PARP inhibitors slow progression and increases survival in men with BRCA gene mutations

The PROfound Trial has reported (here) significant improvements in progression-free survival in men with BRCA2, BRCA1, and ATM gene mutations who took the PARP inhibitor, olaparib (Lynparza). BRCA2, BRCA1, and ATM germline gene mutations are found in about 8% of men with metastatic castration-resistant prostate cancer (mCRPC). The study also included men in whom those genes were mutated in their tumors (called "somatic" mutations). PARP inhibitors inhibit an enzyme that supports the survival of DNA-damaged cancer cells. Lynparza is FDA-approved for ovarian cancer and breast cancer. Other FDA-approved PARP inhibitors comprise Rubraca (rucaparib) and Zejula (niraparib) for ovarian cancer, and Talzena (talaparib) for breast cancer. They are all in clinical trials for prostate cancer (see this link).

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)

Among the combined cohorts (A+B):

• 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

Median overall survival (OS) (updated 9/22/20 ):

• Cohort A: 19.1 months vs 14.7 months (HR=0.69, p=0.02)
• Cohort A+B: 17.3 months vs 14.0 months (not statistically significant)
• Cohort B: 14.1 months vs 11.5 months (not statistically significant)
• Two-thirds of controls crossed-over to receive olaparib
• After adjusting for cross-over, the hazard ratio improved to 0.42 in Cohort A, but were not significant in Cohort B or Cohort A+B

Adverse Events:

• 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

(update 5/19/20) The FDA approved Lynparza for mCRPC patients with germline or somatic homologous recombination repair mutations who have progressed on Zytiga or Xtandi.

In a small study (12 BRCA1/2-mutant, 5 ATM-mutant), Marshall et al. reported activity in men with BRCA1/2 mutations, but not ATM mutations:

• 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) were 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.

(update 8/23) The percent who had a reduction in PSA greater than 50%:

• BRCA1/2: 53%
• PALPB2: 55%
• ATM: 3.4%
• CDK1/2: 6.7%
• CHEK2: 14%
• Other DDR: 23%

There was high treatment-related toxicity in these heavily pre-treated patients:

• 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%)

(Update 5/15/20) The FDA approved rucaparib for men who have the BRCA mutation (either germline or somatic, and have had prior taxane chemotherapy and AR-directed hormone therapy.

(Update 2/18/23) Triton 3  compared rucaparib to physician's choice of abiraterone, enzalutamide or docetaxel in 405 patients who were either BRCA+ or ATM+. After 62 months of follow-up:

• radiographic Progression Free Survival (rPFS) was 10.2 mos. vs 6.4 mos. -- 39% improvement for rucaparib.
• rPFS was 11.2 mos. vs 6.4 months in those who were BRCA+ (50% improvement)
• rPFS was not significantly different for ATM+ patients
• (update) rPFS improvement was 36% compared to docetaxel, and 53% compared to abi or enza
• In those with BRCA+, rPFS improvement was 47% compared to docetaxel, and 62% compared to abi or enza
• fatigue, nausea, and high BP were the most non-hematological frequent adverse events
• anemia and neutropenia were the most serious hematological events

(Update 2/22/21) Early results of the TALAPRO-1 trial of talaparib have been presented. The 128 patients were previously treated with docetaxel, and half had cabazitaxel too. The trial only included patients with genomic DNA damage-repair (DDR) defects.

• The overall objective response rate (ORR) was 30% 
• 46-50% for BRCA1/2
• 25% for PALB2
• 12% for ATM
• ORR took 3.4 months to be observable and lasted for 12.8 months
• Radiographic progression-free survival (rPFS) was 5.6 months
• 11.2 months for BRCA1/2
• 5.6 months for PALB2
• 3.5 months for ATM and other DDR defects
• Most saw a reduction in tumor burden (82%), PSA (72%), and CTC (82%)
• Reductions greatest BRCA1/2>PALB2>ATM (similar patterns in overall survival and time to PSA progression).
• The most common treatment-emergent adverse events were anemia (49%), nausea (33%), decreased appetite (28%) and asthenia (24%).
• Serious/life-threatening adverse events included anemia (31%), decreased platelet count (9%), neutropenia (8%), and pulmonary embolism (6%)
• 12% discontinued treatment due to adverse events

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).