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A PARP inhibitor works for men whose prostate cancer carries a BRCA fault, and does not work for men whose fault is in ATM. Which gene is broken decides whether the drug helps.
TRITON3 is the cleanest demonstration in prostate cancer that homologous recombination repair is not one thing. Of 4,855 men prescreened or screened, 405 were randomised 2:1 to rucaparib 600 mg twice daily (270) or physician's choice of docetaxel or a second androgen receptor pathway inhibitor (135). Of these, 201 and 101 had a BRCA alteration.
At 62 months, imaging-based progression-free survival was significantly longer with rucaparib in the BRCA subgroup, median 11.2 against 6.4 months, hazard ratio 0.50 (95 percent confidence interval 0.36 to 0.69), and in the intention-to-treat population, 10.2 against 6.4 months, hazard ratio 0.61 (0.47 to 0.80), p<0.001 for both.
In the exploratory ATM subgroup, median imaging-based progression-free survival was 8.1 months with rucaparib and 6.8 months with control, hazard ratio 0.95 (0.59 to 1.52). That is no effect. ATM is routinely counted as a homologous recombination repair gene on panel reports, and TRITON3 is the evidence that counting it that way over-promises.
The most frequent adverse events with rucaparib were fatigue and nausea. The screening ratio, 4,855 to 405, is worth quoting to any man being offered genomic testing: the eligible genotype is uncommon, and a negative result is the usual result.
Numbers are from the trial as recorded here; see the source links in the table below. This is orientation, not medical advice: ask your team how closely the trial population matches you.
405 randomised.
Exploratory analysis; no benefit.
Source| Endpoint | Arm | n | Value | HR (95% CI) | p | Source |
|---|---|---|---|---|---|---|
| Imaging-based progression-free survival, BRCA subgroup (median)primary | Rucaparib 600 mg twice daily | 201 | 11.2 months | 0.5 (0.36 to 0.69) | <0.001 | link |
| Physician's choice | 101 | 6.4 months | ||||
| Imaging-based progression-free survival, intention to treat (median) | Rucaparib 600 mg twice daily | 270 | 10.2 months | 0.61 (0.47 to 0.8) | <0.001 | link |
| Physician's choice | 135 | 6.4 months | ||||
| Imaging-based progression-free survival, ATM subgroup (median) | Rucaparib 600 mg twice daily | - | 8.1 months | 0.95 (0.59 to 1.52) | - | link |
| Physician's choice | - | 6.8 months |
Shares Clovis Oncology, Rucaparib, PARP, Prostate cancer.
Shares Clovis Oncology, Rucaparib, PARP, PARP inhibitors.
Shares Rucaparib, Homologous recombination deficiency (HRD), PARP, PARP inhibitors.
Shares PROfound, ATM, Homologous recombination deficiency (HRD), PARP.
Shares Clovis Oncology, Rucaparib, Homologous recombination deficiency (HRD), BRCA1 / BRCA2 (HRD).
Shares MAGNITUDE, PARP, PARP inhibitors, BRCA1 / BRCA2 (HRD).
Shares PROfound, PARP, PARP inhibitors, BRCA1 / BRCA2 (HRD).
Shares Clovis Oncology, Rucaparib, ATM, Homologous recombination deficiency (HRD).