Phase Ib/II Study of Enzalutamide with Samotolisib (LY3023414) or Placebo in Patients with Metastatic Castration-Resistant Prostate Cancer

Christopher J Sweeney, Ivor J Percent, Sunil Babu, Jennifer L Cultrera, Bryan A Mehlhaff, Oscar B Goodman, David S Morris, Ian D Schnadig, Costantine Albany, Neal D Shore, Paul R Sieber, Susan C Guba, Wei Zhang, Volker Wacheck, Gregory P Donoho, Anna M Szpurka, Sophie Callies, Boris Kin Lin, Johanna C Bendell, Christopher J Sweeney, Ivor J Percent, Sunil Babu, Jennifer L Cultrera, Bryan A Mehlhaff, Oscar B Goodman, David S Morris, Ian D Schnadig, Costantine Albany, Neal D Shore, Paul R Sieber, Susan C Guba, Wei Zhang, Volker Wacheck, Gregory P Donoho, Anna M Szpurka, Sophie Callies, Boris Kin Lin, Johanna C Bendell

Abstract

Purpose: To report efficacy and safety of samotolisib (LY3023414; PI3K/mTOR dual kinase and DNA-dependent protein kinase inhibitor) plus enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) following cancer progression on abiraterone.

Patients and methods: In this double-blind, placebo-controlled phase Ib/II study (NCT02407054), following a lead-in segment for evaluating safety and pharmacokinetics of samotolisib and enzalutamide combination, patients with advanced castration-resistant prostate cancer with progression on prior abiraterone were randomized to receive enzalutamide (160 mg daily)/samotolisib (200 mg twice daily) or placebo. Primary endpoint was progression-free survival (PFS) assessed by Prostate Cancer Clinical Trials Working Group criteria (PCWG2). Secondary and exploratory endpoints included radiographic PFS (rPFS) and biomarkers, respectively. Log-rank tests assessed treatment group differences.

Results: Overall, 13 and 129 patients were enrolled in phase Ib and II, respectively. Dose-limiting toxicity was not reported in patients during phase Ib and mean samotolisib exposures remained in the targeted range despite a 35% decrease when administered with enzalutamide. In phase II, median PCWG2-PFS and rPFS was significantly longer in the samotolisib/enzalutamide versus placebo/enzalutamide arm (3.8 vs. 2.8 months; P = 0.003 and 10.2 vs. 5.5 months; P = 0.03), respectively. Patients without androgen receptor splice variant 7 showed a significant and clinically meaningful rPFS benefit in the samotolisib/enzalutamide versus placebo/enzalutamide arm (13.2 months vs. 5.3 months; P = 0.03).

Conclusions: Samotolisib/enzalutamide has tolerable side effects and significantly improved PFS in patients with mCRPC with cancer progression on abiraterone, and this may be enriched in patients with PTEN intact and no androgen receptor splice variant 7.

©2022 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.
Figure 1.
Study design: Figure describes the study design followed in the phase Ib and phase II part of the trial. BID, twice a day; ENZ, enzalutamide; mCRPC, metastatic castration-resistant prostate cancer; n, number of patients; QD, every day; RR, response rate.
Figure 2.
Figure 2.
PFS and rPFS of patients from phase II. A, The PFS of samotolisib + enzalutamide arm versus placebo + enzalutamide arm. B, The rPFS of samotolisib + enzalutamide arm versus placebo + enzalutamide arm.
Figure 3.
Figure 3.
Waterfall plot of best prostate-specific antigen (PSA) response.
Figure 4.
Figure 4.
rPFS by AR-v7 status. A, The PFS of samotolisib + enzalutamide arm versus placebo + enzalutamide arm in patients without AR-v7. B, The PFS of samotolisib + enzalutamide arm versus placebo + enzalutamide arm in patients with AR-v7.
Figure 5.
Figure 5.
rPFS by PTEN (IHC) assay. A, The PFS of samotolisib + enzalutamide arm versus placebo + enzalutamide arm in patients with PTEN loss. B, The PFS of samotolisib + enzalutamide arm versus placebo + enzalutamide arm in patients without PTEN loss.

