Trucap Simplification

Background and Pathophysiological Rationale

• Role of PTEN Deficiency in Prostate Cancer

  • Phosphatase and tensin homolog ($PTEN$) deficiency is associated with advanced-stage prostate cancer, accelerated clinical recurrence rates in localized disease, shorter time to disease progression, and reduced clinical benefit from standard-of-care treatments.

  • In metastatic castration-resistant prostate cancer ($mCRPC$), $PTEN$ deficiency is linked to rapid disease progression and adverse overall clinical outcomes.

  • Real-world evidence indicates that $PTEN$ loss functions as a major oncogenic driver of disease progression across all stages of advanced prostate cancer, including metastatic hormone-sensitive prostate cancer ($mHSPC$).

• PI3K/AKT Pathway Activation and Crosstalk

  • $mHSPC$ cell growth and survival are primarily sustained by androgen receptor ($AR$) signaling.

  • Loss of $PTEN$ function leads to aberrant activation of the phosphoinositide 3-kinase ($PI3K$)/protein kinase B ($AKT$) signaling axis.

  • $AKT$ regulates fundamental cellular processes including proliferation, survival, and metabolism.

  • Pathway activation provides an independent, parallel proliferative drive that permits tumor cell survival despite complete blockage of $AR$ signaling.

  • Reciprocal feedback crosstalk exists between the $AR$ and $PI3K$/$AKT$ pathways: inhibiting $AR$ signaling with standard hormonal therapy can upregulate $PI3K$/$AKT$ activity, causing tumor cells to become increasingly reliant on $AKT$ signaling for continued survival.

• Pharmacological Profiles of Study Agents

  • Capivasertib: A novel pyrrolopyrimidine-derived compound functioning as a potent, selective ATP-competitive inhibitor of all three $AKT$ isoforms ($AKT1$, $AKT2$, and $AKT3$). It binds $AKT$ and blocks phosphorylation of downstream signaling substrates, attenuating oncogenic processes.

  • Abiraterone: An androgen receptor pathway inhibitor ($ARPI$) that, when combined with prednisone or prednisolone and androgen deprivation therapy ($ADT$), represents a foundational standard of care in $mHSPC$.

• Preclinical and Clinical Rationale for Dual Inhibition

  • In preclinical $PTEN$-null prostate tumor models, combining capivasertib with $AR$ axis blockade (via castration, enzalutamide, or abiraterone) yields marked tumor growth inhibition superior to $AR$ blockade alone.

  • Simultaneous targeted inhibition of $PI3K$/$AKT$ and $AR$ pathways directly addresses two primary oncogenic drivers in $mHSPC$.

  • Dual pathway inhibition previously demonstrated efficacy in $PTEN$-deficient subgroups in $mCRPC$ trials; however, prior to the CAPItello-281 study, prospective evidence in a population selected specifically for $PTEN$ deficiency in $mHSPC$ was lacking.

CAPItello-281 Trial Design, Eligibility, and Interventions

• Study Characteristics and Governance

  • Trial Identifier: CAPItello-281 ($\text{NCT04493853}$).

  • Design: Global, phase III, randomized ($1:1$), double-blind, placebo-controlled prospective trial.

  • Presentation & Publication: Presented at ESMO Congress 2025 ($17\text{--}21\text{ October } 2025$, Berlin, Germany) and published in Annals of Oncology (Vol $37$, Issue $1$, $2026$).

  • Governance: Steering group of medical oncology and uro-oncology experts; trial sponsor AstraZeneca; data analysis performed by clinical research organization Phastar (London, UK).

• Patient Eligibility Criteria

  • Age: Males $\ge 18\,\text{years}$.

  • Disease Stage: De novo $mHSPC$ with histologically confirmed adenocarcinoma of the prostate.

  • Performance Status: Eastern Cooperative Oncology Group ($ECOG$) performance status $0$ or $1$

  • Prior Therapy Restrictions: Prior $ADT$ with or without abiraterone (plus prednisone/prednisolone) for de novo disease permitted up to a maximum of $93\,\text{days}$ prior to randomization. No other prior systemic therapy for prostate cancer allowed.

