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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

  • N=387
  • mCRPC
  • Progressive disease
  • ≥1 HRR gene alteration*
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

  • N=12
  • mCRCP
  • With bone metastases
Key efficacy results

6-month rPFS

57%
95% CI: 28–80

PSA50

16.7%

ALP30

67%

Study: TRITON2

(NCT02952534)a ; [4]

Phase

Treatment arms

Patient population

II

Rucaparib

  • N=115
  • mCRPC
  • Progressive disease
  • DDR gene alterations
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

  • N=165+
  • mCRPC
  • Progressive disease
  • Biallelic HRD alteration
 Key efficacy results

ORR

In patients with BRCA1/2 mutations

41.4%

Study: NiraRad

(NCT02854436); [7]

Phase

Treatment arms

Patient population

Ib

Niraparib
plus Ra223

  • N=30
  • mCRPC
  • Progressive disease
 Key efficacy results

PSA50

10%

ALP30

43%

Study: TALAPRO-1

(NCT03148795); [8]

Phase

Treatment arms

Patient population

II

Talazoparib

  • N=128
  • mCRPC
  • Progressive disease
  • HRR gene alterations**
 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.

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