The PROfound Trial (details here) compared the effectiveness of Lynparza to either Xtandi or Zytiga (cohort B) in men who had already failed one of them. They compared the two groups in men who had somatic mutations in BRCA 1/2 or ATM (Cohort A, n=245) and in men who had somatic mutations in any of 12 other DNA-repair genes (Cohort B, n=142), and in men who had any of the 15 DNA-repair mutations (Cohort A+B, n=387). The trial was conducted at 229 sites. The 12 other DNA-repair mutated genes were BARD1, BRIP1, CDK12, CHK1/2, FANCL, PALB2, PPP2R2A, RAD51B/C/D, and RAD54L.
Their interim (median 1 year) findings comparing Lynparza vs Xtandi/Zytiga were as follows:
Median radiographic progression-free survival (rPFS):
- Cohort A: 7.4 months vs 3.6 months (HR=0.34, p<0.0001)
- Cohort A+B: 5.8 months vs 3.5 months (HR=0.49, p<0.0001)
- 6-month rPFS: 60% vs 23%
- 12-month rPFS: 28% vs 9%
- Objective Response Rate: 33% vs 2%
- Time to pain progression: not reached vs 10 months
- Cohort A: 18.5 months vs 15.1 months (HR=0.64, p=0.017)
- Cohort A+B: 17.5 months vs 14.3 months (HR=0.67, p=0.006)
- Lynparza patients had more anemia, nausea, fatigue & asthenia, decreased appetite, diarrhea/constipation, vomiting, and respiratory issues.
- 16.4% discontinued with Lynparza vs 8.5% discontinued with hormonal therapy
- Nevertheless, they stuck with Lynparza for 7.4 months vs 3.9 months with hormonal therapy
- Reduction of PSA by at least 50% was seen in 83% of men with BRCA1/2 mutations vs 0% of men with ATM mutations.
- Progression-free survival was 12.3 months in men with BRCA1/2 mutations vs 3.3 months in men with ATM mutations.
Similarly good responses among men with bi-allelic (both genes mutated) BRCA1/2 mutations vs other DNA-repair mutations were reported in a Phase 2 trial of niraparib. The FDA has granted it "breakthrough therapy" designation.
Men with CDK12 mutations (one of the DNA repair mutations in Cohort B of the PROfound trial) unsurprisingly did not respond to PARP inhibitors (see this link).
Preliminary results of the TRITON 2 clinical trial of rucaparib in men with DNA-damage repair (DDR) deficiencies (either germline or somatic) was also reported. Clinical benefit (the % who had no radiographic progression and stayed with rucaparib) at 6 months and 12 months for each of the DDR genes found were as follows:
- BRCA1/2: 56% (47/84) at 6 mos., 25% (6/53) at 12 mos.
- ATM: 29% (14/48) at 6 mos., 8% (2/25) at 12 mos.
- CDK12: 21% (3/14) at 6 mos., 7% (1/14) at 12 mos.
- CHK2: 67% (2/3) at 6 mos., 0% (0/1) at 12 mos.
- Other DDR: 50% (6/12) at 6 mos., 33% (3/9) at 12 mos.
- Treatment interruption or dose reduction in 54%
- Discontinuation in 9.5%
- Most common serious (grade 3+) adverse events: anemia (18%), fatigue (11%), thrombocytopenia (6%)
- 5 deaths (3%)
I would guess that the FDA will want to see the planned three-year results for olaparib, which are expected in 2021, although Astra-Zeneca may try to obtain fast-tracked approval based on this interim analysis. Meanwhile, patients are encouraged to get the relatively inexpensive ($249) germline test, or if negative for actionable mutations, a genomic test of a tumor biopsy or of cell-free DNA (from a blood test).