• Central Diagnostic Biomarker Screening Protocol

  • Assessed via central immunohistochemistry ($IHC$) testing using the investigational antibody $SP218$ (Roche Diagnostics, Tucson, AZ).

  • Evaluated by qualified pathologists assigning a percentage score ($0\text{--}100\%$) of viable malignant cells with no specific cytoplasmic $PTEN$ staining.

  • Randomized Study Cut-off: $\ge 90\%$ of viable malignant cells exhibiting complete absence of cytoplasmic $PTEN$ staining (equivalent to cytoplasmic $PTEN$ staining in $\le 10\%$ of viable malignant cells).

• Screening and Randomization Flow Metrics

  • Screening Period: July 13, 2020, to February 5, 2024, across $32\,\text{countries}$.

  • Total Screened: $N = 6566\,\text{patients}$.

  • Tissue Submitted for Central $IHC$: $6201\,\text{patients}$.

  • Valid $IHC$ Test Results Obtained: $6003\,\text{patients}$ ($96.8\%$ test success rate).

  • $PTEN$-Deficient Frequency ($\ge 90\%$ cutoff): $1519/6003\,\text{patients}$ ($25.3\%$ prevalence).

  • Total Randomized Population: $n = 1012\,\text{patients}$.

  • Non-Randomized Screening Failures/Exclusions: $n = 5554$ ($5432$ screening failures, $94$ patient decisions, $25$ other reasons, $3$ deaths).

• Treatment Regimens and Administration Schedule

  • Capivasertib + Abiraterone Arm ($n = 507$ randomized, $n = 503$ treated):

  • Capivasertib: $400\,\text{mg}$ orally twice daily ($BID$), administered on an intermittent schedule of $4\,\text{days on}$ and $3\,\text{days off}$.

  • Abiraterone: $1000\,\text{mg}$ orally once daily ($QD$).

  • Concomitant: Prednisone or prednisolone ($5\,\text{mg}$ twice daily) plus continuous $ADT$.

  • Placebo + Abiraterone Arm ($n = 505$ randomized, $n = 503$ treated):

  • Matching Placebo $BID$ ($4\,\text{days on, } 3\,\text{days off}$) + Abiraterone $1000\,\text{mg}$ $QD$ + Prednisone/Prednisolone + $ADT$.

  • Dose Modification Rules:

  • Capivasertib/Placebo dose reductions: Step 1 to $320\,\text{mg}$ $BID$; Step 2 to $200\,\text{mg}$ $BID$. Re-escalation was prohibited.

  • Abiraterone dose modifications/re-escalations permitted according to local prescribing labels.

  • Continuation of single-agent treatment permitted upon discontinuation of one drug prior to disease progression at investigator discretion.

  • Crossover from placebo to capivasertib was strictly prohibited.

• Stratification Factors

  • Metastatic disease volume and visceral status:

  1. High metastatic volume with visceral metastasis.

  2. High metastatic volume without visceral metastasis.

  3. Low metastatic volume.     (High volume defined per $CHAARTED$ criteria as visceral metastases and/or $\ge 4$ bone lesions with $\ge 1$ beyond vertebral bodies and pelvis).

  • Geographic region:

  1. North America, Western Europe, and Australia.

  2. Latin America and Eastern Europe.

  3. Asia.

• Study Endpoints and Statistical Powering

  • Primary Endpoint: Investigator-assessed Radiographic Progression-Free Survival ($rPFS$) per $RECIST\text{ v1.1}$ (soft tissue) and $PCWG3$ criteria (bone lesions), or death from any cause.

  • Primary Power Calculation: Assumed true hazard ratio $\text{HR} = 0.70$, targeted $\sim 386\,\text{events}$ ($38.6\%$ maturity) to provide $94\%$ statistical power at a two-sided $\alpha = 0.05$ significance level.

  • Key Secondary Endpoints: Overall Survival ($OS$; final analysis targeted at $522\,\text{deaths}$ / $52.2\%$ maturity), Time to First Subsequent Therapy ($TFST$), Symptomatic Skeletal Event-Free Survival ($SSE-FS$), Time to Pain Progression ($TTPP$).

  • Other Secondary Endpoints: Time to Castration Resistance ($TTCR$), Time to $PSA$ Progression ($TTPSA$).

