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Clinical Trial
. 2024 Jul:205:114103.
doi: 10.1016/j.ejca.2024.114103. Epub 2024 May 8.

Capivasertib in combination with enzalutamide for metastatic castration resistant prostate cancer after docetaxel and abiraterone: Results from the randomized phase II RE-AKT trial

Pasquale Rescigno  1 , Nuria Porta  2 , Laura Finneran  2 , Ruth Riisnaes  2 , Ines Figueiredo  2 , Suzanne Carreira  2 , Penny Flohr  2 , Susana Miranda  2 , Claudia Bertan  2 , Ana Ferreira  2 , Mateus Crespo  2 , Daniel Nava Rodrigues  2 , Bora Gurel  2 , Jenny Nobes  3 , Simon Crabb  4 , Zafar Malik  5 , Christy Ralph  6 , Ursula McGovern  7 , Peter Hoskin  8 , Robert J Jones  9 , Alison Birtle  10 , Joanna Gale  11 , Peter Sankey  12 , Suneil Jain  13 , Duncan McLaren  14 , Eliot Chadwick  15 , Aude Espinasse  2 , Emma Hall  2 , Johann de Bono  16
Affiliations
Clinical Trial

Capivasertib in combination with enzalutamide for metastatic castration resistant prostate cancer after docetaxel and abiraterone: Results from the randomized phase II RE-AKT trial

Pasquale Rescigno et al. Eur J Cancer. 2024 Jul.

Abstract

Background: PTEN loss and aberrations in PI3K/AKT signaling kinases associate with poorer response to abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC). In this study, we assessed antitumor activity of the AKT inhibitor capivasertib combined with enzalutamide in mCRPC with prior progression on AA and docetaxel.

Methods: This double-blind, placebo-controlled, randomized phase 2 trial, recruited men ≥ 18 years with progressing mCRPC and performance status 0-2 from 15 UK centers. Randomized participants (1:1) received enzalutamide (160 mg orally, once daily) with capivasertib (400 mg)/ placebo orally, twice daily on an intermittent (4 days on, 3 days off) schedule. Primary endpoint was composite response rate (RR): RECIST 1.1 objective response, ≥ 50 % PSA decrease from baseline, or circulating tumor cell count conversion (from ≥ 5 at baseline to < 5 cells/7.5 mL). Subgroup analyses by PTENIHC status were pre-planned.

Results: Overall, 100 participants were randomized (50:50); 95 were evaluable for primary endpoint (47:48); median follow-up was 43 months. RR were 9/47 (19.1 %) enzalutamide/capivasertib and 9/48 (18.8 %) enzalutamide/placebo (absolute difference 0.4 % 90 %CI -12.8 to 13.6, p = 0.58), with similar results in the PTENIHC loss subgroup. Irrespective of treatment, OS was significantly worse for PTENIHC loss (10.1 months [95 %CI: 4.6-13.9] vs 14.8 months [95 %CI: 10.8-18]; p = 0.02). Most common treatment-emergent grade ≥ 3 adverse events for the combination were diarrhea (13 % vs 2 %) and fatigue (10 % vs 6 %).

Conclusions: Combined capivasertib/enzalutamide was well tolerated but didn't significantly improve outcomes from abiraterone pre-treated mCRPC.

