary efficacy endpoint—freedom from biochemical or clinical failure—is ongoing, the current analysis focuses on the co-primary safety endpoints. Acute gastrointestinal (GI) and genitourinary (GU) toxicities of Radiation Therapy Oncology Group (RTOG) grade ≥2 were evaluated within 12 weeks of treatment completion. No significant differences were observed between MHRT and UHRT in the incidence of grade ≥2 GU toxicity (27% vs. 28%, respectively; P=0.89). Rates of grade ≥2 GI toxicity were likewise comparable between groups (11% vs. 13%; P=0.53). Severe toxicities were uncommon in both arms, with grade ≥3 GU events occurring in 1–2% of patients and grade ≥3 GI events in fewer than 1% (5).

When toxicity was assessed using Common Terminology Criteria for Adverse Events (CTCAE) criteria, grade ≥2 GU events occurred at similar frequencies, although a borderline increase was noted with UHRT (28% vs. 34%; P=0.05). In contrast, CTCAE grade ≥2 GI toxicity was significantly more frequent in the UHRT arm (17% vs. 10%; P=0.001), though this excess was largely transient and diminished by 12 weeks after treatment. Patient-reported outcomes using Expanded Prostate Cancer Index Composite (EPIC) 26 mirrored these findings: urinary irritation and obstruction scores were temporarily worse at 12 weeks following UHRT, while overall urinary bother did not differ meaningfully between treatment groups. A higher proportion of patients receiving UHRT reported bowel-related symptoms at four weeks, reaching the minimum clinically important difference (MHRT 44% vs. UHRT 55%; P<0.001), with resolution by the 12-week assessment. Collectively, these results suggest that early GI toxicity associated with UHRT is predominantly short-lived and reversible (5).

The safety profile observed in PACE-C is consistent with previously published evidence (6). In a meta-analysis by Baccaglini et al., encompassing eight studies and 2,929 patients with localized prostate cancer, no significant differences were identified between UHRT and either MHRT or conventional radiotherapy (CRT) regarding acute GU toxicity (21.0% vs. 23.8%; P=0.46) or acute GI toxicity (4.9% vs. 6.9%; P=0.21). Furthermore, six included studies demonstrated comparable rates of late GU toxicity (3.9% vs. 4.7%; P=0.16) and late GI toxicity (2.1% vs. 3.5%; P=0.05) across treatment approaches (6). The PACE-C findings therefore reinforce the conclusions of this prior meta-analysis.

Additional support for ultrahypofractionation comes from the HOPE trial, a phase II, multi-center randomized study enrolling men with localized prostate cancer classified as unfavorable intermediate-, high-, or very-high-risk according to National Comprehensive Cancer Network criteria. This trial compared ultrahypofractionated whole-pelvis radiotherapy (WPRT) with conventionally fractionated WPRT combined with high-dose-rate prostate brachytherapy (HDR-BT). Both strategies were well tolerated, with no significant differences in acute toxicity rates. Notably, ultrahypofractionated WPRT was associated with less acute deterioration in EPIC-50 bowel-related scores and a higher proportion of patients achieving clinically meaningful improvements in urinary domains. No relevant differences were observed between groups in sexual or hormonal quality-of-life measures (7). When HDR-BT was incorporated into the comparator arm, ultrahypofractionation demonstrated a more favorable acute safety profile.

In summary, the interim safety outcomes from PACE-C provide important reassurance regarding the tolerability of UHRT. Ongoing follow-up assessing oncologic efficacy, late adverse effects, and long-term quality-of-life outcomes will be essential to more clearly delineate the relative roles of UHRT and MHRT in the contemporary management of prostate cancer.

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