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Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with BRCA1/2- and Non–BRCA1/2-Mutant Cancers

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Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with BRCA1/2- and Non–BRCA1/2-Mutant Cancers Published OnlineFirst June 12, 2020; DOI: 10.1158/2159-8290.CD-20-0163 RESEARCH ARTICLE Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with BRCA1/2- and Non–BRCA1/2-Mutant Cancers Timothy A. Yap1,2, Rebecca Kristeleit3, Vasiliki Michalarea1, Stephen J. Pettitt4,5, Joline S.J. Lim1, Suzanne Carreira2, Desamparados Roda1,2, Rowan Miller3, Ruth Riisnaes2, Susana Miranda2, Ines Figueiredo2, Daniel Nava Rodrigues2, Sarah Ward1,2, Ruth Matthews1,2, Mona Parmar1,2, Alison Turner1,2, Nina Tunariu1, Neha Chopra1,4, Heidrun Gevensleben2, Nicholas C. Turner1,4, Ruth Ruddle2, Florence I. Raynaud2, Shaun Decordova2, Karen E. Swales2, Laura Finneran2, Emma Hall2, Paul Rugman6, Justin P.O. Lindemann6, Andrew Foxley6, Christopher J. Lord4,5, Udai Banerji1,2, Ruth Plummer7, Bristi Basu8, Juanita S. Lopez1,2, Yvette Drew7, and Johann S. de Bono1,2 Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst June 12, 2020; DOI: 10.1158/2159-8290.CD-20-0163 ABSTRACT Preclinical studies have demonstrated synergy between PARP and PI3K/AKT path- way inhibitors in BRCA1 and BRCA2 (BRCA1/2)–deficient andBRCA1/2 -proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose- escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibi- tor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage response (DDR) or PI3K–AKT pathway alterations. The combination was well tolerated. Recommended phase II doses for the two schedules were: olaparib 300 mg twice a day with either capivasertib 400 mg twice a day 4 days on, 3 days off, or capivasertib 640 mg twice a day 2 days on, 5 days off. Pharmacokinetics were dose proportional. Pharmacodynamic studies confirmed phosphorylated (p) GSK3β suppression, increased pERK, and decreased BRCA1 expression. Twenty-five (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST complete response/partial response or stable disease ≥ 4 months), including patients with tumors harboring germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without DDR and PI3K–AKT pathway alterations. SIGNIFICANCE: In the first trial to combine PARP and AKT inhibitors, a prospective intrapatient dose- escalation design demonstrated safety, tolerability, and pharmacokinetic–pharmacodynamic activ- ity and assessed predictive biomarkers of response/resistance. Antitumor activity was observed in patients harboring tumors with germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without somatic DDR and/or PI3K–AKT pathway alterations. INTRODUCTION BRCA1/2­mutated advanced ovarian cancer and in patients with germline BRCA1/2­mutated pancreatic cancer (4, 5). PARP inhibitors are the first clinically approved drugs Olaparib is also FDA­approved for the treatment of patients designed to exploit synthetic lethality in homologous recom­ with germline BRCA1/2­mutant, HER2­negative metastatic bina tion (HR)–deficient cells,demonstrating proof­of­con­ breast cancers (6, 7). In addition, there are now early clinical cept activity in BRCA1/2-mutant cancers (1, 2). The PARP trial data from patients with tumors harboring other DNA inhibitor olaparib (Lynparza; AstraZeneca) was the first in repair aberrations (8). class to be approved by the FDA in the advanced recurrent Despite these broader indications, the greatest clinical ben­ ovarian cancer setting for women with BRCA1/2­mutant can­ efit from PARP inhibitor monotherapy has been observed in cers (3). Olaparib has subsequently received FDA approval the high­grade serous germline BRCA1/2­mutant ovarian can­ in the maintenance setting for recurrent platinum­sensitive cer population (3). However, these patients almost inevitably ovarian cancers regardless of BRCA1/2 status and, most develop PARP inhibitor resistance and disease progression. recently, in the first­line maintenance setting post–platinum­ The utility of PARP inhibitor monotherapy in patients with based chemotherapy both in women with germline or somatic different cancers harboring other DNA­repair aberrations is also limited by the emergence of drug resistance and generally short­lived antitumor responses (9). Even for patients with 1 2 Royal Marsden Hospital, London, United Kingdom. The Institute of Cancer advanced solid tumors bearing deleterious BRCA1/2 muta­ Research, London, United Kingdom. 3University College London, London, United Kingdom. 4The Breast Cancer Now Toby Robins Research Centre, The tions, response rates are between 30% and 60% depending Institute of Cancer Research, London, United Kingdom. 