  • Multiplicity Adjustment: Alpha-exhaustive recycling testing strategy used to transfer $\alpha = 0.05$ from $rPFS$ to $OS$ testing.

Patient Disposition and Baseline Characteristics

• Demographics and Clinical Parameters

• Age:

  • Capivasertib + Abiraterone: Median $67\,\text{years}$ (range $42\text{--}87\,\text{years}$).

  • Placebo + Abiraterone: Median $68\,\text{years}$ (range $43\text{--}88\,\text{years}$).

• Race Distribution:

  • White: $266$ ($52.5\%$) vs $259$ ($51.3\%$).

  • Asian: $186$ ($36.7\%$) vs $189$ ($37.4\%$).

  • Black or African American: $6$ ($1.2\%$) vs $6$ ($1.2\%$).

  • Other: $23$ ($4.5\%$) vs $25$ ($5.0\%$).

  • Missing/Not reported: $26$ ($5.1\%$) vs $26$ ($5.1\%$).

• ECOG Performance Status:

  • Status 0: $329$ ($64.9\%$) vs $320$ ($63.4\%$).

  • Status 1: $178$ ($35.1\%$) vs $185$ ($36.6\%$).

• Anatomic Sites of Metastases:

  • Bone: $462$ ($91.1\%$) vs $467$ ($92.5\%$).

  • Non-regional Lymph Nodes: $217$ ($42.8\%$) vs $214$ ($42.4\%$).

  • Lung: $69$ ($13.6\%$) vs $72$ ($14.3\%$).

  • Liver: $30$ ($5.9\%$) vs $25$ ($5.0\%$).

  • Other: $21$ ($4.1\%$) vs $19$ ($3.8\%$).

• Disease Risk and Volume Classifications:

  • High Disease Risk ($\ge 2$ factors: Gleason $\ge 8$, $\ge 4$ bone lesions, visceral metastasis): $311$ ($61.3\%$) vs $333$ ($65.9\%$).

  • Low Disease Risk: $184$ ($36.3\%$) vs $164$ ($32.5\%$).

  • High Metastatic Volume ($CHAARTED$ definition): $374$ ($73.8\%$) vs $378$ ($74.9\%$).

  • Low Metastatic Volume: $131$ ($25.8\%$) vs $126$ ($25.0\%$).

• Histological Gleason Score:

  • Gleason Score $< 8$: $94$ ($18.5\%$) vs $95$ ($18.8\%$).

  • Gleason Score $\ge 8$: $398$ ($78.5\%$) vs $399$ ($79.0\%$).

• Disease Timing and Prior Treatment:

  • Time from diagnosis to randomization: Median $2.5\,\text{months}$ (range $0.3\text{--}12.8$) vs $2.5\,\text{months}$ (range $0.6\text{--}27.4$); Mean $2.56\,\text{months}$ ($\text{SD } 1.11$) vs $2.49\,\text{months}$ ($\text{SD } 1.43$).

  • Time from prior $ADT$ to randomization: Median $1.4\,\text{months}$ ($n = 499$) vs $1.4\,\text{months}$ ($n = 497$).

  • Time from prior abiraterone to randomization: Median $1.2\,\text{months}$ ($n = 56$) vs $1.4\,\text{months}$ ($n = 58$).

  • Treatment Duration Metrics (Data Cut-Off: October 7, 2024)

• Capivasertib: Median treatment duration $13.6\,\text{months}$ (range $0.1\text{--}46.6$); actual treatment duration accounting for interruptions $12.1\,\text{months}$ ($0.1\text{--}46.4$).

• Abiraterone: Median duration $14.9\,\text{months}$ in capivasertib arm vs $14.9\,\text{months}$ in placebo arm; actual treatment duration $14.5\,\text{months}$ vs $14.7\,\text{months}$.

• Follow-up Duration: Median rPFS follow-up in censored patients was $18.4\,\text{months}$ ($0.03\text{--}44.3$) in capivasertib arm and $18.5\,\text{months}$ ($0.03\text{--}44.5$) in placebo arm.

Primary and Secondary Efficacy Outcomes

• Primary Endpoint: Radiographic Progression-Free Survival (rPFS)

• Primary Analysis Maturity: $398\,\text{events}$ ($39.3\%$ maturity).

• Event Counts: $183/507$ ($36.1\%$) in Capivasertib + Abiraterone vs $215/505$ ($42.6\%$) in Placebo + Abiraterone.

• Median rPFS: $33.2\,\text{months}$ ($95\%\,\text{CI}: 25.8\text{--}44.2$) with Capivasertib + Abiraterone versus $25.7\,\text{months}$ ($95\%\,\text{CI}: 22.0\text{--}29.9$) with Placebo + Abiraterone.

• Absolute Improvement: Median rPFS prolonged by $7.5\,\text{months}$.

• Statistical Significance: $\text{HR} = 0.81$ ($95\%\,\text{CI}: 0.66\text{--}0.98$), $P = 0.034$.

• Prespecified Subgroup Consistency:

  • High metastatic volume with visceral mets: $\text{HR} = 0.77$ ($95\%\,\text{CI}: 0.52\text{--}1.14$).

  • High metastatic volume without visceral mets: $\text{HR} = 0.91$ ($95\%\,\text{CI}: 0.70\text{--}1.17$).

  • Low metastatic volume: $\text{HR} = 0.67$ ($95\%\,\text{CI}: 0.39\text{--}1.12$).

  • High-risk disease: $\text{HR} = 0.88$ ($95\%\,\text{CI}: 0.70\text{--}1.11$).

  • Low-risk disease: $\text{HR} = 0.88$ ($95\%\,\text{CI}: 0.59\text{--}1.31$).

  • Baseline $PSA \le 6.415\,\text{ng/mL}$: $\text{HR} = 0.93$ ($95\%\,\text{CI}: 0.69\text{--}1.24$).

  • Baseline $PSA > 6.415\,\text{ng/mL}$: $\text{HR} = 0.79$ ($95\%\,\text{CI}: 0.60\text{--}1.03$).

  • Gleason Score $\ge 8$: $\text{HR} = 0.82$ ($95\%\,\text{CI}: 0.65\text{--}1.02$).

  • Prior $ADT$: $\text{HR} = 0.83$ ($95\%\,\text{CI}: 0.68\text{--}1.01$).

  • Key Secondary Endpoints

• Overall Survival (OS):

  • Interim Analysis Maturity: $26.4\%$ maturity ($267\,\text{total deaths}$).

  • Deaths: $129/507$ ($25.4\%$) in Capivasertib arm vs $138/505$ ($27.3\%$) in Placebo arm.

  • Stratified Hazard Ratio: $\text{HR} = 0.90$ ($95\%\,\text{CI}: 0.71\text{--}1.15$), $P = 0.401$.

  • Medians: Not reached in either arm ($95\%\,\text{CI}: 42.5\text{--}\text{NC}$ in capivasertib arm).

  • Formal sequential statistical testing stopped at OS due to lack of statistical significance at this interim cut-off; subsequent secondary endpoints reflect nominal $P\text{-values}$.

• Time to First Subsequent Therapy (TFST):

  • Events: $192/507$ ($37.9\%$) vs $206/505$ ($40.8\%$) ($39.3\%$ maturity).

  • Median TFST: $37.0\,\text{months}$ ($95\%\,\text{CI}: 28.0\text{--}\text{NC}$) vs $28.5\,\text{months}$ ($95\%\,\text{CI}: 23.7\text{--}\text{NC}$).

  • Hazard Ratio: $\text{HR} = 0.91$ ($95\%\,\text{CI}: 0.75\text{--}1.11$), nominal P = 0.364$.\n - **Symptomatic Skeletal Event-Free Survival (SSE-FS)**:\n - Events: 150/507$($29.6\%$) vs$176/505$($34.9\%$) ($32.2\% maturity).\n - Median SSE-FS: 42.5\, ext{months}$($95\%\, ext{CI}: 35.9 ext{--} ext{NC}$) vs$37.3\, ext{months}$($95\%\, ext{CI}: 28.3 ext{--} ext{NC}).\n - Hazard Ratio: \text{HR} = 0.82$($95\%\, ext{CI}: 0.66 ext{--}1.02$), nominal$P = 0.079$.

• Time to Castration Resistance (TTCR):

  • Events: $185/507$ ($36.5\%$) vs $231/505$ ($45.7\%$) ($41.1\%$ maturity).