References

    1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. . Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209–49.
    1. Kelly SP, Anderson WF, Rosenberg PS, Cook MB. Past, current, and future incidence rates and burden of metastatic prostate cancer in the United States. Eur Urol Focus 2018;4:121–7.
    1. Omlin A, Pezaro C, Mukherji D, Mulick Cassidy A, Sandhu S, Bianchini D, et al. . Improved survival in a cohort of trial participants with metastatic castration-resistant prostate cancer demonstrates the need for updated prognostic nomograms. Eur Urol 2013;64:300–6.
    1. Patrikidou A, Loriot Y, Eymard JC, Albiges L, Massard C, Ileana E, et al. . Who dies from prostate cancer? Prostate Cancer Prostatic Dis 2014;17:348–52.
    1. Ritch C, Cookson M. Recent trends in the management of advanced prostate cancer. F1000Res 2018;7:F1000.
    1. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. . AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014;371:1028–38.
    1. Eisenberger MA, Antonarakis ES. Hormonal therapy or chemotherapy for metastatic prostate cancer - Playing the right CARD. N Engl J Med 2019;381:2564–6.
    1. de Wit R, de Bono J, Sternberg CN, Fizazi K, Tombal B, Wulfing C, et al. . Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med 2019;381:2506–18.
    1. de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, et al. . Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med 2020;382:2091–102.
    1. Armstrong AJ, Halabi S, Luo J, Nanus DM, Giannakakou P, Szmulewitz RZ, et al. . Prosepctive multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer: The PROPHECY Study. J Clin Oncol 2019;37:1120–9.
    1. Bastos DA, Antonarakis ES. CTC-derived AR-V7 detection as a prognostic and predictive biomarker in advanced prostate cancer. Expert Rev Mol Diagn 2018;18:155–63.
    1. de Bono JS, Chowdhury S, Feyerabend S, Elliott T, Grande E, Melhem-Bertrandt A, et al. . Antitumour activity and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with abiraterone acetate plus prednisone for ≥24 weeks in Europe. Eur Urol 2018;74:37–45.
    1. Carver BS, Chapinski C, Wongvipat J, Kieronymus H, Chen Y, Chandarlapaty S, et al. . Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 2011;19:575–86.
    1. Bendell JC, Varghese AM, Hyman DM, Bauer TM, Pant S, Callies S, et al. . A first-in-human phase 1 study of LY3023414, an oral PI3K/mTOR dual inhibitor, in patients with advanced cancer. Clin Cancer Res 2018;24:3253–62.
    1. Braglia L, Zavatti M, Vinceti M, Martelli AM, Marmiroli S. Deregulated PTEN/PI3K/AKT/mTOR signaling in prostate cancer: Still a potential druggable target? Biochim Biophys Acta Mol Cell Res 2020;1867:118731.
    1. Bitting RL, Armstrong AJ. Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer. Endocr-Relat Cancer 2013;20:R83–99.
    1. Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, et al. . Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366:520–9.
    1. Thomas C, Lamoureux F, Crafter C, Davies BR, Beraldi E, Fazli L, et al. . Synergistic targeting of PI3K/Akt pathway and androgen receptor axis significantly delays castration-resistant prostate cancer progression in vivo. Mol Cancer Ther 2013;12:2342.
    1. Adelaiye-Ogala R, Gryder BE, Nguyen YTM, Alilin AN, Grayson AR, Bajwa W, et al. . Targeting the PI3K/AKT pathway overcomes enzalutamide resistance by inhibiting induction of the glucocorticoid receptor. Mol Cancer Ther 2020;19:1436–47.
    1. de Bono JS, De Giorgi U, Rodrigues DN, Massard C, Bracarda S, Font A, et al. . Randomized phase II study evaluating Akt blockad with ipatasertib, in combination with abiraterone, in patients with metastatic prostate cancer with and without PTEN loss. Clin Cancer Res 2019;25:928–36.
    1. de Bono JS, Bracarda S, Sternberg CN, Chi KN, Olmos D, Sandhu S, et al. . IPATential150: Phase III study of ipatasertib (ipat) plus abiraterone (abi) vs placebo (pbo) plus abi in metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol 2020;31:S1142–S215.
    1. Dylgjeri E, McNair C, Goodwin JF, Raymon HK, McCue PA, Shafi AA, et al. . Pleiotropic impact of DNA-PK in cancer and implications for therapeutic strategies. Clin Cancer Res 2019;25:5623–37.
    1. Goodwin JF, Kothari V, Drake JM, Zhao S, Dylgjeri E, Dean JL, et al. . DNA-PKcs-mediated transcriptional regulation drives prostate cancer progression and metastasis. Cancer Cell 2015;28:97–113.
    1. Smith MC, Mader MM, Cook JA, Iversen P, Ajamie R, Perkins E, et al. . Characterization of LY3023414, a novel PI3K/mTOR dual inhibitor eliciting transient target modulation to impede tumor growth. Mol Cancer Ther 2016;15:2344–56.
    1. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. . Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: Recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008;26:1148–59.
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. . New response evaluation criterai in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–47.
    1. World Medical Association. Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013;310:2191–4.
    1. Armstrong AJ, Halabi S, Healy P, Alumkal JJ, Winters C, Kephart J, et al. . Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer. Eur J Cancer 2017;81:228–36.
    1. Kolinsky MP, Rescigno P, Bianchini D, Zafeiriou Z, Mehra N, Mateo J, et al. . A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer. Ann Oncol 2020;31:619–25.
    1. Sweeney C, Bracarda S, Sternberg CN, Chi KN, Olmos D, Sandhu S, et al. . Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial. Lancet 2021;398:131–42.
    1. Xtandi (enzalutamide) package insert. Astellas, Pfizer; 2020. Available from: .
    1. Rodon J, Brana I, Shiu LL, De Jonge MJ, Homji N, Mills D, et al. . Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. Invest New Drugs 2014;32:670–81.
    1. Wei XX, Hsieh AC, Kim W, Friedlander T, Lin AM, Louttit M, et al. . A phase I study of abiraterone acetate combined with BEZ235, a dual PI3K/mTOR inhibitor, in metastatic castration resistant prostate cancer. Oncologist 2017;22:503–e43.
    1. Lee EK, Jamani R, Berry SR, DeAngelis C, Giotis A, Emmenegger U. Characterizing the risk of drug-drug interactions in patients receiving enzalutamide for castration-resistant prostate cancer. J Clin Oncol 2015;33:261.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi