Substantially improving the cure rate of high-risk BRCA1-like breast cancer patients with personalized therapy (SUBITO) an international randomized phase III trial

The prognosis of women with high-risk breast cancer is still poor (stage III:
10-year survival of 30-40%). Current guidelines for adjuvant systemic treatment
make no distinction between stage II or stage III breast cancer, due to a lack
of personalized treatments and companion diagnostics.

Evidence from preclinical and clinical studies has emerged that breast cancer
cells deficient in homologous recombination to repair DNA double strand breaks
(DSBs), as in BRCA1/2-mutated cells, offers a target for DNA DSB-inducing
regimens, such as alkylating agents, platinum compounds or poly(ADP)ribose
polymerase (PARP) inhibitors. Recently, a putative companion diagnostic has
been derived from the characteristic DNA copy number aberrations present in
BRCA1-mutated breast cancers. This test has been coined the *BRCA1-like test*.

BRCA1-like tumors comprise ±7.5% of all breast cancers. In a retrospective
analysis the BRCA1-like test appeared a promising companion diagnostic for
adjuvant intensified alkylating (IA) chemotherapy (CT) in stage III breast
cancer patients. In BRCA1-like patients the 7-year recurrence-free survival
improved from 30% with standard CT to 78% with IA CT (adjusted hazard rate (HR)
0.12; p=0.001), while no benefit was observed in non-BRCA1-like patients6.
These striking data asked for further exploration, and were confirmed by two
other retrospective studies (adjusted HR 0.15; p=0.03 and adjusted HR 0.18;
p=0.003).

In addition, there are strong indications that a PARP inhibitor is active in
BRCA1-like breast cancers. Currently, olaparib is being investigated in the
adjuvant setting in BRCA-mutated, triple negative breast cancer patients.
Patients who have completed standard adjuvant chemotherapy are randomized
between 1-year olaparib monotherapy and 1-year placebo (OlympiA trial:
NCT02032823). To avoid generating results that will be outdated in 5-years*
time, 1-year olaparib monotherapy will be added to the optimal standard-dosed
treatment arm in the SUBITO trial.

This study has been transitioned to CTIS with ID 2024-516196-32-00 check the CTIS register for the current data.

To investigate whether (neo)adjuvant systemic treatment of intensified
alkylating chemotherapy with peripheral stem cell rescue (mini-CTC) compared to
AC-CP chemotherapy followed by 1-year olaparib monotherapy substantially
improves overall survival (OS) in stage III BRCA1-like breast cancer patients.

Investigator-initiated, international, multicentre, randomized, open-label,
(neo)adjuvant phase III study in target population (stage III, HER2-negative,
BRCA1-like breast cancer patients) comparing optimized standard-dose
chemotherapy with intensified, alkylating chemotherapy with stem cell rescue.

Both study arms:
3 x ddAC q 2 weeks
doxorubicin 60 mg/m² as an i.v. bolus and cyclophosphamide 600 mg/m² as an i.v.
bolus on day 1 every 2 weeks
ddAC must be supported with prophylactic pegfilgrastim 6 mg s.c. given 24-48
hours after completion of administration of EVERY chemotherapy cycle

Experimental arm: 2 x IA CT q 3-4 weeks:
Stem cell mobilization
4th ddAC cycle with G-CSF *300 ug sc for 8-10 days according to local protocols
leukapheresis days 10-14 according to local protocols

intensified alkylating *mini* CTC (2x)
cyclophosphamide 3000 mg/m2 day 1
mesna 500 mg (push) + 2000 mg in 24 hours day 1
carboplatin (400 mg/m2; (or AUC=5 in patients with a calculated
creatinine-clearance of <100 ml/min)) days 1,2
thiotepa 250 mg/m2 day 2

AC-CP-olaparib:
Patients will receive a 4th cycle of ddAC, followed by carboplatin/paclitaxel
(CP) consisting of carboplatin (AUC 6) on day 1 and paclitaxel (80 mg/m2) on
day 1,8 and 15 of a 21 days cycle. In total 4 courses of CP will be
administered. Olaparib will be administered as monotherapy for one year at a
dose of 300 mg BID, starting 3 weeks after adjuvant radiotherapy, or, if
radiotherapy is not indicated, 3-5 weeks after the last CP cycle.

Capecitabin:
Patients in both arms that do not achieve a (near) complete pathologic response
(pCR) in neoadjuvant setting will receive adjuvant capetcitabine in addition to
their allocated study treatment.
Adjuvant capecitabine at a starting dose of 1000-1250 mg/m2, twice a day, on
days 1-14 every 3 weeks for eight cycles. In case of DPYD-deficiency a dose
reduction is recommended depending on the DPYD variant.

After IA CT or AC-CP:
Patients will undergo radiotherapy, if indicated.
Endocrine treatment for at least 5 years (according to the most recent Dutch
national guidelines), starting 1 to 6 weeks after radiotherapy for patients
with positive estrogen and/or progesterone receptors.

Blood will be drawn for biomarker research, hematology, and serum chemistry.
Patients are at risk for development of doxorubicin-, cyclophosphamide-,
carboplatin-, paclitaxel-, thiotepa-, and olaparib or capecitabin-related side
effects (depending on the actual treatment administered). Patients in the
treatment arm with leukapheresis and stem cell rescue are at risk for venous
catheter-related complications, and intensified alkylating chemotherapy with
autologous stem cell rescue-related complications.