Breast Cancer

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Ongoing Developments

There are many ongoing trials exploring the use of PARP inhibitors in other breast cancer settings or using alternative treatment strategies. These include use of talazoparib and niraparib in the metastatic setting, use of olaparib in the adjuvant setting, use of talazoparib in the neoadjuvant setting, identifying patients responsive to PARP inhibitor treatment including use of the RAD51 assay to identify potential responders to veliparib and combination strategies with chemotherapy and immunotherapies as the combination partner.

Neoadjuvant setting

A small phase II trial (NCT02282345) has evaluated neoadjuvant talazoparib for 6 months in patients with invasive breast cancer and a deleterious BRCA mutation, and reported promising results with the residual cancer burden (RCB) reduced to 0 for 9 out of 17 (53%) patients, and 10 out of 17 (59%) with RCB 0-1 prior to surgery [1]. To explore this further, a larger phase II trial (NCT03499353) has begun recruiting patients with germline BRCA-mutated early triple negative breast cancer (TNBC), and results are expected from 2021.

GeparOLA (NCT02789332) is a phase II study comparing neoadjuvant olaparib + paclitaxel versus carboplatin + paclitaxel, followed by a standard regimen of epirubicin + cyclophosphamide in patients with early HER2 negative breast cancer with HRD, including but not limited to BRCA mutations [2]. The olaparib + paclitaxel combination has shown a pathological complete response rate of 55% (90% CI 45-65%), similar to carboplatin-paclitaxel (49%, 90% CI 34-63%). Higher response rates in the subgroup analysis deserve further research. 

Adjuvant setting

The phase III, randomised OlympiA trial is evaluating adjuvant use of olaparib in patients with high-risk HER2-negative breast cancer with gBRCA mutations, and should reveal whether PARP inhibition can improve outcomes in breast cancer if given in an earlier treatment setting (NCT02032823) [3]. 

Metastatic setting

A number of trials are investigating PARP inhibitors in the metastatic breast cancer setting. Several of these now specify that patients must carry an identified mutation in an HRR-related gene before entering the study.

A phase II trial investigating talazoparib (TBB; NCT02401347) monotherapy in advanced, triple-negative or HER2-negative BRCA1/2 wild-type breast cancer is enrolling patients with demonstrated HRD [4]. Talazoparib demonstrated an ORR of 25% and was well tolerated [5]. This trial is similar in design to the NOBROLA trial (NCT03367689), a phase II study is assessing the efficacy of olaparib monotherapy in patients with previously treated, non-BRCA metastatic breast cancer, but who have another identified HRD-related mutation [6]. Eligible patients will be identified using the tissue-based Foundation Medicine, Inc. Lynparza Homologous Recombination Repair (HRR) test that assesses a panel of 15 HRR genes (BRCA1, BRCA2, ATM, RAD51B, RAD51C, RAD54L, RAD51D, FANCJ/BRIP1, FANCL, PALB2, BARD1, CHEK1, CHEK2, CDK12, PPP2) [6].

The phase III BRAVO trial (NCT01905592) of niraparib versus physician's choice in metastatic or locally advanced HER2 negative, gBRCA mutation-positive breast cancer was set to determine whether niraparib had a similar beneficial effect in breast cancer as it has in ovarian cancer. This study was prematurely closed after an interim analysis showed too many patients were not completing the necessary assessments in the control arm, and it was no longer suitable as a registration trial.

The phase II RUBY trial (NCT02505048) reported clinical benefit in a subset of patients with germline BRCA wild-type metastatic breast cancer whose tumour had high loss of heterozygosity scores (LOH)[7]. The clinical benefit rate was 13.5%, which included 1 complete response in a patient with high LOH, three partial responses in two patients with high LOH and 1 patient with a somatic BRCA mutation, and one patient with a somatic BRCA mutation with stable disease for more than 31 weeks.

Combination Strategies

A number of trials are exploring novel combinations of PARP inhibitors with other agents to improve efficacy and combat resistance in breast cancer, particularly combining them with established chemotherapies and immunotherapies [8]. A selection of these are presented below, but the list is not exhaustive.

Veliparib is the main PARP inhibitor to be combined with chemotherapy, for both early stage and metastatic breast cancer. The phase III BrighTNess trial assessed veliparib plus carboplatin versus carboplatin plus standard chemotherapy versus standard chemotherapy in early stage triple negative breast cancer (NCT02032277) [9]. The study identified a benefit in pathological complete response with the addition of carboplatin (58%), but not veliparib (53%), to standard paclitaxel (31%), followed by anthracycline-based regimen. The phase III BROCADE 3 trial is assessing carboplatin and paclitaxel with or without veliparib in HER2 negative metastatic or locally advanced BRCA-associated breast cancer (NCT02163694). In the phase II trial testing this combination (NCT01506609), veliparib plus carboplatin-paclitaxel showed a higher ORR compared to placebo-carboplatin-paclitaxel, 78% versus 61%, that did not translate in benefits in PFS (14.1 versus 12.3 months) [10].

Combinations of PARP/DDR targeted agents are also being explored. The phase II VIOLETTE study (NCT03330847) is currently studying the efficacy of olaparib monotherapy compared with olaparib + AZD6738 (ATR inhibitor) in previously treated patients with advanced TNBC [11]. The trial will stratify patients by HRR status (A: BRCA mutated; B: non-BRCA HRR mutated; C: non-HRR mutated) and by prior platinum exposure.

There is sound rationale for combining PARP inhibitors with immunotherapies based on preclinical studies that have demonstrated cross-talk between PARP inhibition/DDR pathway and tumour-associated immunosuppression [12, 13]. In particular there are trials underway assessing the combination of PARP inhibitors with immune checkpoint blockade agents like PD-L1 or PD-1 [12, 13].

• The phase II MEDIOLA trial is investigating olaparib plus durvalumab, an anti-PD-L1 antibody in solid tumours, including breast and ovarian cancer (NCT02734004) [14]. Initial results have indicated a high objective response rate of 70% of patients, and a low incidence of grade ≥3 adverse events or immune-related adverse events (any grade) [14].
• The phase II DORA trial (NCT03167619) is comparing olaparib versus the combination of olaparib plus durvalumab as maintenance therapy following clinical benefit with platinum-based therapy in metastatic TNBC [15, 16].
• The phase I/II TOPACIO/Keynote-162 is assessing niraparib plus pembrolizumab in patients with advanced triple-negative breast cancer or recurrent ovarian cancer (NCT02657889) [17].

 Identifying Patients Responsive to PARPi treatment

An ongoing trial (REPAIR; NCT03044795) is investigating how to improve identification of patients to personalise treatment with veliparib and improve outcomes from PARP inhibition by using RAD51 assay as a biomarker for identifying patients with increased risk of HRD.
It is important to note that there is a general lack of consensus as to what is the optimal HRD test, either available or in development, for identifying HRD and guiding therapy choice.

References

1. Litton JK, Scoggins M, Hess KR et al. Neoadjuvant talazoparib (TALA) for operable breast cancer patients with a BRCA mutation (BRCA+). Journal of Clinical Oncology 2018; 36: 508-508.
2. Fasching PA, Jackisch C, Rhiem K et al. GeparOLA: A randomized phase II trial to assess the efficacy of paclitaxel and olaparib in comparison to paclitaxel/carboplatin followed by epirubicin/cyclophosphamide as neoadjuvant chemotherapy in patients (pts) with HER2-negative early breast cancer (BC) and homologous recombination deficiency (HRD). Journal of Clinical Oncology 2019; 37: 506-506.
3. Tutt A, Kaufman B, Garber J et al. 216TiPOlympiA: A randomized phase III trial of olaparib as adjuvant therapy in patients with high-risk HER2-negative breast cancer (BC) and a germline BRCA1/2 mutation (gBRCAm). Annals of Oncology 2017; 28: mdx362.065-mdx362.065.
4. Afghahi A, Chang PJ, Ford JM, Telli ML. Abstract OT2-05-04: The Talazoparib Beyond BRCA (TBB) trial: A phase II clinical trial of talazoparib (BMN 673) in BRCA1 and BRCA2 wild-type patients with (i) advanced triple-negative breast cancer (TNBC) and homologous recombination deficiency (HRD) as assessed by myriad genetics HRD assay, and (ii) advanced HER2-negative breast cancer (BC) with either a germline or somatic mutation in homologous recombination (HR) pathway genes. Cancer Research 2016; 76: OT2-05-04.
5. Gruber JJ, Afghahi A, Hatton A et al. Talazoparib beyond BRCA: A phase II trial of talazoparib monotherapy in BRCA1 and BRCA2 wild-type patients with advanced HER2-negative breast cancer or other solid tumors with a mutation in homologous recombination (HR) pathway genes. J Clin Oncol 37, 2019 (suppl; abstr 3006) 2019.
6. Aguirre E, Amillano K, Cortés A et al. Abstract CT165: A two-stage Simon Design phase II study for NOn-BRCA metastatic BReast cancer (MBC)patients with homologous recombination deficiency treated with OLAparib single agent.(NOBROLA study). Cancer Research 2018; 78: CT165.
7. Patsouris A, Tredan O, Nenciu D et al. RUBY: A phase II study testing rucaparib in germline (g) BRCA wild-type patients presenting metastatic breast cancer (mBC) with homologous recombination deficiency (HRD). J Clin Oncol 37, 2019 (suppl; abstr 1092).
8. O'Connor MJ. Targeting the DNA Damage Response in Cancer. Mol Cell 2015; 60: 547-560.
9. Loibl S, O'Shaughnessy J, Untch M et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol 2018; 19: 497-509.
10. Han HS, Diéras V, Robson M et al. Veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer: randomized phase II study. Annals of Oncology 2018; 29: 154-161.
11. Tutt A, Stephens C, Frewer P et al. VIOLETTE: A randomized phase II study to assess DNA damage response inhibitors in combination with olaparib (Ola) vs Ola monotherapy in patients (pts) with metastatic, triple-negative breast cancer (TNBC) stratified by alterations in homologous recombination repair (HRR)-related genes. Journal of Clinical Oncology 2018; 36: TPS1116-TPS1116.
12. Jiao S, Xia W, Yamaguchi H et al. PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression. Clin Cancer Res 2017; 23: 3711-3720.
13. Mouw KW, Konstantinopoulos PA. From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation. Br J Cancer 2018; 118: 933-935.
14. Drew Y, de Jonge M, Hong SH et al. An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed (PSR) ovarian cancer (OC). Gynecol Oncol 2018; 149 Suppl 1: 246-247.
15. Dent R, Tan T, Kim SB et al. Abstract OT3-04-02: The DORA trial: A non-comparator randomised phase II multi-center maintenance study of olaparib alone or olaparib in combination with durvalumab in platinum treated advanced triple negative breast cancer (TNBC). Cancer Research 2018; 78: OT3-04-02.
16. Sammons S, Tan TJY, Traina TA et al. Dora: A randomized phase II multicenter maintenance study of olaparib alone or olaparib in combination with durvalumab in platinum responsive advanced triple-negative breast cancer (aTNBC).
17. Konstantinopoulos PA, Waggoner S, Vidal GA et al. Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma. JAMA Oncology 2019.