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The PI3K/AKT/PTEN pathway is frequently deregulated in metastatic castration-resistant prostate cancer (mCRPC). ProCAID was a phase 2 trial assessing addition of the AKT1/2/3 inhibitor capivasertib to docetaxel for patients with mCRPC. We previously reported that capivasertib did not extend a composite progression-free survival primary endpoint but did significantly improve the secondary endpoint of overall survival (OS). Here we present OS data after 66% of events had occurred in the intent-to-treat population (n = 150). Median OS was 25.3 mo for capivasertib plus docetaxel versus 20.3 mo for placebo plus docetaxel (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.47–1.05; nominal p = 0.09). Receipt of subsequent life-extending treatments was balanced between the treatment arms. The OS benefit associated with capivasertib was maintained in a subset of patients previously treated with abiraterone and/or enzalutamide (median OS 25.0 vs 17.6 mo; HR 0.57, 95% CI 0.36–0.91; nominal p = 0.02) but not in abiraterone/enzalutamide-naïve patients (median OS 31.1 mo vs not reached; HR 1.43, 95% CI 0.63–3.23). We conclude that OS may be extended by addition of capivasertib to docetaxel. Exploratory analysis revealed that the OS benefit was maintained in a subset of patients previously exposed to androgen receptor–targeted agents, which should be evaluated in prospective trials.\ud \ud Patient summary: \ud The ProCAID study examined whether adding the AKT inhibitor drug capivasertib to docetaxel chemotherapy improves outcomes for patients with advanced prostate cancer. Initial analysis of the ProCAID results suggested that capivasertib improved overall survival benefit. This follow-up analysis suggests that capivasertib addition may be particularly beneficial for patients whose cancer was previously treated with drugs that target the androgen receptor.

Objectives AGILE is a Phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection. Methods We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomized 2:1 in groups of 6 participants to 300, 600 and 800 mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was 25% or greater. Secondary outcomes included safety, clinical progression, pharmacokinetics and virological responses. Results Of 103 participants screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 300, 600 and 800 mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800 mg molnupiravir, respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800 mg was estimated at 0.9%. Conclusions Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.

108 Background: The AKT pathway is frequently deregulated in mCRPC. ProCAID tested addition of capivasertib, a potent selective inhibitor of all three AKT isoforms (AKT1/2/3) to docetaxel chemotherapy vs. placebo plus docetaxel for mCRPC. The primary analysis showed no difference between treatment arms for the primary endpoint of composite progression free survival (cPFS). However, OS, which was a secondary endpoint, was extended in the capivasertib plus docetaxel arm. cPFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway biomarker status (Crabb et al, J Clin Oncol 2021;39(3):190-201). Methods: An updated analysis of mature OS data was undertaken once events reached ≥65% by Cox proportional hazards model, adjusted for minimisation factors, within the intent to treat (ITT) population (n = 150). Patients (pts) and investigators remained blinded to treatment allocation. We also investigated OS outcomes within subsets based on prior androgen receptor targeted agent (ARTA) exposure to abiraterone and/or enzalutamide (abi/enza) and the balance of post-trial life extending treatment use by treatment arm. Funding: Cancer Research UK (C9317/A16029, CRUK/12/042) and AstraZeneca. Results: At this OS update, 99 pts (66.0%) had died, with 88 of these deaths (88.9%) due to prostate cancer. 5 pts (3.3%) remained on capivasertib or placebo. Median OS was 25.3 months for the capivasertib plus docetaxel arm vs. 20.3 months for placebo plus docetaxel (hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.47 to 1.05; nominal p = 0.09). One, or more, subsequent life extending treatment options, including abiraterone, enzalutamide, radium-223 and cabazitaxel, were received by 99 pts (66.0%) and were balanced between treatment arms (68% capivasertib, 64% placebo). 101 pts (67.3%; 51 capivasertib, 50 placebo) had received abi/enza prior to entering ProCAID. Within this subgroup, OS benefit for capivasertib plus docetaxel (median OS 31.1 months) was maintained vs. placebo plus docetaxel (median OS 19.3 months; HR 0.57, 95% CI 0.36 to 0.91), but not in the remaining 49 pts who were naive to prior abi/enza (median OS 31.1 vs. not reached respectively; HR 1.43, 95% CI 0.63 to 3.23). These updated OS results remained consistent irrespective of biomarker status for PI3K/AKT/PTEN pathway activation. No clinically significant differences from the previously reported safety outcomes were seen with extended follow up of this trial. Conclusions: OS remains longer within the ProCAID ITT population with the addition of capivasertib to docetaxel for mCRPC. This does not appear to be explained by subsequent treatment choices. Exploratory analysis found prolonged OS with capivasertib within a subset of pts previously exposed to an ARTA which should be evaluated in prospective trials. Clinical trial information: NCT02121639.