Key efficacy data from trials of PARP inhibitors in prostate cancer
Study: PROfound
(NCT02987543)a ; [1,2]
Phase |
Treatment arms |
Patient population |
III |
Olaparib vs enzalutamide or abiraterone, plus prednisone Patients in the control group were eligible to cross over to olaparib after confirmed progression |
|
Key efficacy results
rPFS |
In patients with BRCA1/2 or ATM mutations 7.4 months vs 3.6 months HR: 0.35; 95% CI: 0.25–0.47; p<0.001 |
OS# unadjusted for cross-over to olaparib |
In patients with BRCA1/2, or ATM mutations 19.1 months vs 14.7 months HR: 0.69; 95% CI: 0.50–0.97; p=0.02 |
OS adjusted for crossover to olaparib# |
In patients with BRCA1/2, or ATM mutations HR: 0.42; 95% CI: 0.19–0.9 |
ORR |
In patients with BRCA1/2 or ATM mutations 33% vs 2% OR: 20.86; 95% CI: 4.18–379.18; p<0.001 |
TPP |
In patients with BRCA1/2 or ATM mutations NR vs 9.92 HR: 0.44; 95% CI: 0.22–0.91; p=0.02 |
Study: COMRADE
(NCT03317392) ; [3]
Phase |
Treatment arms |
Patient population |
I/IIb |
Olaparib plus Ra233 |
|
Key efficacy results
6-month rPFS |
57% |
PSA50 |
16.7% |
ALP30 |
67% |
Study: TRITON2
(NCT02952534)a ; [4]
Phase |
Treatment arms |
Patient population |
II |
Rucaparib |
|
Key efficacy results
ORR |
In patients with BRCA1/2 mutations 43.5% 95% CI: 31.0–56.7 |
rPFS |
In patients with BRCA1/2 mutations 9.0 months 95% CI: 8.3–13.5 |
1-year OS+ |
In patients with BRCA1/2 mutations 73.0% 95% CI: 62.9–80.7 |
Study: GALAHAD
(NCT02854436); [5,6]
Phase |
Treatment arms |
Patient population |
II |
Niraparib |
|
Key efficacy results
ORR |
In patients with BRCA1/2 mutations 41.4% |
Study: NiraRad
(NCT02854436); [7]
Phase |
Treatment arms |
Patient population |
Ib |
Niraparib |
|
Key efficacy results
PSA50 |
10% |
ALP30 |
43% |
Study: TALAPRO-1
(NCT03148795); [8]
Phase |
Treatment arms |
Patient population |
II |
Talazoparib |
|
Key efficacy results
ORR |
In patients with BRCA1/2 mutations 46% |
ALP30, ≥30% reduction in alkaline phosphatase level; CI, confidence interval; HR, hazard ratio; HRD, homologous recombination deficiency; mCRPC, metastatic castration-resistant prostate cancer; NR, not reached; ORR, objective response rate; OS, overall survival; rPFS, radiographic progression-free survival; PSA50, ≥50% PSA decline in prostate-specific antigen; TPP, time to pain progression.
a Registration trial
bPhase I study results
# As the majority of patients in the control group crossed over (66%) and ~75% of patients had already received taxane-based chemotherapy before inclusion, olaparib was effectively evaluated as a third-line treatment.
+ Immature data (41% of events reported)
++ As of 23 May 2019
*BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L
**ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C
Emerging data suggest that some HRR alterations are not as predictive as BRCA mutations for patient benefit in mCRPC. Recent analysis of data for non-BRCA alterations and response to rucaparib from the TRITON2 study showed limited responses in men with alterations in ATM, CDK12, or CHEK2.[9] Importantly, responses to rucaparib were observed in association with (less frequent) alterations in FANCA, PALB2, BRIP1, or RAD51B [9]. Similarly, patients with alterations in ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L did not respond to olaparib as well as those with BRCA1/2 mutations.[10,11]. Further study of these biomarkers is clearly warranted.
References
[1] de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020 May 28;382(22):2091-2102.
[2] Hussain M, Mateo J, Fizazi K, et al. Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. 2020 Dec 10;383(24):2345-2357.
[3] McKay RR, Xie W, Ajmera A, et al. A phase 1/2 study of olaparib an radium-233 in men with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases (COMRADE): Results of the phase 1 study. J Clin Oncol. 2021;39(15_suppl): e17020.
[4] Abida W, Patnaik A, Campbell D, et al. Rucaparib in men with metastatic castration-resistant prostate cancer Harboring a BRCA1 or BRCA2 Gene Alteration. J Clin Oncol. 2020 Nov 10;38(32):3763-3772.
[5] Smith MR, Fizazi K, Sandhu SK, et al. Niraparib in patients with metastatic castration-resistant prostate cancer and biallelic DNA-repair gene defects: Correlative measures of tumor response in phase II GALAHAD study. J Clin Oncol. 2020;38(6_suppl):118.
[6] Smith MR, Sandhu SK, Kelly WK, et al. Pre-specified interim analysis of GALAHAD: A phase II study of niraparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD). Ann Oncol. 2020;30(Suppl 5):V884-885.
[7] Kelly WK, Leiby B, Einstein DJ, et al. Radium-223 and niraparib treatment in castrate-resistant prostate cancer patients with and without Prior Chemotherapy. J Clin Oncol. 2020;38(5_suppl):5540.
[8] de Bono JS, Mehra N, Scagliotti GV, et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol. 2021 Aug 10:S1470-2045(21)00376-4.
[9] Abida W, Campbell D, Patnaik A, et al. Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration-resistant prostate cancer: Analysis From the Phase II TRITON2 study. Clin Cancer Res. 2020 Jun 1;26(11):2487-2496.
[10] Marshall CH, Sokolova AO, McNatty AL, Cheng HH, Eisenberger MA, Bryce AH, Schweizer MT, Antonarakis ES. differential response to olaparib treatment among men with metastatic castration-resistant prostate cancer harboring BRCA1 or BRCA2 versus ATM mutations. Eur Urol. 2019 Oct;76(4):452-458.
[11] Stopsack KH. Efficacy of PARP inhibition in metastatic castration-resistant prostate cancer is very different with non-BRCA DNA repair alterations: Reconstructing prespecified endpoints for Cohort B from the Phase 3 PROfound Trial of olaparib. Eur Urol. 2021 Apr;79(4):442-445.