Apalutamide for the treatment of metastatic castration-sensitive prostate cancer.

Prostate cancer is the fifth leading cause of cancer-related death among men with the majority of deaths linked to metastatic disease. Accumulating clinical data have confirmed the substantial survival benefit of the addition of docetaxel or androgen signaling inhibitors to androgen deprivation therapy for the treatment of metastatic castration-sensitive prostate cancer (mCSPC). Apalutamide, a next-generation androgen receptor inhibitor, has recently been shown to provide an added survival benefit in the treatment of mCSPC and consequently approved for this indication. This review summarizes the body of evidence with regards to the preclinical activity and clinical efficacy of apalutamide with a specific focus on its efficacy in the treatment of mCSPC.

Health-related quality of life in GALAHAD: A multicenter, open-label, phase 2 study of niraparib for patients with metastatic castration-resistant prostate cancer and DNA-repair gene defects.

BACKGROUND: Niraparib is a highly selective poly (adenosine diphosphateribose) polymerase-1 and poly (adenosine diphosphate-ribose) polymerase-2 inhibitor indicated for select patients with ovarian, fallopian tube, and primary peritoneal cancer. The phase 2 GALAHAD trial (NCT02854436) demonstrated that niraparib monotherapy is tolerable and efficacious in patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations, particularly those with breast cancer gene (BRCA) alterations who had progressed on prior androgen signaling inhibitor therapy and taxane-based chemotherapy. OBJECTIVE: To report the prespecified patient-reported outcomes analysis from GALAHAD. METHODS: Eligible patients with alterations to BRCA1 and/or BRCA2 (BRCA cohort) and with pathogenic alterations in other HRR genes (other HRR cohort) were enrolled and received niraparib 300 mg once daily. Patient-reported outcome instruments included the Functional Assessment of Cancer Therapy-Prostate and the Brief Pain Inventory-Short Form. Changes from baseline were compared using a mixed-effect model for repeated measures. RESULTS: On average, health-related quality of life (HRQoL) improved in the BRCA cohort by cycle 3 (mean change = 6.03; 95% CI = 2.76-9.29) and was maintained above baseline until cycle 10 (mean change = 2.84; 95% CI = -1.95 to 7.63), whereas the other HRR cohort showed no early change in HRQoL from baseline (mean change = -0.07; 95% CI = -4.69 to 4.55) and declined by cycle 10 (mean change = -5.10; 95% CI = -15.3 to 5.06). Median time to deterioration in pain intensity and pain interference could not be estimated in either cohort. CONCLUSIONS: Patients with advanced mCRPC and BRCA alterations treated with niraparib experienced more meaningful improvement in overall HRQoL, pain intensity, and pain interference compared with those with other HRR alterations. In this population of castrate, heavily pretreated patients with mCRPC and HRR alterations, stabilization, and improvement in HRQoL may be relevant to consider when making treatment decisions. DISCLOSURES: This work was supported by Janssen Research & Development, LLC (no grant number). Dr Smith has received grants and personal fees from Bayer, Amgen, Janssen, and Lilly; and has received personal fees from Astellas Pharma, Novartis, and Pfizer. Dr Sandhu has received grants from Amgen, Endocyte, and Genentech; has received grants and personal fees from AstraZeneca and Merck; and has received personal fees from Bristol Myers Squibb and Merck Serono. Dr George has received personal fees from the American Association for Cancer Research, Axess Oncology, Capio Biosciences, Constellation Pharma, EMD Serono, Flatiron, Ipsen, Merck Sharp & Dohme, Michael J. Hennessey Association, Millennium Medical Publishing, Modra Pharma, Myovant Sciences, Inc., NCI Genitourinary, Nektar Therapeutics, Physician Education Resource, Propella TX, RevHealth, LLC, and UroGPO; has received grants and personal fees from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, and Pfizer; has received personal fees and nonfinancial support from Bayer and UroToday; has received grants from Calithera and Novartis; and has received grants, personal fees, and nonfinancial support from Exelixis, Inc., Sanofi, and Janssen Pharma. Dr Chi has received grants from Janssen during the conduct of the study; has received grants and personal fees from AstraZeneca, Bayer, Astellas Pharma, Novartis, Pfizer, POINT Biopharma, Roche, and Sanofi; and has received personal fees from Daiichi Sankyo, Merck, and Bristol Myers Squibb. Dr Saad has received grants, personal fees, and nonfinancial support from Janssen during the conduct of the study; and has received grants, personal fees, and nonfinancial support from AstraZeneca, Astellas Pharma, Pfizer, Bayer, Myovant, Sanofi, and Novartis. Dr Thiery-Vuillemin has received grants, personal fees, and nonfinancial support from Pfizer; has received personal fees and nonfinancial support from AstraZeneca, Janssen, Ipsen, Roche/Genentech, Merck Sharp & Dohme, and Astellas Pharma; and has received personal fees from Sanofi, Novartis, and Bristol Myers Squibb. Dr Olmos has received grants, personal fees, and nonfinancial support from AstraZeneca, Bayer, Janssen, and Pfizer; has received personal fees from Clovis, Daiichi Sankyo, and Merck Sharp & Dohme; and has received nonfinancial support from Astellas Pharma, F. Hoffman-LaRoche, Genentech, and Ipsen. Dr Danila has received research support from the US Department of Defense, the American Society of Clinical Oncology, the Prostate Cancer Foundation, Stand Up to Cancer, Janssen Research & Development, Astellas Pharma, Medivation, Agensys, Genentech, and CreaTV. Dr Gafanov has received grants from Janssen during the conduct of the study. Dr Castro has received grants from Janssen during the conduct of the study; has received grants and personal fees from Janssen, Bayer, AstraZeneca, and Pfizer; and has received personal fees from Astellas Pharma, Merck Sharp & Dohme, Roche, and Clovis. Dr Moon has received research funding from SeaGen, HuyaBio, Janssen, BMS, Aveo, Xencor, and has received personal fees from Axess Oncology, MJH, EMD Serono, and Pfizer. Dr Joshua has received nonfinancial support from Janssen; consulted or served in an advisory role for Neoleukin, Janssen Oncology, Ipsen, AstraZeneca, Sanofi, Noxopharm, IQvia, Pfizer, Novartis, Bristol Myers Squibb, Merck Serono, and Eisai; and received research funding from Bristol Myers Squibb, Janssen Oncology, Merck Sharp & Dohme, Mayne Pharma, Roche/Genentech, Bayer, MacroGenics, Lilly, Pfizer, AstraZeneca, and Corvus Pharmaceuticals. Drs Mason, Liu, Bevans, Lopez-Gitlitz, and Francis and Mr Espina are employees of Janssen Research & Development. Dr Mason owns stocks with Janssen. Dr Fizazi has participated in advisory boards and talks for Amgen, Astellas, AstraZeneca, Bayer, Clovis, Daiichi Sankyo, Janssen, MSD, Novartis/AAA, Pfizer, and Sanofi, with honoraria to his institution (Institut Gustave Roussy); has participated in advisory boards for, with personal honoraria from, Arvinas, CureVac, MacroGenics, and Orion. Study registration number: NCT02854436.

