Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial

Understanding of the molecular mechanisms of prostate cancer has led to development of therapeutic strategies targeting androgen receptor (AR). These androgen-receptor signaling inhibitors (ARSI) include androgen synthesis inhibitor-abiraterone and androgen receptor antagonists-enzalutamide, apalutamide, and darolutamide. Although these medications provide significant improvement in survival among men with prostate cancer, drug resistance develops in nearly all patients with time. This could be through androgen-dependent or androgen-independent mechanisms. Even weaker signals and non-canonical steroid ligands can activate AR in the presence of truncated AR-splice variants, AR overexpression, or activating mutations in AR. AR splice variant, AR-V7 is the most studied among these and is not targeted by available ARSIs. Non-androgen receptor dependent resistance mechanisms are mediated by activation of an alternative signaling pathway when AR is inhibited. DNA repair pathway, PI3K/AKT/mTOR pathway, BRAF-MAPK and Wnt signaling pathway and activation by glucocorticoid receptors can restore downstream signaling in prostate cancer by alternative proteins. Multiple clinical trials are underway exploring therapeutic strategies to overcome these resistance mechanisms.

Section: Ar Crosstalk With Other Signal Transduction Pathwaysmentioning

confidence: 98%

Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies

Jacob

Raj

Allison

et al. 2021

“…The radiographic PFS was prolonged in the ipatasertib cohort, with similar trends in OS and time-to-PSA progression; in addition, a larger radiographic PFS prolongation for the combination was demonstrated in PTEN-loss tumors. Based on these data, the phase III IPATential150 trial assessed the efficacy ipatasertib in combination with abiraterone compared to abiraterone alone for the first-line treatment of patients with mCRPC [109,137]. The co-primary endpoints were radiographic PFS in the PTEN-loss-by-immunohistochemistry population and in the intention-to-treat population.…”

Section: Pten Loss and Pi3k Alterationsmentioning

confidence: 99%

Optimal Sequencing and Predictive Biomarkers in Patients with Advanced Prostate Cancer

Cattrini

España

Mennitto

et al. 2021

Self Cite

The treatment landscape of advanced prostate cancer has completely changed during the last decades. Chemotherapy (docetaxel, cabazitaxel), androgen-receptor signaling inhibitors (ARSi) (abiraterone acetate, enzalutamide), and radium-223 have revolutionized the management of metastatic castration-resistant prostate cancer (mCRPC). Lutetium-177–PSMA-617 is also going to become another treatment option for these patients. In addition, docetaxel, abiraterone acetate, apalutamide, enzalutamide, and radiotherapy to primary tumor have demonstrated the ability to significantly prolong the survival of patients with metastatic hormone-sensitive prostate cancer (mHSPC). Finally, apalutamide, enzalutamide, and darolutamide have recently provided impactful data in patients with nonmetastatic castration-resistant disease (nmCRPC). However, which is the best treatment sequence for patients with advanced prostate cancer? This comprehensive review aims at discussing the available literature data to identify the optimal sequencing approaches in patients with prostate cancer at different disease stages. Our work also highlights the potential impact of predictive biomarkers in treatment sequencing and exploring the role of specific agents (i.e., olaparib, rucaparib, talazoparib, niraparib, and ipatasertib) in biomarker-selected populations of patients with prostate cancer (i.e., those harboring alterations in DNA damage and response genes or PTEN).

“…PTEN expression was also studied prospectively as a predictive biomarker in mCRPC in a phase II randomized trial, which showed a longer rPFS in PTEN-loss tumors treated with ipatasertib, a small tyrosine-kinase inhibitor (TKI) against AKT [47]. A larger phase III study with ipatasertib (IPATential trial) has confirmed these results, although a different cut-off was used to define PTEN loss tumors (50% or more of the specimen's tumor area having no detectable PTEN) [48]. Nevertheless, the benefit in terms of rPFS was also confirmed using more stringent cutoffs than the pre-specified 50%, consistently with what previously demonstrated in the phase II trial [49].…”

Section: Pten and Pi3k-akt Pathwaymentioning

confidence: 99%

Molecular Characterization of Prostate Cancers in the Precision Medicine Era

Giunta

Annaratone

Bollito

et al. 2021

Prostate cancer (PCa) therapy has been recently revolutionized by the approval of new therapeutic agents in the metastatic setting. However, the optimal therapeutic strategy in such patients should be individualized in the light of prognostic and predictive molecular factors, which have been recently studied: androgen receptor (AR) alterations, PTEN-PI3K-AKT pathway deregulation, homologous recombination deficiency (HRD), mismatch repair deficiency (MMRd), and tumor microenvironment (TME) modifications. In this review, we highlighted the clinical impact of prognostic and predictive molecular factors in PCa patients’ outcomes, identifying biologically distinct subtypes. We further analyzed the relevant methods to detect these factors, both on tissue, i.e., immunohistochemistry (IHC) and molecular tests, and blood, i.e., analysis of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). Moreover, we discussed the main pros and cons of such techniques, depicting their present and future roles in PCa management, throughout the precision medicine era.