5The CRUK Gene on tumor type (3). There is therefore a major unmet need for Function Laboratory, The Institute of Cancer Research, London, United novel antitumor strategies to increase both the proportion of 6 Kingdom. Oncology R&D, AstraZeneca, Cambridge, United Kingdom. patients with clinical benefit as well as the depth and dura­ 7Clinical and Translational Research Institute, Newcastle University, New- castle, United Kingdom. 8Department of Oncology, University of Cambridge, tion of response for patients treated with PARP inhibitors Cambridge, United Kingdom. (10). Such approaches include the development of rational Note: Supplementary data for this article are available at Cancer Discovery combination strategies. Multiple preclinical studies have Online (http://cancerdiscovery.aacrjournals.org/). demonstrated synergistic antitumor activity with the com­ Current address for T.A. Yap: The University of Texas MD Anderson Cancer bination of PARP and PI3K–AKT pathway inhibitors in both Center, Houston, Texas. BRCA­deficient and BRCA­proficient cancer models (11–14). Corresponding Author: Timothy A. Yap, The University of Texas MD Ander- PI3K pathway inhibition has been shown to lead to suppres­ son Cancer Center, 1400 Holcombe Boulevard, Houston, TX 77030. Phone: sion of BRCA gene transcription, which was accompanied by 713-839-5458; E-mail: [email protected] ERK phosphorylation. Overexpression of an active form of Cancer Discov 2020;10:1–16 MEK1 was found to result in ERK activation and downregu­ doi: 10.1158/2159-8290.CD-20-0163 lation of BRCA1, resulting in HR deficiency and subsequent ©2020 American Association for Cancer Research. PARP inhibitor sensitivity, thus providing strong rationale OCTOber 2020 CANCER DISCOVERY | OF2 Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst June 12, 2020; DOI: 10.1158/2159-8290.CD-20-0163 RESEARCH ARTICLE Yap et al. for the development of this combination as an antitumor Safety strategy (11). A phase Ib trial of olaparib in combination with During the dose­escalation phase of the 4­days­on, 3­days­ the PI3Kα­specific inhibitor alpelisib demonstrated RECIST off (4/3) schedule, doses of capivasertib were increased using partial responses (PR) in 10 (36%) of 28 patients with ovarian the prospective intrapatient dose­escalation design from 320 cancer, providing early clinical proof of concept (15). and 400 mg to 480 mg twice a day with a fixed dose of olapa­ Several novel molecularly targeted agents against the rib at 300 mg twice a day (Supplementary Fig. S1). Of 10 PI3K–AKT pathway have now been developed, including the patients treated in this 4/3 schedule, only one dose­limiting AKT inhibitor capivasertib (AZD5363; AstraZeneca; ref. 16). toxicity (DLT) of grade 3 maculopapular rash, typical of that Capivasertib is a potent and selective ATP competitive inhibi­ observed with capivasertib and other AKT inhibitors, was tor of all three isoforms of AKT, which is safe and well­toler­ observed at the highest dose assessed of capivasertib, 480 mg ated in patients with advanced solid tumors, but with limited twice a day, with olaparib 300 mg twice a day (Table 2). The antitumor benefit as a single agent in early­phase clinical erythematous rash fully resolved after both capivasertib and trials (17–19). This is hypothesized to be due to multiple fac­ olaparib were withheld, and no recurrent rash was observed tors, including the development of signaling cross­talk and after both drugs were restarted at a reduced dose of capiva­ disruption of feedback loops, leading to acquired resistance, sertib 400 mg twice a day with olaparib maintained at 300 mg supporting the use of combination strategies in molecularly twice a day. At the dose level of capivasertib 480 mg twice a day defined patients for the optimal development of AKT inhibi­ with olaparib 300 mg twice a day administered in a 4/3 sched­ tors, such as with PARP inhibitors as described above (20, 21). ule, other non­DLT grade 3 toxicities were observed, includ­ On the basis of these promising data, we conducted an ing anemia (n = 1), vomiting (n = 1), and diarrhea (n = 2). investigator­initiated phase Ib clinical trial to determine the Because of the DLT of grade 3 rash, non­DLT grade 3 adverse safety, tolerability, MTD, recommended phase II dose (RP2D), events, and chronic low­grade adverse events, for example, pharmacokinetics, pharmacodynamics, and preliminary anti­ fatigue and anemia, observed outside the DLT period of tumor activity of olaparib in combination with capivasertib 21 days at the dose of capivasertib 480 mg twice a day with in patients with advanced solid tumors. We also assessed olaparib 300 mg twice
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