  • Median TTCR: $29.5\,\text{months}$ ($95\%\,\text{CI}: 22.1\text{--}36.8$) vs $22.0\,\text{months}$ ($95\%\,\text{CI}: 18.2\text{--}24.9$).

  • Hazard Ratio: $\text{HR} = 0.77$ ($95\%\,\text{CI}: 0.63\text{--}0.94$), nominal P = 0.009$.\n - **Time to PSA Progression (TTPSA)**:\n - Events: 60/507$($11.8\%$) vs$82/505$($16.2\%$) ($14.0\% maturity).\n - Medians: Not reached in either arm.\n - Hazard Ratio: \text{HR} = 0.73$($95\%\, ext{CI}: 0.52 ext{--}1.01$), nominal$P = 0.060$.

• Time to Pain Progression (TTPP):

  • Maturity: Low maturity ($9.0\%$ overall maturity).

  • Events: $46$ ($9.1\%$) in capivasertib arm vs $41$ ($8.1\%$) in placebo arm.

  • Hazard Ratio: $\text{HR} = 1.14$ ($95\%\,\text{CI}: 0.75\text{--}1.75$); uninterpretable at current cut-off.

Post Hoc Exploratory Analysis by PTEN Deficiency Cut-Off Thresholds

• Rationale and Gradient Hypothesis

  • Prompted by phase III IPATential150 trial observations in $mCRPC$, post hoc analyses evaluated whether greater extents of $PTEN$ deficiency ($\ge 95\%$, $\ge 99\%$, and $100\%$ protein loss) predicted increased efficacy of dual $AKT$/$AR$ blockade.

• Radiographic Progression-Free Survival (rPFS) Post Hoc Gradient

  • $\ge 90\%$ PTEN Cut-Off (Primary Analysis Set, $n = 1012$):

  • Events: $183/507$ ($36.1\%$) vs $215/505$ ($42.6\%$).

  • Medians: $33.2\,\text{months}$ vs $25.7\,\text{months}$.

  • Effect Size: $\text{HR} = 0.81$ ($95\%\,\text{CI}: 0.66\text{--}0.98$).

  • $\ge 95\%$ PTEN Cut-Off ($n = 814$):

  • Events: $146/404$ ($36.1\%$) vs $186/410$ ($45.4\%$).

  • Medians: $33.2\,\text{months}$ vs $22.7\,\text{months}$.

  • Effect Size: $\text{HR} = 0.75$ ($95\%\,\text{CI}: 0.60\text{--}0.94$).

  • $\ge 99\%$ PTEN Cut-Off ($n = 401$):

  • Events: $69/205$ ($33.7\%$) vs $90/196$ ($45.9\%$).

  • Medians: $34.1\,\text{months}$ vs $22.4\,\text{months}$.

  • Effect Size: $\text{HR} = 0.71$ ($95\%\,\text{CI}: 0.52\text{--}0.97$).

  • $100\%$ PTEN Cut-Off ($n = 331$):

  • Events: $57/169$ ($33.7\%$) vs $76/162$ ($46.9\%$).

  • Medians: $34.1\,\text{months}$ ($95\%\,\text{CI}: 22.1\text{--}\text{NC}$) vs $22.1\,\text{months}$ ($95\%\,\text{CI}: 14.7\text{--}26.5$).

  • Effect Size: $\text{HR} = 0.68$ ($95\%\,\text{CI}: 0.48\text{--}0.96$).

• Overall Survival (OS) Post Hoc Gradient

  • $\ge 90\%$ Cut-Off: $\text{HR} = 0.90$ ($95\%\,\text{CI}: 0.71\text{--}1.15$).

  • $\ge 95\%$ Cut-Off: $\text{HR} = 0.80$ ($95\%\,\text{CI}: 0.62\text{--}1.04$).

  • $\ge 99\%$ Cut-Off: $\text{HR} = 0.77$ ($95\%\,\text{CI}: 0.53\text{--}1.12$).

  • $100\%$ Cut-Off: $\text{HR} = 0.77$ ($95\%\,\text{CI}: 0.51\text{--}1.14$).

• Mechanistic Biological Drivers of the Cut-Off Effect

  • Capivasertib + abiraterone efficacy remained consistent across increasing $PTEN$ loss thresholds (median rPFS $33.2\text{--}34.1\,\text{months}$).