Phase Ib dose-finding study of abiraterone acetate plus buparlisib (BKM120) or dactolisib (BEZ235) in patients with castration-resistant prostate cancer.

BACKGROUND: The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signalling axis and androgen receptor (AR) pathways exhibit reciprocal feedback regulation in phosphatase and tensin homologue (PTEN)-deficient metastatic castration-resistant prostate cancer (CRPC) in preclinical models. This phase Ib study evaluated the pan-PI3K inhibitor buparlisib (BKM120) and the dual pan-PI3K/ mammalian target of rapamycin (mTOR) inhibitor dactolisib (BEZ235) in combination with abiraterone acetate (AA) in patients with CRPC. MATERIALS AND METHODS: Patients with CRPC who had progressed on AA therapy received escalating doses of either buparlisib or dactolisib, along with fixed doses of AA (1000 mg once daily (qd)) and prednisone (5 mg twice daily (bid)). The primary objective was to define the maximum tolerated dose (MTD) and/or the recommended dose for expansion (RDE) of either buparlisib or dactolisib in combination with AA. Secondary objectives included safety, antitumour activity (Prostate Cancer Working Group 2 (PCWG2) criteria; 30% of prostate-specific antigen (PSA) decline at ≥week 12) and pharmacokinetic (PK) profile. RESULTS: In buparlisib + AA arm, 25 patients received buparlisib + AA (median age, 67 years; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1/2 for 7/17/1 patients, respectively). At 100 mg qd; two patients experienced dose-limiting toxicities (DLTs) (grade 3 hyperglycaemia; grade 2 asthenia), and this was the maximum buparlisib dose explored. Buparlisib + AA showed a 26% lower median area under the curve from time zero to 24°h (AUC0-24) and 48% lower median maximum serum concentration (Cmax) versus the single-agent buparlisib assessed in first-in-human study. No objective response and few PSA decreases were reported. In dactolisib + AA arm, 18 patients (median age, 71 years; ECOG PS of 0/1 for 6/12 patients, respectively) received dactolisib + AA at the first dose level (200 mg bid). Five patients had 9 DLTs (grades 2&3 stomatitis; grade 3 hyperglycaemia; grades 2& 3 diarrhoea; grades 1& 2 pyrexia, grade 2 vomiting, and grade 2 chills). CONCLUSIONS: Based on the assessment of available pharmacokinetics, safety, and efficacy data, no further study is planned for either buparlisib or dactolisib in combination with AA in CRPC.

A phase 2 study of intravenous panobinostat in patients with castration-resistant prostate cancer.

PURPOSE: Panobinostat, a pan-deacetylase inhibitor, increases acetylation of proteins associated with growth and survival of malignant cells. This phase 2 study evaluated the efficacy of intravenous (IV) panobinostat in patients with castration-resistant prostate cancer (CRPC) who had previously received chemotherapy. The primary end point was 24-week progression-free survival. Secondary end points included safety, tolerability, and the proportion of patients with a prostate-specific antigen (PSA) decline. METHODS: IV panobinostat (20 mg/m(2)) was administered to patients on days 1 and 8 of a 21-day cycle. Tumor response was assessed by imaging every 12 weeks (4 cycles) according to modified response evaluation criteria in solid tumors (Scher et al. in Clin Cancer Res 11:5223-5232, 23), and PSA response was defined as a 50 % decrease from baseline maintained for ≥4 weeks. Safety monitoring was routinely performed and included electrocardiogram monitoring. RESULTS: Of 35 enrolled patients, four (11.4 %) were alive without progression of disease at 24 weeks. PSA was evaluated in 34 (97.1 %) patients: five (14.3 %) patients demonstrated a decrease in PSA but none ≥50 %; one patient (2.9 %) had carcinoembryonic antigen as a marker of his prostate cancer, which declined by 43 %. Toxicities regardless of relationship to panobinostat included fatigue (62.9 %), thrombocytopenia (45.7 %), nausea (51.4 %), and decreased appetite (37.1 %). CONCLUSIONS: Despite promising preclinical data and scientific rationale, treatment with IV panobinostat did not show a sufficient level of clinical activity to pursue further investigation as a single agent in CRPC.