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Clinical Trial
. 2022 Jun 1;28(11):2237-2247.
doi: 10.1158/1078-0432.CCR-21-2326.

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

Christopher J Sweeney  1 , Ivor J Percent  2 , Sunil Babu  3 , Jennifer L Cultrera  4 , Bryan A Mehlhaff  5 , Oscar B Goodman  6 , David S Morris  7 , Ian D Schnadig  8 , Costantine Albany  9 , Neal D Shore  10 , Paul R Sieber  11 , Susan C Guba  12 , Wei Zhang  12 , Volker Wacheck  12 , Gregory P Donoho  12 , Anna M Szpurka  12 , Sophie Callies  12 , Boris Kin Lin  12 , Johanna C Bendell  13
Affiliations
Clinical Trial

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

Christopher J Sweeney et al. Clin Cancer Res. .

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.

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Figures

Figure 1. Study design: Figure describes the study design followed in the phase Ib and phase II part of the trial.
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. 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 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. Waterfall plot of best prostate-specific antigen (PSA) response.
Figure 3.
Waterfall plot of best prostate-specific antigen (PSA) response.
Figure 4. rPFS by AR-v7 status. A, The PFS of samotolisib + enzalutamide arm versus placebo + enzalutamide arm in patients without AR v-7. B, The PFS of samotolisib + enzalutamide arm versus placebo + enzalutamide arm in patients with AR v-7.
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. 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.
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.
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References

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