據國外看病專業服務機構盛諾一家了解到，在伴有PTEN缺失的轉移性去勢抵抗性前列腺癌患者中，與標準治療加安慰劑相比，ipatasertib加乙酸阿比特龍酯和潑尼松/潑尼松龍的聯合方案改善了患者的放射影像學無進展生存期。
在伴有PTEN缺失的轉移性去勢抵抗性前列腺癌(mCRPC)患者中，與標準治療加安慰劑相比，ipatasertib加乙酸阿比特龍酯(Zytiga)和潑尼松/潑尼松龍的聯合方案改善了患者的放射影像學無進展生存期(rPFS)，滿足下文所述3期IPATential150試驗(NCT03072238)的聯合主要終點之一。
研究結果表明，與標準治療組相比，ipatasertib方案明顯降低了疾病進展或死亡的風險。此外，發現實驗組的安全性特徵與先前的研究結果一致。據國外看病專業服務機構盛諾一家了解到，該項3期試驗的全部結果將在即將舉行的醫學會議上展示。
Ipatasertib的製造商基因泰克(羅氏)在新聞稿中表示，總生存期(OS)獲益和其他次要終點尚不成熟，在下一次計劃的分析之前將繼續進行該項研究，而且研究結果將與監管機構共享。
「前列腺癌仍然是全球男性的主要死亡原因，而轉移性去勢抵抗性前列腺癌患者尤為難治。」基因泰克首席醫學官兼全球產品開發部負責人Levi Garraway醫生在新聞稿中如是表示，「在我們致力於開發針對晚期前列腺癌患者的新型治療選擇的過程中，IPATential150研究的早期結果使我們看到光明的前景。」
Ipatasertib是一種具有高度特異性的口服藥物，可靶向並結合AKT的所有3種亞型，從而阻斷PI3K/AKT信號通路，而該通路也與抗雄激素治療的耐藥性有關。雄激素受體(AR)抑制與AKT通路激活增加有關。
在40%至60%的mCRPC患者中觀察到腫瘤中存在PTEN功能缺失，導致PI3K/AKT通路過度激活。該疾病特徵還與腫瘤等級和分期升高、根治性前列腺切除術後的早期生化復發、轉移、前列腺癌特異性死亡，以及雄激素非依賴性進展有關。
在該項雙盲、安慰劑對照的隨機3期IPATential150研究中，研究者正在評估ipatasertib聯合阿比特龍加潑尼松/潑尼松龍相比安慰劑加阿比特龍和潑尼松/潑尼松龍用於約1100名無症狀或伴有輕度症狀的先前未經治療的mCRPC成人患者時的效果。
據國外看病專業服務機構盛諾一家介紹，為了有資格入組該項研究，患者必須符合以下條件：ECOG體能狀態為0或1、在首次研究治療前28天內具有足夠的血液和器官功能，以及預期壽命至少為6個月。在其他標準中，符合以下條件的患者被排除在該項研究之外：既往接受過AR抑制劑、全身放射性藥物，以及已知出現中樞神經系統轉移。
在第1周期的第1天，口服ipatasertib，每日一次，劑量為400 mg，而阿比特龍為每日一次，口服，劑量為1000 mg，外加潑尼松/潑尼松龍，每日兩次，劑量為5 mg，直至疾病進展或出現不可接受的毒性。以28天為一周期，向患者提供治療。
共同主要終點是研究者確定的總體研究人群中的rPFS，以及通過免疫組織化學(IHC)評估的伴有PTEN缺失的腫瘤的人群中的rPFS。次要終點包括OS、安全性、至疼痛進展時間、至啟動細胞毒性化療時間，以及至功能惡化時間。
據國外看病專業服務機構盛諾一家介紹，來自1/2 A期MARTIN研究的先前結果表明，ipatasertib用於既往接受過治療的mCRPC患者時具有早期臨床活性。在該項試驗中，研究者將253名既往接受過多西他賽治療的mCRPC患者隨機分為3組：400 mg ipatasertib組、200 mg ipatasertib組或安慰劑組，而且上述藥物均與阿比特龍和潑尼松聯合使用。根據預先定義的標準，通過IHC評估PTEN的表達情況，並通過螢光原位雜交和下一代測序檢測PTEN基因組缺失。
。400
研究發現表明，在初步分析中，觀察到173項rPFS事件。165例(65%)病例的PTEN狀態可通過IHC進行評估，而且在71例(43%)病例中觀察到PTEN缺失。與安慰劑組相比，兩個ipatasertib治療組的伴有PTEN缺失的患者的rPFS均有所改善，但在400 mg劑量組中觀察到程度更大的獲益
還在三陰性乳腺癌和激素受體陽性HER2陰性乳腺癌患者中對Ipatasertib的效果進行了評估，預計將於今年下半年獲得研究結果。
連結：
https://www.onclive.com/view/ipatasertib-abiraterone-regimen-improves-radiographic-pfs-in-mcrpc-with-pten-loss
IpatasertibAbiraterone Regimen Improves Radiographic PFS in mCRPC With PTEN Loss
The combination of ipatasertib plus abiraterone acetate and prednisone/prednisolone improved radiographic progression-free survival compared with standard treatment plus placebo in patients with metastatic castration-resistant prostate cancer who have PTEN loss.
