LBA4 IPATential150: Phase III study of ipatasertib (ipat) plus abiraterone (abi) vs placebo (pbo) plus abi in metastatic castration-resistant prostate cancer (mCRPC)

Bono, Johann S. de; Bracarda, Sergio; Sternberg, Cora N.; N., Kim; Olmos, David; Sandhu, Shahneen; Massard, Christophe; Matsubara, Nobuaki; Alekseev, B. Ya.; Gafanov, Rustem; Parnis, Francis; Buchschacher, Gary L.; Corrales, Luis; Borre, Michael; Alves, Gustavo Vasconcelos; Garcia, Josep; Harle-Yge, M-L.; Chen, G.; Wongchenko, Matthew J.; Sweeney, Christopher J.

doi:10.1016/j.annonc.2020.08.2250

Cited by 32 publications

(22 citation statements)

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“…Currently, the randomized phase II CHAARTED2 trial is actively recruiting mCRPC patients who received prior docetaxel chemotherapy for high volume mHSPC to receive abiraterone acetate with or without cabazitaxel [ 82 ]. In the recently presented IPATENTIAL 150 phase III study, the combination of abiraterone and the PI3K inhibitor ipatasertib was shown to increase radiographic PFS compared to abiraterone alone as first-line mCRPC therapy in patients with loss of PTEN; OS data are awaited to define the role of this combination in the treatment of mCRPC [ 20 ]. A number of different combinations of hormonal and chemotherapeutic agents with other agents such as radiopharmaceuticals (radium-223), PARP inhibitors (olaparib), or immunotherapeutic agents (nivolumab, pembrolizumab) have reported clinical activity in mCRPC [ 83 , 84 , 85 , 86 ].…”

Section: Optimal Sequencing In Mhspc Nmcrpc and Mcrpcmentioning

confidence: 99%

Optimal Sequencing and Predictive Biomarkers in Patients with Advanced Prostate Cancer

Cattrini

España

Mennitto

et al. 2021

Cancers

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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).

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Section: Optimal Sequencing In Mhspc Nmcrpc and Mcrpcmentioning

confidence: 99%

Optimal Sequencing and Predictive Biomarkers in Patients with Advanced Prostate Cancer

Cattrini

España

Mennitto

et al. 2021

Cancers

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“…This drug was tested in a phase I basket study of 58 polytreated patients, obtaining a PFS of 6 months. Ipatasertib associated with abiraterone is currently in a phase III study based on promising previous results [76].…”

Section: Mechanisms To Sensitize To Parp Inhibitors and Reverse Resistancementioning

confidence: 99%

Changing the History of Prostate Cancer with New Targeted Therapies

et al. 2021

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The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) is changing due to the emergence of new targeted therapies for the treatment of different molecular subtypes. Some biomarkers are described as potential molecular targets different from classic androgen receptors (AR). Approximately 20–25% of mCRPCs have somatic or germline alterations in DNA repair genes involved in homologous recombination. These subtypes are usually associated with more aggressive disease. Inhibitors of the enzyme poly ADP ribose polymerase (PARPi) have demonstrated an important benefit in the treatment of these subtypes of tumors. However, tumors that resistant to PARPi and wildtype BRCA tumors do not benefit from these therapies. Recent studies are exploring drug combinations with phosphatidylinositol-3-kinase (PI3K) or protein kinase B (AKT) inhibitors, as mechanisms to overcome resistance or to induce BRCAness and synthetic lethality. This article reviews various different novel strategies to improve outcomes in patients with prostate cancer.

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“…For example, PTEN copy number loss was only observed in NR, consistent with reduced PTEN expression by immunohistochemistry in tumors persisting after treatment on our clinical trial 27 . It is possible that HRLPC patients with PTEN loss should not receive neoadjuvant API, but rather may benefit from a different therapy such as AKT inhibition as is currently being evaluated with ipatasertib in the IPATential150 trial (NCT03072238) 65 . Furthermore, 2 NR patients had copy number evidence of HRD in the absence of BRCA mutation, which may indicate sensitivity to PARP inhibition 52,66 .…”

Section: Discussionmentioning

confidence: 99%

“…PTEN loss should not receive neoadjuvant API, but rather may benefit from a different therapy such as AKT inhibition as is currently being evaluated with ipatasertib in the IPATential150 trial (NCT03072238) 65 . Furthermore, 2 NR patients had copy number evidence of HRD in the absence of BRCA mutation, which may indicate sensitivity to PARP inhibition 52,66 .…”

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confidence: 99%

Molecular features of exceptional response to neoadjuvant anti-androgen therapy in high-risk localized prostate cancer

Tewari

Cheung

Crowdis

et al. 2021

Preprint

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High-risk localized prostate cancer (HRLPC) is associated with a substantial risk of recurrence and prostate cancer-specific mortality1. Recent clinical trials have shown that intensifying anti-androgen therapies administered prior to prostatectomy can induce pathologic complete responses (pCR) or minimal residual disease (MRD) (<5 mm), together termed exceptional response, although the molecular determinants of these clinical outcomes are largely unknown. Here, we performed whole exome (WES) and whole transcriptome sequencing (RNA-seq) on pre-treatment multi-regional tumor biopsies from exceptional responders (ER: pCR and MRD patients) and non-responders (NR: pathologic T3 or lymph node positive disease) treated with intensive anti-androgen therapies prior to prostatectomy. SPOP mutation and SPOPL copy number loss were exclusively observed in ER, while TP53 mutation and PTEN copy number loss were exclusively observed in NR. These alterations were clonal in all tumor phylogenies per patient. Additionally, transcriptional programs involving androgen signaling and TGFβ signaling were enriched in ER and NR, respectively. The presence of these alterations in routine biopsies from patients with HRLPC may inform the prospective identification of responders to neoadjuvant anti-androgen therapies to improve clinical outcomes and stratify other patients to alternative biologically informed treatment strategies.

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LBA4 IPATential150: Phase III study of ipatasertib (ipat) plus abiraterone (abi) vs placebo (pbo) plus abi in metastatic castration-resistant prostate cancer (mCRPC)

Cited by 32 publications

References 0 publications

Optimal Sequencing and Predictive Biomarkers in Patients with Advanced Prostate Cancer

Optimal Sequencing and Predictive Biomarkers in Patients with Advanced Prostate Cancer

Changing the History of Prostate Cancer with New Targeted Therapies

Molecular features of exceptional response to neoadjuvant anti-androgen therapy in high-risk localized prostate cancer

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