Integrating PARP Inhibitors Into the Management of Breast Cancer

Where Are We?

Hamdy A. Azim; Loay Kassem; Hatem Azim Jr

Chin Clin Oncol. 2021;10(5):50

Abstract and Introduction

Abstract

During the last 2 decades, extensive research has focused on the molecular functions of BRCA1 and BRCA2 genes. This has led to the development of Poly(ADP-ribose) polymerase inhibitors (PARPi), as effective target therapies, based on their preferential cytotoxicity in tumor cells harboring germline BRCA1 and BRCA2 mutations. At the present time, 2 PARPi (Olaparib and Talazoparib) are approved as single agent for the treatment of patients with metastatic HER2–ve breast cancer, who have BRCA germline mutations. The clinical benefit of these agents might be also anticipated in patients harboring germline mutations in some additional genes involved in the process of homologous recombination repair (HRR) other than BRCA1/BRCA2. In this review, we summarize the molecular rational for the therapeutic development of PARPi and the clinical evidence supporting their use as anticancer drugs in breast cancer patients with BRCA1/BRCA2 germline mutations. We also discuss the role of platinum-based chemotherapy and how it compares with PARPi in the management of these patients. We will go through some relevant clinical trials of various combinations of PARPi with cytotoxic or immunotherapeutic agents, which may potentially provide better treatment results, compared to what is already achieved with their use as monotherapy.

Introduction

Approximately 5–10% of breast cancers are secondary to inherited mutations.

Table 1. Comparison between efficacy and safety outcomes of the OlympiAD and EMBRACA studies
Endpoint	OlympiAD: Olaparib vs. PCT	EMBRACA: Talazoparib vs. PCT
PFS (ITT)	7.0 vs. 4.2 months; HR 0.58 (95% CI, 0.43–0.80); P<0.001	8.6 vs. 5.6 months; HR 0.54 (95% CI, 0.41–0.71) P<0.001
PFS (HR+ patients)	HR =0.82 NS	HR =0.47
PFS (TN patients)	HR =0.43	HR =0.60
PFS (Platinum Rx)	HR =0.67 NS	HR =0.76 NS
PFS (no platinum Rx)	HR =0.60	HR =0.52
OS	19.3 vs. 17.1 months; HR: 0.90 (95% CI: 0.66–1.23; P=0.513)	19.3 vs. 19.5 months; HR: 0.85 (95% CI: 0.67–1.07; P=0.17)
ORR (ITT)	59.9% vs. 28.8%	62.6% vs. 27.2%
ORR (HR+ patients)	65.4% vs. 36.4	63.2% vs. 37.9%
ORR (TN patients)	54.7% vs. 21.2%	61.8% vs. 12.5%
TTR	47 vs. 45 days (NS)	2.6 vs. 1.7 months (NS)
DOR	6.2 vs. 7.1 months; HR NA	5.4 vs. 3.1 months; HR =0.43
TTDQoL	NR vs. 15.2 months; HR: 0.44 (95% CI: 0.25–0.77; P=0.0043)	24.3 vs. 6.3 months; HR 0.38 (95% CI, 0.26–0.55; P<0.0001)
Main AEs
Nausia	58% vs. 35%	48.6% vs. 46.8%
Anemia	40% vs. 26.4%	52.8% vs. 18.3%
Fatigue	29.8% vs. 24.2%	50.3% vs. 42.9%
D/c due to AEs	4.9% vs. 8.7%	5.9% vs. 8.7%

PFS, progression free survival; OS, overall survival; ORR, overall response rate; TN, triple negative; HR+, hormone receptor positive; TTDQoL, time to deterioration in global HRQoL; DOR, duration of response; TTR, time to response; AEs, adverse events; D/c, treatment discontinuation; NS, not significant; NR, not reached; HR, hazard ratio.

Table 2. Studies using Combination of veliparib + carboplatin/paclitaxel chemotherapy versus placebo + carboplatin/paclitaxel chemotherapy in early and advanced breast cancer women
Study	N	Phase	Disease setting	% gBRCA positive	PARPi dose	Chemo regimen	% pCR vs. Pla	% ORR vs. Pla	mPFS in mos vs. Pla	mOS in mos vs. Pla
BrighTNess	634*	Phase III, randomized (2:1:1)	Neoadj	15%	V 50 mg PO bid D1–7/3 weeks	C: AUC6; P: 80 mg/m²/week x12 weeks	53% vs. 58%; NS	83.4 vs. 83.3%; NS	NA	NA
BROCKADE 2	290**	Phase II, randomized (1:1:1)	aBC	100%	V 120 mg PO bid D1–7/3 weeks	C: AUC6; P: 175 mg/m²/3 weeks	NA	77.8% vs. 61.3%; P=0.027	14.1 vs. 12.3; P=0.227	28.3 vs. 25.9; P=0.156
BROCKADE 3	512	Phase III; randomized (2:1)	aBC	100%	V 120 mg PO bid; D-2 to D5/3 weeks	C: AUC6/3 wks. P: 80 mg/m²/week	NA	75.8% vs. 74%; NS	14.5 vs. 12.6; P=0.002	33.5 vs. 28.2; NS

*, 316 patients randomized to paclitaxel plus carboplatin plus veliparib, 160 patients randomized to paclitaxel plus carboplatin plus placebo, (and 158 patients randomized to paclitaxel alone, their data are not shown in Table 2); **, 97 patients randomized to paclitaxel plus carboplatin plus veliparib, 99 patients randomized to paclitaxel plus carboplatin plus placebo (and 94 patients randomized to temozolomide and veliparib, their data are not shown in Table 2). P, paclitaxel; C, carboplatin; V, veliparib; Pla, placebo; pCR, pathological complete remission; ORR, overall response rate; PFS, progression free survival; OS, overall survival; Mos, months; Wk, week; NS, not significant; aBC, advanced breast cancer; Neoadj, neoadjuvant.