Olaparib monotherapy in advanced triple-negative breast cancer patients with homologous recombination deficiency and without germline mutations in BRCA1/2: The NOBROLA phase 2 study

Abstract

Purpose

To evaluate olaparib in advanced triple negative breast cancer (TNBC) patients with homologous recombination deficiency (HRD) and no germline BRCA1/2 mutations (gBRCA1/2mut).

Methods

NOBROLA (NCT03367689) is a single-arm, open-label, multicenter, phase IIa trial, enrolling adult patients with advanced TNBC without gBRCA1/2mut and with HRD, who were treated with olaparib. The primary endpoint was clinical benefit rate (CBR) per RECIST v.1.1.

Results

Six of 114 patients were eligible and received olaparib. Median follow up was 8.5 months. CBR and overall response rate (ORR) were 50 % (95 % CI, 11.8–88.2).

Conclusions

The observed results could prompt further investigation.

Trial

ClinicalTrials.gov identifier NCT03367689.

Highlights

• •TNBC is a heterogenous disease with poor prognosis and limited therapeutic options.
• •Olaparib was approved for HER2-negative advanced BC patients with gBRCA1/2mut.
• •Out of 114 patients screened, only 6 were eligible and received olaparib.
• •Olaparib showed 50 % of CBR and ORR in advanced TNBC patients with HRD and without gBRCA1/2mut.
• •The patient population was low, and the results warrant further investigation in larger trials.

1. Introduction

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) that represents 10–20 % of BC cases [1,2]. TNBC, defined by lack of tumor cell expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) [3], exhibits increasing tumor heterogeneity [4] and genomic instability, which can be caused by homologous recombination deficiency (HRD) [1,5]. HRD can result from germline mutations in BRCA1/2 genes, as well as somatic BRCA1/2 mutations or germline mutations in other genes involved in homologous recombination repair (HRR), found in 10–15 % and less than 4 % of TNBC, respectively [6,7]. Loss-of-function mutations in HRR genes sensitise tumors to poly (ADP-ribose) polymerase inhibitors (PARPi) [8,9]. In TNBC, PARPi are approved for patients with germline BRCA1/2 mutations (gBRCA1/2mut) [2,10]; however, HRD tumors without gBRCA1/2mut display synthetic lethality with PARPi [[11], [12], [13], [14], [15], [16]]. The NOBROLA trial aimed to evaluate the activity of olaparib monotherapy in advanced TNBC patients with HRD and without gBRCA1/2mut.

2. Material and methods

2.1. Study design

NOBROLA (NCT03367689) was a single-arm, open-label, multicenter phase IIa trial conducted across 17 Spanish sites enrolling adult patients with advanced TNBC without gBRCA1/2mut and HRD, determined by Myriad myChoice® HRD Plus CDx or FoundationOne® CDx tests. Detailed eligibility criteria are provided in Supplementary Material.

This study was performed in agreement with the Declaration of Helsinki and Good Clinical Practice guidelines and was approved by Institutional Review Boards or independent ethics committees at each site. All patients provided written informed consent.

2.2. Procedures

Patients received 300 mg of olaparib orally, twice daily, throughout 28-day cycles until disease progression, symptomatic deterioration, unacceptable toxicity, death, withdrawal of consent, or study completion, whichever occurred first. Detailed procedures are reported in Supplementary Material.

2.3. Outcomes

The primary endpoint was clinical benefit rate (CBR), assessed by investigators as per RECIST v.1.1. Secondary efficacy and safety outcomes are detailed in Supplementary Material.

2.4. Statistical analysis

Statistical analyses are detailed in Supplementary Material.

3. Results

Between April 2018 and December 2021, 114 patients were screened and only six received olaparib (Fig. 1, Table 1). The study was prematurely terminated because of slow accrual.

Fig. 1.

Patient disposition.

Table 1.

Patient disposition.

