5-year outcomes from PACE B: an international phase III randomized controlled trial comparing stereotactic body radiotherapy (SBRT) vs. conventionally fractionated or moderately hypo fractionated external beam radiotherapy for localized prostate cancer

Purpose/Objective(s)
External beam radiotherapy (EBRT) is a curative treatment for Localized Prostate Cancer (LPCa). Large randomized controlled trials (RCTs) have shown moderately hypo fractionated regimens (2.5 – 3 Gy/fraction(f)) as non-inferior to 2Gy/f regimens. PACE-B aims to demonstrate non-inferiority of SBRT compared to conventionally or moderately hypo fractionated regimens for biochemical and/or clinical failure (BCF).

Materials/Methods
PACE (NCT01584258) is an international phase III open-label multiple-cohort RCT. Men with LPCa, stage T1-T2, ≤ Gleason 3 + 4, PSA ≤ 20 ng/mL, unsuitable for surgery or preferring EBRT, were eligible. Participants (pts) were randomized (1:1) to SBRT (36.25 Gy / 5f in 1-2 weeks (wks)) or control radiotherapy (CRT) (78 Gy / 39 f over 7.5 wks, or 62 Gy / 20 f in 4 wks) to the planning target volume. Androgen deprivation therapy was not permitted. The primary endpoint was freedom from biochemical (BF)/clinical (CF) failure. BF is based on PSA rises, commencement of ADT or date of orchiectomy and CF is based on local recurrence, nodal recurrence, distant metastases and death from prostate cancer. 858 pts were needed to rule out 6% inferiority (80% power, one-sided alpha 5%) assuming 85% event-free rate with CRT, corresponding to a critical hazard ratio (HR) of 1.45. Analysis was done by intention to treat.

Results
874 pts were randomized from 38 centers (n=441 (CRT) and n=433 (SBRT)) between 08/2012 and 01/2018. Baseline characteristics were well balanced across CRT and SBRT groups: median age 69.8 years (IQR 65.4,74.0); median PSA ng/mL (IQR): 8.1 (6.3,11) vs 7.9 (5.5,10.9); NCCN risk group 9.3% low, 90.7% intermediate. With median follow-up of 73.1 months (IQR 62.6, 84.0), 5-year BCF event free-rate (95% CI) was 94.6% (91.9% - 96.4%) vs 95.7% (93.2% - 97.3%) for CRT and SBRT groups respectively. SBRT was non inferior to CRT with unadjusted HR (90% CI) = 0.74 (0.47 - 1.17), p-value for non-inferiority=0.007. The estimated absolute differences in the proportion of patients event free in the SBRT group compared with that in the CRT group at 5 years was: 1.36% (90% CI: 0.87 - 2.80). At 5 years, RTOG grade 2 or worst (G2+) genitourinary toxicity was seen in 3.2% (11/348) pts who received CRT and 5.5% (20/363) pts who received SBRT (p=0.14); RTOG G2+gastrointestinal toxicity was seen in 1/348 receiving CRT and 1/363 received SBRT (p=0.99).

Conclusion
Five-year BCF free rates are high in PACE-B participants. After median follow-up of six years, five-fraction-SBRT is non-inferior to CRT for BCF. SBRT reduces pts attendances, shortens treatment time and 5 fraction SBRT should be a new standard of care for pts with low/favourable intermediate risk LPCa.