LHRH sparing therapy in patients with chemotherapy-naïve, mCRPC treated with abiraterone acetate plus prednisone: results of the randomized phase II SPARE trial.

BACKGROUND: Although the benefit of androgen deprivation therapy (ADT) continuation in metastatic castration-resistant prostate cancer (mCRPC) remains controversial, clinical evidence is lacking. Recent results indicated that treatment with abiraterone acetate (AA) plus prednisone (P) further suppresses serum testosterone levels over ADT alone, suggesting that continuation of ADT in the treatment of mCRPC may not be necessary. METHODS: In this exploratory phase 2 study, mCRPC patients were randomized with a 1:1 ratio to receive either continued ADT plus AA + P (Arm A) or AA + P alone (Arm B). The primary endpoint was the rate of radiographic progression-free survival (rPFS) at month 12. Secondary endpoints included PSA-response rate, objective response, time to PSA progression and safety. RESULTS: A total of 68 patients were equally randomized between the two study arms. Median testosterone-levels remained below castrate-levels throughout treatment in all patients. According to the intention-to-treat analysis the rPFS rate was 0.84 in Arm A and 0.89 in Arm B. Moderate and severe treatment-emergent adverse events were reported for 72% of the patients in Arm A and for 85% of the patients in Arm B. CONCLUSIONS: AA + P treatment without ADT may be effective in mCRPC patients and ADT may not be necessary in patients receiving AA + P.

The intracellular distribution of the components of the GET system in vascular plants.

The guided entry of tail-anchored proteins (GET) pathway facilitates targeting and insertion of tail-anchored proteins into membranes. In plants, such a protein insertion machinery for the endoplasmic reticulum as well as constituents within mitochondrial and chloroplasts were discovered. Previous phylogenetic analysis revealed that Get3 sequences of Embryophyta form two clades representing cytosolic ("a") and organellar ("bc") GET3 homologs, respectively. Cellular fractionation of Arabidopsis thaliana seedlings and usage of the self-assembly GFP system in protoplasts verified the cytosolic (ATGet3a), plastidic (ATGet3b) and mitochondrial (ATGet3c) localization of the different homologs. The identified plant homologs of Get1 and Get4 in A. thaliana are localized in ER and cytosol, respectively, implicating a degree of conservation of the GET pathway in A. thaliana. Transient expression of Get3 homologs of Solanum lycopersicum, Medicago × varia or Physcomitrella patens with the self-assembly GFP technique in homologous and heterologous systems verified that multiple Get3 homologs with differing subcellular localizations are common in plants. Chloroplast localized Get3 homologs were detected in all tested plant systems. In contrast, mitochondrial localized Get3 homologs were not identified in S. lycopersicum, or P. patens, while we confirmed on the example of A. thaliana proteins that mitochondrial localized Get3 proteins are properly targeted in S. lycopersicum as well.

Abiraterone acetate plus LHRH therapy versus abiraterone acetate while sparing LHRH therapy in patients with progressive, metastatic and chemotherapy-naïve, castration-resistant prostate cancer (SPARE): study protocol for a randomized controlled trial.

BACKGROUND: The value of continuation of luteinizing hormone-releasing hormone (LHRH) therapy in castration-resistant prostate cancer (CRPC) remains controversial and clear evidence is lacking. Argumentation for cessation of LHRH therapy is the prolonged suppression of testosterone levels after the withdrawal of LHRH analogues and the fact that disease progression occurs despite castration levels of testosterone. Especially upon treatment with the life-prolonging cytochrome P450 17-alpha-hydroxylase (Cyp17)-inhibitor, abiraterone, which has the ability to further suppress testosterone serum levels over LHRH therapy alone, continuation of LHRH therapy seems to be negligible. However, the proven increase of luteinizing hormone levels after LHRH withdrawal, which is even further increased by abiraterone, may counteract the effects of abiraterone by the induction of enzymes of steroidogenesis. Therefore, cessation of LHRH therapy when starting treatment with abiraterone in CRPC may display an unpredictable hazard to the patients. This study will explore the role of continuation of LHRH therapy when starting treatment with abiraterone in patients with asymptomatic or mildly symptomatic, chemotherapy-naïve CPRC. METHODS/DESIGN: The trial will assess radiographic progression-free survival after 12 months of treatment with abiraterone/prednisone in patients who will be randomized to receive continuing LHRH therapy versus LHRH withdrawal at the time of starting abiraterone therapy. DISCUSSION: This multicenter, prospective, randomized, exploratory phase-II trial will bring about new data regarding the efficacy and safety of abiraterone/prednisone treatment with or without continuation of LHRH therapy. In addition, further insight into the complex hormonal changes under treatment will be gained and the results of this trial may give rise to a larger phase-III trial to examine the possibility of withdrawing LHRH therapy in patients with CRPC. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02077634 . Registered on 9 December 2013.