Parameter	n (%) N = 114
Patients tested with FoundationOne® CDx	53 (46.5)
Included	2 (3.8)
Excluded	51 (96.2)
Patient's decision	2 (3.8)
Withdrawal of consent	2 (3.8)
Non-fulfilment of inclusion criteria	47 (88.7)
HRD negativea	24 (45.3)
Inadequate or unavailable tissue sample	7 (13.2)
Disease progression to a prior platinum-based treatment	11 (20.7)
Hormone receptor statusb	3 (5.7)
Non-measurable disease only	1 (1.9)
Number or type of prior lines of treatment	1 (1.9)
Patients tested with Myriad myChoice® HRD Plus CDx	61 (53.5)
Included	4 (6.6)
Excluded	57 (93.4)
Death	4 (6.6)
Recruitment closed	2 (3.3)
Non-fulfilment of inclusion criteria	51 (83.6)
HRD negativea	18 (29.5)
Inadequate or unavailable tissue sample	13 (21.3)
Disease progression to a prior platinum-based treatment	10 (16.4)
Number or type of prior lines of treatment	7 (11.5)
ECOG PS ≥ 2	1 (1.6)
Non-measurable disease only	1 (1.6)
Hormone receptor status	1 (1.6)

Percentages may not add up to 100 because of rounding.

Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; HRD, homologous recombination deficiency.

^aHRD negative indicates either no relevant alteration in any HRD-related genes (FoundationOne® CDx test) or a score <33 (Myriad myChoice® HRD Plus CDx test).

^bLogistic issues led to 3 patients receiving delayed results.

All patients were women, with a median age of 60 (range, 45–76) years and received up to three prior lines of treatment in the advanced setting. Baseline characteristics are in Table 2. By November 24, 2022, median follow-up time was of 8.5 months (range, 4.2–34.4). All patients discontinued treatment because of disease progression. At data cutoff, one patient was alive, four had died, and one was lost to follow-up 6 months after the study beginning. Three patients achieved partial responses for a CBR at 24 weeks of 50 % (95 % CI, 11.8–88.2) among 6 patients and an overall response rate (ORR) of 50 % (95 % CI, 11.8–88.2) (Table 3).

Table 2.

Baseline patient characteristics.

Baseline characteristics	n (%) N = 6
Age; median (min; max) (years)	60 (45; 76)
Sex
Female	6 (100)
Male	0 (0)
Disease status
Locally advanced disease	0 (0)
Metastatic disease	6 (100)
ECOGPS
0	2 (33)
1	4 (67)
Measurable disease
Yes	6 (100)
No	0 (0)
Number of target lesions
1	3 (50)
2	1 (17)
3	2 (33)
Metastatic sites
Bone	1 (17)
Brain	1 (17)
Liver	1 (17)
Lung	2 (33)
Lymph nodes	2 (33)
Previous treatment for early disease
Yes	6 (100)
No	0 (0)
(Neo)adjuvant treatment for early disease
Taxane	6 (100)
Platinum	6 (100)
Anthracycline	6 (100)
Cyclophosphamide	6 (100)
Anastrozole	1 (17)
Trastuzumab	1 (17)
Fluorouracil	1 (17)
Others	6 (100)
Number of previous lines of therapy for ABC
1	1 (17)
2	2 (33)
3	3 (50)
Previous treatment for ABC
Taxane	6 (100)
Platinum	1 (17)
Anthracycline	1 (17)
Capecitabine	5 (83)
Eribulin	1 (17)
Gemcitabine	1 (17)
Targeted therapy	3 (50)
Atezolizumab	1 (17)
Others	6 (100)

Abbreviations: ABC, advanced breast cancer; ECOG PS, Eastern Cooperative Oncology Group performance status.

Table 3.

Efficacy analyses (per RECIST v1.1) assessed by investigators.