  • Placebo + abiraterone control arm performance deteriorated steadily as the degree of $PTEN$ loss increased ($25.7\,\text{months} \rightarrow 22.7\,\text{months} \rightarrow 22.4\,\text{months} \rightarrow 22.1\,\text{months}$).

  • Biological Basis: Non-clinical models confirm that only $PTEN$-deficient cells derive benefit from $AKT$ inhibition during $AR$ blockade. Higher fractions of $PTEN$-null cells intensify cell dependence on $AKT$ overactivation, worsening prognosis on $ARPI$ monotherapy while maximizing sensitivity to capivasertib.

Safety, Tolerability, and Adverse Event Management

• Safety Analysis Set Overview

  • Safety Population: $n = 503$ patients receiving Capivasertib + Abiraterone; $n = 503$ patients receiving Placebo + Abiraterone.

  • Any Adverse Event ($AE$): $497$ ($98.8\%$) in capivasertib arm vs $463$ ($92.0\%$) in placebo arm.

  • Grade $\ge 3$ $AEs$: $337$ ($67.0\%$) vs $203$ ($40.4\%$).

• Common Treatment-Emergent Adverse Events ($>10\%$ Frequency)

  • Diarrhea:

  • All Grades: $261$ ($51.9\%$) vs $40$ ($8.0\%$).

  • Grade $\ge 3$: $31$ ($6.2\%$) vs $2$ ($0.4\%$).

  • Diarrhea severity: Grade 1 in $60.5\%$ ($58/261$), Grade 2 in $27.6\%$ ($72/261$).

  • Resolution: $238$ patients ($91.2\%$ of cases) recovered or were recovering at cut-off.

  • Capivasertib discontinuation due to diarrhea: $5\,\text{patients}$ ($1.0\%$) vs $0\%$ placebo.

  • Hyperglycemia (Grouped Term):

  • All Grades: $191$ ($38.0\%$) vs $65$ ($12.9\%$).

  • Grade $\ge 3$: $52$ ($10.3\%$) vs $3$ ($0.6\%$).

  • Expanded Grouped Term (blood glucose increased, diabetes mellitus, hyperglycemia, type 2 diabetes): All Grades $232$ ($46.1\%$) vs $72$ ($14.3\%$); Grade $\ge 3$ $70$ ($13.9\%$) vs $3$ ($0.6\%$).

  • Discontinuation due to hyperglycemia: $5\,\text{patients}$ ($1.0\%$) vs $0\%$ placebo.

  • Rash (Grouped Term: erythema, rash, macular, maculopapular, papular, pruritic):

  • All Grades: $178$ ($35.4\%$) vs $35$ ($7.0\%$).

  • Grade $\ge 3$: $62$ ($12.3\%$) vs $1$ ($0.2\%$).

  • Discontinuation due to rash: $24\,\text{patients}$ ($4.8\%$) vs $0\%$ placebo.

  • Anemia:

  • All Grades: $120$ ($23.9\%$) vs $64$ ($12.7\%$); Grade $\ge 3$: $26$ ($5.2\%$) vs $5$ ($1.0\%$).

  • Hypokalemia:

  • All Grades: $111$ ($22.1\%$) vs $64$ ($12.7\%$); Grade $\ge 3$: $44$ ($8.7\%$) vs $24$ ($4.8\%$).

  • Hypertension:

  • All Grades: $100$ ($19.9\%$) vs $120$ ($23.9\%$); Grade $\ge 3$: $29$ ($5.8\%$) vs $39$ ($7.8\%$).

  • Fatigue:

  • All Grades: $80$ ($15.9\%$) vs $63$ ($12.5\%$); Grade $\ge 3$: $2$ ($0.4\%$) vs $4$ ($0.8\%$).

  • ALT Increased:

  • All Grades: $71$ ($14.1\%$) vs $67$ ($13.3\%$); Grade $\ge 3$: $22$ ($4.4\%$) vs $17$ ($3.4\%$).

  • Urinary Tract Infection:

  • All Grades: $69$ ($13.7\%$) vs $51$ ($10.1\%$); Grade $\ge 3$: $21$ ($