Abstract Background: Olaparib is a PARP inhibitor that has shown high response rates and clinical activity in patients with advanced HER2-negative breast cancer (BC) and a germline BRCA1 and BRCA2 mutation. There is also evidence of cellular sensitivity to PARP inhibitors associated to defects in other genes involved in homologous recombination DNA repair (HRR) or mismatch repair pathway (microsatellite instability MSI). Moreover, about 15% of patients with ER+/HER2- metastatic BC have at least 100 mutations in their tumor, leading to genomic instability and potential sensitivity to PARP inhibitors. Several preclinical and clinical studies have suggested the benefit of an association of immune checkpoint blockade, like durvalumab, with PARP inhibitor. Indeed, tumors with BRCA1/2 mutations or other deficiency in HRR have high mutagenic burden and produce a larger number of neoantigens. Most BRCA-associated BC are ER+/HER2-. Although loss of the BRCA gene function is a key driver of oncogenesis in these patients, ER-pathway appears to remain a key target for their therapy. Preclinical data indicate that olaparib may enhance endocrine therapy efficacy and circumvent resistance. Therefore, the combination of durvalumab, olaparib and endocrine therapy could be a therapeutic option for patients with BRCA1/2 mutation or for patients with selected ER+/HER2- advanced BC. Trial design: DOLAF is an open-label, international, multicentric, phase II trial assessing the combination of olaparib, fulvestrant, and durvalumab. Olaparib will be administered orally twice daily at 300 mg. Fulvestrant will be administered as two intramuscular injections of 250 mg (Cycle 1 Days 1 and 15, and Day 1 of each subsequent 28-day cycle). Durvalumab will be started 4 weeks after the first dose of olaparib at 1500 mg intravenous every 4 weeks. Eligibility criteria include: ER+/HER2- metastatic or locally advanced BC with documented germline alteration in BRCA1 or BRCA2 or deleterious germline or somatic alterations implicated in the HRR pathway (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FAND2, FANCL, MRE11A, NBN, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D and RAD54L) or in MSI status or other actionable genes (AKT1, ESR1, FGFR1, FGFR2, FGFR3, and PIK3CA) all based on central tumor next generation DNA sequencing. Patients could have received 1 line of endocrine therapy and/or 1 line of chemotherapy in the metastatic setting.Specific aims: To evaluate the efficacy of the combination in terms of progression-free survival rate at 24 weeks using RECIST v1.1. Secondary endpoints include: safety (according to the NCI-CTCAE v5.0), overall survival, progression-free survival, objective response rate, duration of response in the overall study population and in the germline BRCA mutated population. Statistical methods: Given the lack of safety data from this association, a safety run-in of 6 patients was planned. With an optimum two-stage Simon design,α = 2.5%, β = 5%, p0 (the probability of inefficiency maximum) = 50%, p1 (the probability of minimum efficiency) = 65%, it would be necessary to include 149 evaluable patients. The strategy could be considered sufficiently effective if there are at least 87 successes. According to the established design (including a rate of 5% of patients lost to follow-up or non-evaluable), it will be necessary to include 158 patients. We hypothesized that about 20% of screened patients will have a molecular alteration to allow enrollment. Thus, we need to screen 790 patients. The study is recruiting. The safety run-in is over. By July 1, 2020, 62 patients have been screened and 8 have been treated (NCT04053322). Contact information: DOLAF@unicancer.fr Citation Format: Severine Guiu, Judith Balmana, Lise Roca, Anthony Goncalves, Audrey Mailliez, Frederic Bigot, Thomas Bachelot, Florence Dalenc, Nadine Dohollou, Dominique Genet, Isabelle Desmoulins, Camille Chakiba, Suzette Delaloge, Geraldine Martineau, Veronique Haddad, Philippe Follana. Dolaf- an international multicenter phase 2 trial of durvalumab (medi4736) plus olaparib plus fulvestrant in metastatic or locally advanced er-positive, her2-negative breast cancer patients selected using criteria that predict sensitivity to olaparib (UCBG308) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-13-05.
