DASL-HiCaP NCT04136353
ForVery high-risk localised PCa, or PSA persistent/recurrent within 1 yr of RP
HR 0.42
95% CI 0.27-0.66, p=0.0001; 4-yr 95% vs 88%
TL;DR4-yr MFS-CI 95% vs 88%, HR 0.42 (0.27-0.66), adding darolutamide to 96-wk ADT plus prostate/bed and pelvic nodal RT in very high-risk disease.
Every pt received pelvic nodal RT with 96 wk of LHRH analog, so darolutamide's MFS-CI HR 0.42 is measured on top of elective nodal coverage, not instead of it. 29% were node-positive on CT and the benefit held across primary vs salvage RT and N+ vs N0 (subgroup HRs not in source). The decision it moves is ARSI intensification alongside whole-pelvis RT, not RT field or dose.
In very high-risk localised prostate cancer planned for 96 wk of ADT with prostate and pelvic nodal RT, this supports darolutamide intensification for MFS-CI; it does not yet establish an OS gain and gives thin data for post-RP salvage pts (15% of the cohort).
The RT backbone was fixed: prostate or prostate bed plus pelvic nodes in both arms, so the HR 0.42 adds to elective nodal RT rather than replacing it. Benefit was reported consistent for salvage RT and for CT node-positive pts (29%), but only 15% had prior RP and subgroup HRs are not in source.
Darolutamide 600 mg BID for 96 wk on top of 96 wk ADT cut MFS-CI events 27 vs 63 with G≥3 AEs 43% vs 36%, and fractures and cardiac G≥2 events no higher than placebo. OS (HR 0.88) and PCSS remain immature, so the ARSI choice in this setting hinges on surrogacy holding.
10 details 1 trial watching
International, placebo-controlled, randomised 1:1 phase III, N=1,106 accrued 30APR20 to 09AUG23. Single prespecified interim after 87 MFS-CI events, disclosed only if 2-sided p<0.012. Median follow-up 3.8 yr (IQR 3.3-4.5).
Very high-risk localised prostate cancer, or biochemically persistent/recurrent disease within 1 yr after RP. Median age 71, Gleason 9-10 in 73%, pelvic nodal involvement on CT in 29%, prior RP in 15%.
Darolutamide 600 mg BID vs placebo for 96 wk, both arms on an LHRH analog for 96 wk.
Definitive or salvage RT to prostate or prostate bed plus pelvic nodes in both arms. Dose and fractionation not reported in source.
Primary: MFS on conventional imaging (CT and/or Tc bone scan), chosen per ICECaP surrogacy for OS. Secondary: PSA-PFS, PCSS, OS.
Primary met at interim (table above). OncLive reports MFS benefit consistent across primary vs salvage RT and N+ vs N0, and castration resistance and subsequent hormonal therapy endpoints favouring darolutamide; no numbers given for those.
| Endpoint | Darolutamide N=553 | Placebo N=553 | HR (95% CI) |
|---|---|---|---|
| MFS-CI | 27 (95%) | 63 (88%) | 0.42 (0.27-0.66), p=0.0001 |
| PSA-PFS | 46 (91%) | 95 (83%) | 0.47 (0.33-0.67) |
| PCSS | 4 (99%) | 7 (99%) | 0.58 (0.17-1.97) |
| OS | 21 (97%) | 24 (95%) | 0.88 (0.49-1.59) |
| AE | Darolutamide | Placebo |
|---|---|---|
| Fatigue/asthenia G≥2 | 14% | 10% |
| Hypertension G≥2 | 7% | 9% |
| Fractures G≥2 | 2% | 3% |
| Cardiac G≥2 | 3% | 3% |
| Any AE G≥3 | 43% | 36% |
Any G≥3 AE 43% vs 36%. G≥2 fatigue/asthenia 14% vs 10%; hypertension, fractures and cardiac events not higher with darolutamide.