Keywords: AKT-inhibitor; Enzalutamide; PTEN; Phase II randomized trial; Prostate cancer.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JdB reports advisory board fees from many companies including Acai Therapeutics, Amgen, Astra Zeneca, Astellas, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Crescendo, Daiichi, Dark Blue Therapeutics, Eisai, Genentech/Roche, Genmab, GSK, Harpoon, ImCheck Therapeutics, Janssen, Merck Serono, Merck Sharp & Dohme, Menarini/Silicon Biosystems, MetaCurUm, Myricx, Novartis, Nurix Therapeutics, Oncternal, Orion, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Takeda, Tango Therapeutics, Terumo, Vertex Pharmaceuticals. He is an employee of The ICR, which have received funding or other support for his research work from Acai Therapeutics, Amgen, AstraZeneca, Astellas, Bayer, Cellcentric, Crescendo, Daiichi, Genentech, Genmab, GSK, Harpoon, Immunic Therapeutics, Janssen, Merck Serono, Merck Sharp & Dohme, Menarini/Silicon Biosystems, MetaCurUm, Myricx, Nurix Therapeutics, Oncternal, Orion, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals. The ICR have a commercial interest in abiraterone, PARP inhibition in DNA repair defective cancers and PI3K/AKT pathway inhibitors (no personal income). JDB was named as an inventor, with no financial interest for patent 8,822,438, submitted by Janssen that covers the use of abiraterone acetate with corticosteroids. EH reports that their institution has received an Investigator Initiated Research grant (IIR) from AstraZeneca for the central coordination of the trial. EH reports grants received by their institution as contribution to support central trial costs for non-commercial trials from Accuray, Varian Medical Systems, AstraZeneca, Janssen-Cilag, Bayer, Roche Products, and Merck Sharp and Dohm. SJ reports advisory boards and speaker fees received from AAA/Novartis, Accord, Astellas, Astra Zeneca, Bayer, Boston Scientific, Janssen and Pfizer, as well as consultancy fees received from Boston Scientific and BXT Nanotherapy. SJ also reports conferences travel received from Bayer and Janssen. AJB reports honoraria from Janssen-Cilag, consulting or advisory roles from Roche, Astellas Medivation, Janssen Oncology, AstraZeneca, Sanofi, Bayer Schering Pharma, Bristol-Myers-Squib, Merck Serono and Pfizer. AJB also reports speakers’ fees received from Bayer, Janssen Oncology and Pfizer. RJ reports honoraria from Astellas Pharma, Janssen, AstraZeneca, MSD Oncology, Bristol Myers Squibb, Pfizer, Novartis, Ipsen, Bayer, Roche/Genentech, Merck Serono, Eisai, WebMD, Advanced Accelerator Applications/Novartis and Elsevier. RJ also reports speakers’ fees received from Merck Serono, Pfizer, Janssen, Astellas Pharma, MSD Oncology, AstraZeneca, Ipsen, Bristol Myers Squibb/Celgene and Bayer. RJ also reports research Funding received from Roche (Inst), Astellas Pharma (Inst), AstraZeneca (Inst), Exelixis (Inst), Clovis Oncology (Inst) and Bayer (Inst), as well as travel, accommodations and expenses received from Ipsen, Bayer, Janssen, Astellas Pharma, MSD, Merck Serono and Pfizer. PR, NP, LF, AE, SM, PF, JG, JN, RR, BG, DR, IF, SC, CB, AF, MC, SC, ZM, CR, UMC, PH, PS, EC and DML have no conflicts to declare.

Figures

Fig. 1
Fig. 1
Consort diagram.
Fig. 2
Fig. 2
Antitumor activity by allocated treatment group. a) Swimmer plot of time on treatment for each patient according to treatment group, indicating periods where enzalutamide/capivasertib, patients received enzalutamide alone. Treatment periods of ≥ 6 months and ≥ 12 months are highlighted. PSA=prostate-specific antigen. b) Percentage change from baseline in PSA at 12 weeks. c) Best percentage change from baseline in CTC at any time during allocated treatment. d) Best percentage change from baseline in sum of target lesions at any time during allocated treatment e)) Kaplan Meier curve for radiographic progression-free survival by treatment group. f) Kaplan Meier curve for overall survival by treatment group. ENZ: enzalutamide, CAP: capivasertib, PLA: placebo.
Fig. 3
Fig. 3
Exploring role of PTENIHCas prognostic or predictive marker. a) Radiographic Progression-Free Survival by PTENIHC status. b) Overall Survival by PTENIHC status. c) Radiographic Progression-Free Survival by PTENIHC status and treatment group. d) Overall Survival by PTENIHC status and treatment group.ENZ: enzalutamide, CAP: capivasertib, PLA: placebo.
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