5017 Background: Docetaxel and cabazitaxel represent now the standard of care in men with mCRPC with similar efficacy reported in metastatic first-line setting in the FIRSTANA phase 3 trial. We assessed patients’ preference between the two taxanes. Methods: Patients with taxane-naïve mCRPC were randomized in a 1:1 ratio to receive either docetaxel 75mg/m2/q3w x 4 followed by cabazitaxel 25mg/m2/q3w x 4 (DO-CA), or the reverse sequence (CA-DO). Randomization was stratified based on prior next generation AR axis inhibitors use. The primary endpoint was patient preference between taxanes, as assessed by questionnaires in patients who had received at least one cycle of each taxane and who had not experienced a progression while on the first taxane. Results: From June 2014 to October 2016, 195 men were randomized in 17 centers. After adjusting for the treatment period effect, more patients preferred cabazitaxel (43%) vs docetaxel (27%) (p < 0.004); 30% had no preference between taxanes. Fatigue, patient-defined quality of life, hair loss, and pain were the most common factors influencing patient preference. Febrile neutropenia was experienced by 5 (7.1%) men treated with cabazitaxel during the first period who received G-CSF and by 2 (7.1%) of those who did not. No febrile neutropenia was reported with docetaxel in both arms and with cabazitaxel during the 2nd period, irrespectively of the use of G-CSF. The incidence of diarrhea during the first 3-month period was slightly reduced with G-CSF use in men receiving cabazitaxel (32.1% vs 24.3%) but not in those receiving docetaxel (23.8% vs 25%). The median progression-free survival was 9.81 in the DO-CA arm and 9.33 months in the CA-DO arm. The median overall survival was also similar in the two groups (22.64 in the DO-CA arm and 20.73 months in the CA-DO arm. Conclusions: Although cabazitaxel and docetaxel have similar efficacy when used as first-line in mCRPC men, more patients prefer cabazitaxel. Clinical trial information: NCT02044354.
Imatinib has been recognized as a major treatment for patients with chronic myelogenous leukemia (CML). Strategies to overcome imatinib resistance that might occur at the standard of 400 mg/day include imatinib-based combination therapies and high dose imatinib. High dose imatinib can be considered as a reasonable option, since most of these studies have shown no maximum tolerated dose and no increase in non-hematological toxicity at doses up to 1000 mg/day. In order to obtain a higher rate of cytogenetic response and to overcome resistances, new strategies using combination of cytotoxic drugs with imatinib have emerged. Although resistance to imatinib develops most frequently in patients in advanced phase, this event may occur in chronic phase patients. Preliminary results obtained with high dose imatinib as well as with combination therapies are promising. High dose of imatinib may also be used in order to recapture responses in patients who fail or have suboptimal response to standard dose imatinib.
Abstract Background: Triple negative breast cancer (TNBC) is an heterogeneous disease and encompasses at least 4 subtypes. One of these expresses the androgen receptor (AR). Several prospective trials demonstrated antitumour efficacy with anti-androgen treatment in patients with advanced breast cancer. Darolutamide is an androgen-receptor antagonist with a potent anti-tumour efficacy in metastatic prostate cancer with a favorable safety profile. We conducted a randomized non-comparative phase II trial to study the efficacy and tolerability of darolutamide and capecitabine in AR-positive TNBC (NCT03383679). Material and methods: Patients (Pts) with a metastatic, centrally reviewed, AR-positive (≥ 10% by immunohistochemistry) and TNBC who have received a maximum of one line of chemotherapy for advanced disease were eligible. They were randomised in a 2:1 ratio to receive darolutamide (D arm) 600 mg twice daily or capecitabine (C arm) at 1000 mg/m² twice daily 2 weeks on and 1-week off, until progression or unacceptable toxicity. The primary endpoint was clinical benefit rate (CBR) defined as the proportion of pts presenting a complete response (CR), partial response (PR), or stable disease (SD) at 16 weeks. Main secondary endpoints included objective response rate, overall survival, progression-free survival and safety. An interim statistical analysis was planned when 19 assessable pts will be available in the D arm. According to an optimal 2-stage Simon’s design,if <5 patients experienced a CBR the trial should be stopped for futility; if 5 or more experienced a CBR the trial should continue up to a total of 54 patients in the D arm. Results: Out of 133 pts screened and centrally analyzed, from 37 centres, 54% (72/133) were AR-positive. 45 pts were randomized (29 in D arm and 16 in C arm) from April 2018 to December 2019. In arm D, median age was 60 years (range 47-88). and 13.8 % received a first line of chemotherapy for metastatic disease. A total of 19 pts were eligible and assessable for the primary endpoint in D arm. 5 CBR were confirmed at 16 weeks (26.3%; 95% CI: 9.2%-51.2 %) including 1 confirmed PR and 4 SD. In arm D, fatigue (23.8%), ASAT increased (23.8%), and blood alkaline phosphatase increased (23.8%) were the most common drug-related adverse events; the majority of them being grade 1 or 2. 6 pts presented with drug-related serious adverse events: one in D arm and 5 in C arm. Conclusions: According to the planned interim analysis, the efficacy objective is met (5 CBR) in D arm. Moreover, darolutamide is well tolerated. Thus, patients are now recruited in the second stage. Keywords: Androgen receptor,triple-negative breast cancer, darolutamide, advanced breast cancer Citation Format: Hervé Bonnefoi, Florence Lerebours, Olivier Tredan, Florence Dalenc, Christelle Levy, Mahasti Saghatchian, Marie Ange Mouret Reynier, Delphine Mollon, Severine Guiu, Laurence Venat Bouvet, Elisabeth Carola, Geraldine Martineau, Marina Pulido, Gaetan MacGrogan, Anthony Goncalves. First efficacy results of a 2-stage Simon’s design randomised phase 2 of darolutamide or capecitabine in patients with triple-negative, androgen receptor positive advanced breast cancer (UCBG06-3) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-05.