CBR	ORR	BOR	TTR (months)	DOR (months)	PFS		OS
					Months	Event	Months	Event
Individual patient data
Yes	Yes	PR	3.6	4.7	8.3	PD	12.0	No
Yes	Yes	PR	1.8	13.2	15.1	PD	19.5	Death
Yes	Yes	PR	1.9	4.9	7.0	PD	7.8	Death
No	No	SD < 24W			3.5	PD	34.4	Death
No	No	PD			1.0	PD	4.3	Death
No	No	SD < 24W			5.4	PD	6.7	Loss to FU
Global data∗
50 (11.8–88.2)			1.9 (1.8–3.6)	4.9 (4.7–13.2)	6.2 (0.8–15.1)		19.4 (4.2–34.4)

Abbreviations:BOR: Best Overall Response; CBR: Clinical Benefit Rate; DOR: Duration Of Response; FU: Follow-Up; ORR: Overall Response Rate; OS: Overall Survival; PD: Progressive Disease; PFS: Progression-Free Survival; PR: Partial Response; SD: Stable Disease; TTR: Time to response; W: Weeks.

^∗The values in parentheses for CBR, ORR, PFS, and OS are expressed as 95% confidence intervals. The values in parentheses for TTR and DOR are expressed as minimum and maximum.

Median time to response was 1.9 months (95 % CI, 1.8–3.6) and median duration of response was 4.9 months (95 % CI, 4.7–13.2). Median progression-free survival was 6.2 months (95 % CI, 0.8–15.1) and median overall survival was 19.4 months (95 % CI, 4.2–34.4) (Supplementary Fig. 1).

Treatment-emergent adverse events (TEAEs) were grade 1–2 (5 [83.3 %] events). Grade 3 TEAEs occurred in 66.6 % patients, being anemia the most frequent (33 %). There were no grade 4 TEAEs (Supplementary Table 1). The most common TEAEs of any grade were anemia (83 % patients), and fatigue (50 % patients). All TEAEs are shown in Supplementary Table 2. Any patient experienced serious TEAEs related to olaparib. No treatment-related deaths occurred.

4. Discussion

The NOBROLA phase II trial showed antitumor activity of olaparib monotherapy in 50 % of advanced TNBC patients with HRD and without gBRCA1/2mut, a rare group of patients with limited treatment options and who have not been considered in previous clinical trials.

Tumors with gBRCA1/2mut in the homologous recombination pathway are significantly prevalent in TNBC and associated with response to PARPi [11,16]; however, PARPi also have activity in tumors beyond gBRCA1/2mut [17]. The Talazoparib Beyond BRCA phase II trial reported 54 % CBR in patients with mutations in genes different from BRCA1/2 [12]. Similarly, the TBCRC 048 phase II trial demonstrated 50 % CBR with olaparib in BC patients with germline non-BRCA1/2 [14]. The PETREMAC phase II study achieved 51.9 % ORR using olaparib in TNBC without germline BRCA1/2 and PALB2 mutations [18]. Apart from the small sample size, clinical responses observed in our study may probably occur because HRD is associated with response to PARPi, even independently of the BRCA1/2 status [19], and other HRD-related genes beyond BRCA1/2 may be sensitive to these treatments [20].

NOBROLA was a non-randomized trial in which low frequency of HRD cases was detected after more than 100 analyses and, therefore, the trial was closed earlier than expected. Most of screened subjects had no relevant alterations in the HRD-related genes. HRD can result from deleterious mutations in HRR genes in a very low percentage of TNBC patients [6,7]. BRCA1/2 mutations are the most common mutations to cause HRD [21]; however, mutations in other HRD-related genes (such as RAD51 or ATM) may occur, although these events are less frequent [[21], [22], [23]]. Altogether, this may explain the low incidence of HRD cases in the screened population. The results of this study must be interpreted with caution due to some limitations, which included (a) the heterogeneous definition of the HRD status, which is related to differences in the methods used to assess HRD, the biological complexity of HRR pathways, and the types of genomic alterations evaluated [24], (b) the slow patient accrual rate due to the low incidence of HRD cases and, consequently, (c) the small sample size and limited dataset, which weakened the statistical power of the results and precluded several planned analyses.

This only prompts more data and more relevant selection criteria. The low incidence in this population presents a significant challenge that limits conducting studies with a large sample size. If results from future trials were similar, entities should reconsider the approval of new drugs in infrequent patient populations without requiring pivotal phase III studies.

5. Conclusions

Olaparib provided antitumor activity in 50 % of patients. These results warrant further investigation in larger trials.

CRediT authorship contribution statement

Alfonso Cortés: Writing – original draft, Validation, Supervision, Investigation. Elena López-Miranda: Writing – original draft, Validation, Supervision, Resources, Investigation. Adela Fernández-Ortega: Writing – original draft, Validation, Supervision, Resources, Project administration, Investigation. Vicente Carañana: Writing – original draft, Validation, Supervision, Resources, Investigation. Sonia Servitja: Writing – original draft, Validation, Supervision, Investigation. Ander Urruticoechea: Writing – original draft, Validation, Supervision, Investigation. Laura Lema-Roso: Writing – original draft, Validation, Supervision, Resources, Investigation. Antonia Márquez: Writing – original draft, Validation, Supervision, Resources, Investigation. Alexandros Lazaris: Writing – original draft, Validation, Resources, Project administration. Daniel Alcalá-López: Writing – original draft, Formal analysis, Data curation. Leonardo Mina: Writing – original draft, Formal analysis, Data curation. Petra Gener: Writing – original draft, Validation. Jose Rodríguez-Morató: Writing – original draft, Validation. Gabriele Antonarelli: Writing – original draft, Validation, Investigation. Antonio Llombart-Cussac: Writing – original draft, Validation, Supervision, Investigation, Funding acquisition, Conceptualization. José Pérez-García: Writing – original draft, Validation, Supervision, Investigation, Conceptualization. Javier Cortés: Writing – original draft, Validation, Supervision, Investigation, Funding acquisition, Conceptualization.

Data sharing statement

Data collected within the NOBROLA study will be made available to researchers upon revision and approval based on scientific merit by the trial management group (which includes a qualified statistician) of a detailed proposal for their use. The data required for the approved, specified purposes and the trial protocol will be provided after the completion of a data-sharing agreement that will be set up by the study sponsor. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

Declaration of competing interest

AC declares consulting or advisory role (GSK, AZ, Pfizer, and Daiichi Sankyo), speaker's bureau (GSK, AZ, MSD, Clovis, and Accord), research funding (Pfizer, and GSK), travel expenses (Daiichi Sankyo, and Pfizer), and other relationships (Co-founder ONCAR). EL-M declares consultant or advisory board role (Roche, AstraZeneca, and Daiichi Sankyo), and travel expenses (Roche, and Gilead). SS declares speakers' bureau (Daiichi-Sankyo, AstraZeneca, RocheO, and Novartis), advisory board role (Seagen, Genomic Health, MSD, and Daiichi-Sankyo) and travel expenses (Daiichi-Sankyo). AL, DA-L, LM, PG, and JR-M declare to be employees at Medica Scientia Innovation Research (MEDSIR). GA declares honoraria from Medica Scientia Innovation Research (MEDSIR). AL-C declares research support (Roche, Agendia, Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Gilead, and Daichii-Sanyo), consulting or advisory role (Lilly, Roche, Pfizer, and Novartis). speakers’ bureaus (Lilly, AstraZeneca, and Merck Sharp & Dohme), travel expenses (Roche, Pfizer, and AstraZeneca), and stock or other ownership (MEDSIR and Initia-Research). JP-G declares advisory role (Lilly, Roche, Eisai, Daichii Sankyo, AstraZeneca, Seattle Genetics, and Gilead). travel expenses (Roche) and employment (MEDSIR). JC declares consulting or advisory role (Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Expres2ion Biotechnologies), honoraria (Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, Daiichi Sankyo, Astrazeneca), research funding to the Institution (Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F. Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London), Stock (MedSIR, Nektar Pharmaceuticals, Leuko [relative]), Travel, accommodation, expenses (Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, AstraZeneca, Gilead), and patents (Pharmaceutical Combinations of A Pi3k Inhibitor And A Microtubule Destabilizing Agent. Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde. WO 2014/199294 A. ISSUED; Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Aleix Prat, Antonio Llombart, Javier Cortés.US 2019/0338368 A1_LICENSED). AF-O, VC, AU, LL-R, and AM declare no conflicts of interests.

Appendix A. Supplementary data

The following is the supplementary data to this article: