Predicting Olaparib Sensitivity in Patients With Unresectable Locally Advanced/Metastatic HER2-negative Breast Cancer. (RADIOLA)

Description

This is an open-label, single arm, multicentre phase II study evaluating treatment with olaparib in patients with unresectable locally advanced or metastatic breast cancer (MBC) in two cohorts:

1. with mutation in germline/somatic BRCA1/2, PALB2 or RAD51C/D and
2. RAD51-foci low score in wild type HRR tumours or without known deleterious BRCA1/2, PALB2 or RAD51C/D mutations at study entry.

Although efficacy and safety will be investigated. The primary objective consists in identifying a predictive biomarker for clinical benefit of treatment with olaparib.

All patients recruited in the study will be selected based on the following 3 principles:

• Genetic selection:
• Cohort 1: HER2-negative ABC with documented germline or somatic mutation in BRCA1, BRCA2, PALB2, RAD51C or RAD51D that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function). Patients with BRCA1, BRCA2, PALB2, RAD51C or RAD51D mutations that are considered to be non-detrimental (eg, "Variants of uncertain clinical significance" or "Variant of unknown significance" or "Variant, favor polymorphism" or "benign polymorphism," etc) will not be eligible for this cohort.
• Cohort 2: HER2-negative ABC with RAD51-foci low score in the most recent locally recurrence or metastatic biopsy and without known or with negative germline or somatic mutation in BRCA1, BRCA2, PALB2, RAD51C or RAD51D predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function). Mutation status will be assessed in, at least, olaparib responding patients in this subgroup.
• Phenotypic tumour selection: Patients can have either triple-negative breast cancer (defined as ER and PgR negative (IHC nuclear staining <1%) and HER2 negative (IHC 0, 1+ or 2+ and/or ISH non-amplified with ratio less than 2.0) or ER/PgR positive breast cancer, as long as they are HER2 negative.
• Treatment setting:
• Patients with ER and/or PgR positive breast cancer must have received and relapsed/progressed on at least one line of endocrine with/without CDK4/6 inhibitors either in the neo/adjuvant or advanced setting. or are not considered appropriate for endocrine w/wo CDK4/6i treatment.
• All patients should have unresectable locally advanced or metastatic breast cancer.
• No more than 2 prior lines of cytotoxic chemotherapy for advanced disease are allowed which means that to be eligible, patients should be suitable for single agent chemotherapy in either 1st, 2nd or 3rd line setting.
• Prior therapy with platinum for metastatic breast cancer is allowed provided there has been no evidence of disease progression during platinum treatment and the screening biopsy was performed after the end of treatment with the platinum-based antineoplastic drugs.
• In addition, patients may have received prior platinum and or PARP inhibitors as potentially curative treatment for prior cancer (e.g., ovarian cancer) or as adjuvant/neoadjuvant treatment for breast cancer, as long as there is a period of at least 6 months between the last dose of platinum and/or PARP inhibitors and start of study treatment.

In cohort 1, patients will be enrolled according to their mutation status. The most recent locally recurrence/metastatic sample will be requested to retrospectively assess the RAD51-foci score and correlate with treatment efficacy. In cohort 2, patients will first undergo a pre-screening process with centralized determination of the quality of the sample, assessment of the RAD51-foci score and eligibility. After confirmation of all eligibility criteria, eligible patients will receive olaparib 300 mg po twice daily. Treatment will continue until disease progression as assessed by the investigator, the development of unacceptable toxicity, withdrawal of consent, whichever occurs first.

For estimation of overall response rate (ORR), clinical benefit rate (CBR), duration of response (DoR) and progression-free survival (PFS), tumour response will be based on RECIST v.1.1. Tumour assessments will be performed every 8 weeks (56 days ± 1 week) for the first 6 months, then every 12 weeks (84 days ± 1 week), until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or the end of the study, whichever occurs first. Tumour assessments will be performed on the specified schedule regardless of treatment delays.

Safety assessments will include the incidence, nature, and severity of adverse events (AEs) and laboratory abnormalities graded per the NCI CTCAE v.5 Laboratory safety assessments will include the regular monitoring of haematology, blood chemistry and pregnancy test. Justification for dose The dose of olaparib used in this study is 300 mg twice daily which is the currently approved dose.

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