Overall survival is increasing in cancer patients, rai- sing questions about the possible treatment of elderly chronic mye- logenous leukemia (CML) patients with costly tyrosine kinase inhibi- tors. The emergence of imatinib, which results in strong haemato- logical and cytogenetic responses and impressive survival rates, merits consideration in the treat- ment of elderly patients. Indeed, its side effects are non-serious and easily managed. Follow-up care in this patient population is now based on molecular analysis, which requires less bone marrow aspiration, improving quality of life. Based on the results of ima- tinib use, and now other tyrosine kinase inhibitors such as dasatinib and nilotinib (in case of imatinib resistance), these molecules could be administered to elderly patients without restriction.
SCT is frequently used as salvage or curative therapy in patients (pts) with advanced CML or Ph+ ALL previously treated with Imatinib. While one study showed higher incidence of GVHD, VOD and TRM, most studies have demonstrated that Imatinib therapy prior to SCT does not adversely affect SCT outcome. Dasatinib is a SRC/ABL kinase inhibitor currently being used in pts with Imatinib-resistant. Most of these pts will eventually undergo SCT, raising the question of whether Dasatinib therapy may adversely affect SCT outcome. We report eight pts: CML – 6 (CP1-4, low sokal score –3, high sokal score –1, CP2-1, AP-1) and Ph+ ALL –2 who received Dasatinib prior to alloSCT (n=7) or autoSCT (n=1). Donors were matched siblings –4 or unrelated –2 or mismatch related (haploSCT) –1. 5 were male and 3 female with a median age of 46.5 (16-56) years. First line therapies included Hydroxyurea & Interferon or chemotherapy followed by Imatinib for the CP CML and advanced CML/Ph+ ALL pts, respectively. All pts subsequently received Dasatinib 70mg × 2/day due to resistance to Imatinib, resulting in complete hematological response in all, as well as complete (n=5) or partial cytogenetic response (CyR) (n=2) prior to SCT. One pt did not achieve CyR prior to SCT. The pts were conditioned with either a myeloablative (n=5) or a reduced intensity protocol (n=3). GVHD prophylaxis consisted of CSA and MTX (n=6) or complete T-cell depletion (n=1). Pts received a mobilized peripheral blood stem cell graft with 11.4–19.8 × 106 CD34+ cells/ kg. The pt who underwent autoSCT was successfully mobilized (2 apheresis cycles yielding 5.7 × 106 CD34+/kg). Dasatinib was stopped 6 days before mobilization. All pts engrafted reaching ANC > 0.5×109/L on day +14 (11-21) and PLT >20×109/L on day +12.5 (11-17). Chimerism was 99.4 – 100%. Transplant related toxicities were minimal. Only 1 pt developed severe mucositis. No pt developed hyperbilirubinemia or VOD. There was no increased risk of infections. Acute GVHD (Gr II) was observed in only 1 pt, while 2 developed extensive chronic GVHD. With a median followup of 8.5 (2-13) months, 6 pts are alive, 5 in CR, while 2 died of disease progression. We may conclude that in pts undergoing SCT following Dasatinib there is no evidence that Dasatinib adversely affect post SCT outcome as no increased transplant related organ toxicities, non-engraftment, GVHD or infections were observed. Larger studies are obviously indicated to confirm our preliminary results.