The combination of ipatasertib plus abiraterone acetate (Zytiga) and prednisone/prednisolone improved radiographic progression-free survival (rPFS) compared with standard treatment plus placebo in patients with metastatic castration-resistant prostate cancer (mCRPC) who have PTENloss, meeting one of the co-primary end points of the phase 3 IPATential150 trial (NCT03072238).1
Results showed that the ipatasertib regimen led to a statistically significant reduction in the risk of disease progression or death compared with the standard-of-care arm. Moreover, the safety profile in the experimental arm was found to be consistent with prior studies. Full findings of the phase 3 trial will be presented at an upcoming medical meeting.
Genentech (Roche), the manufacturer of ipatasertib, stated in a press release that the overall survival (OS) benefit and additional secondary end points are immature, and that the study will continue until the next planned analysis—results of which will be shared with regulatory authorities.
「Prostate cancer remains a leading cause of death in men worldwide and patients with metastatic castration-resistant prostate cancer can be difficult to treat,」 Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development, Genentech, stated in the press release. 「The early results of the IPATential150 study are encouraging in our ongoing mission to develop new treatment options for people with advanced prostate cancer.」
Ipatasertib is an oral, highly specific agent that targets and binds to all 3 isoforms of AKT, which blocks the PI3K/AKT signaling pathway, which has also been associated with resistance to antiandrogen treatment; androgen receptor (AR) inhibition is associated with an increase in AKT pathway activation.
Functional loss of PTEN in the tumor is seen in 40% to 60% of patients with mCRPC, which leads to hyperactivation of the PI3K/AKT pathway. The disease characteristic is also linked with increased tumor grade and stage, earlier biochemical recurrence following radical prostatectomy, metastasis, prostate cancer–specific death, and androgen-independent progression.
In the double-blind, placebo-controlled, randomized phase 3 IPATential150 study, investigators are assessing ipatasertib in combination with abiraterone plus prednisone/prednisolone versus placebo plus abiraterone and prednisone/prednisolone in approximately 1100 adult patients with asymptomatic or mildly symptomatic, previously untreated mCRPC.
To be eligible for enrollment, patients must have an ECOG performance status of 0 or 1, adequate hematologic and organ function within 28 days before first study treatment, and a life expectancy of at least 6 months. Patients who received prior AR inhibitors, systemic radiopharmaceuticals, and had known central nervous system metastases, among other criteria, were excluded from enrolling on the study.
Ipatasertib is given orally at 400 mg once daily on day 1 of cycle 1, while abiraterone is given orally at 1000 mg once daily plus 5 mg of twice-daily prednisone/prednisolone until disease progression or unacceptable toxicity. Treatment was given in 28-day cycles.
The co-primary end points are investigator-determined rPFS in the overall study population, as well as in those whose tumors have PTEN loss, as assessed by immunohistochemistry (IHC). Secondary end points include OS, safety, time to pain progression, time to initiation of cytotoxic chemotherapy, and time to function deterioration.
Prior findings from the phase 1/2 A. MARTIN study demonstrated early clinical activity with ipatasertib in patients with mCRPC who had received prior treatment. In the trial, Investigators randomized 253 patients with mCRPC who were previously treated with docetaxel to 3 arms: ipatasertib at 400 mg, ipatasertib at 200 mg, or placebo, all of which were given in combination with abiraterone and prednisone. PTEN expression was assessed by IHC with prospectively defined criteria, and PTEN genomic loss was detected by fluorescence in situ hybridization and next-generation sequencing.
Findings showed that, at the primary analysis, 173 rPFS events were observed; PTEN status was evaluable by IHC in 165 cases (65%) and PTEN loss was seen in 71 cases (43%). Patients with PTEN loss had improved rPFS in both ipatasertib arms compared with the placebo arm, but a greater benefit was observed with the 400-mg dose. The median rPFS was 11.5 months (HR, 0.39; 95% CI, 0.22-0.70; P = .0064), 11.1 months (HR, 0.46; 95% CI, 0.25-0.83; P = .0285), and 4.6 months in the 400-mg, 200-mg, and placebo arms, respectively.
Ipatasertib is also being evaluated in triple-negative breast cancer and hormone receptor– positive, HER2-negative breast cancer, results of which are anticipated later this year.
連結：
https://www.onclive.com/view/ipatasertib-abiraterone-regimen-improves-radiographic-pfs-in-mcrpc-with-pten-loss
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