Tests the same ARSI-added-to-ADT-plus-RT question as ENZARAD (enzalutamide) and ATLAS (apalutamide), and sits against the STAMPEDE abiraterone data that currently anchor intensification in high-risk nonmetastatic disease. DASL-HiCaP differs by mandating pelvic nodal RT and including early post-RP salvage pts.
Staging and progression on conventional imaging in a PSMA-era practice; salvage pts are only 15%. Backbone was 96 wk ADT plus pelvic RT in everyone, so benefit with shorter ADT or prostate-only fields is untested.
The MFS-CI gain is large but OS events are few (21 vs 24) and PCSS is 99% in both arms at 4 yr. Whether this becomes a darolutamide option alongside abiraterone in this setting depends on surrogacy holding at final analysis.
CONSORT flow
Prespecified interim analysis, not the final primary analysis; MFS-CI surrogate with PCSS and OS immature (OS HR 0.88, CI crosses 1). Randomised, placebo-controlled design is otherwise clean.
- Does MFS-CI benefit translate to OS at final analysis?
- Benefit in PSMA PET-staged very high-risk disease recruiting Treatment of High-Risk Prostate Cancer Guided by Novel Diagnostic Radio- and Molecular Tracers Phase 2/3n=493 · primary completion 2030-07 · ph3 RT ± darolutamide, tracer-staged high-risk
- Darolutamide vs abiraterone intensification with pelvic RT
📚 Sources · 📄 3 papers
Abstract
Abstract
Abstract
The longer read
The question DASL-HiCaP answers is narrower than the headline suggests, and that is its strength. Radiotherapy was not randomised: every patient received prostate or prostate-bed irradiation with elective pelvic nodal coverage and 96 weeks of LHRH analog. What was tested is whether a second-generation AR inhibitor adds to an already intensive, field-generous local-plus-hormonal backbone. A metastasis-free survival hazard ratio of 0.42, with 27 versus 63 events, says it does, at least on conventional imaging. For a radiation oncologist the useful corollary is that the benefit sits on top of elective nodal RT; it gives no licence to shrink the field and no information about dose, which the source does not report.
The trial joins ENZARAD and ATLAS in asking the ARSI-plus-RT question, and it will be read against the STAMPEDE abiraterone data that currently justify intensification in high-risk nonmetastatic disease. Two design features distinguish it. Pelvic nodal RT was mandatory rather than optional, which removes one source of heterogeneity that complicates cross-trial reading. And it admitted pts with biochemically persistent or recurrent disease within a year of prostatectomy, a population that most intensification trials leave out. That inclusion is less informative than it looks: only 15% had prior RP, so the salvage estimate is drawn from a small subset, and the reported subgroup consistency comes without subgroup hazard ratios in the source.
The confidence a reader places in the result should move in two directions. Upward, because it is placebo-controlled, the interim was prespecified with a stringent disclosure threshold, and the PSA-PFS signal (HR 0.47) runs in the same direction. Downward, because this is an interim read of a surrogate. The authors chose MFS-CI on the strength of ICECaP surrogacy, but that validation came from an era of shorter ADT and different salvage options; whether a metastasis-free gain translates to survival when the control arm already receives two years of ADT plus pelvic RT is precisely what remains open. PCSS sits at 99% in both arms at four years and the OS interval spans 0.49 to 1.59, so the survival question is unanswered rather than negative.
Staging deserves its own caution. Metastases were defined by CT and technetium bone scan. In a population increasingly staged with PSMA PET, some patients classed here as nonmetastatic would be upstaged, and some MFS events would be detected earlier. That likely shifts absolute event rates more than the relative effect, but the 95% versus 88% four-year figures should not be transplanted directly onto PSMA-staged patients.
The toxicity cost appears modest: grade 3 or higher events rose from 36% to 43%, with fatigue the main added cluster and no excess in fractures or cardiac events. For the very high-risk patient already committed to two years of ADT and pelvic RT, the result makes darolutamide a credible intensification partner; what would make it wrong is an OS analysis that fails to follow the surrogate.