Pivotal Role Remains With Bone-Targeting Agents in mCRPC

Excerpt:

“Prostate cancer researchers are continuing to explore strategies to optimally integrate bone-targeted agents into patient care.

“For example, an ongoing trial is assessing the combination of a radiopharmaceutical, radium-223 dichloride (Xofigo), with an androgen receptor-directed therapy, either abiraterone acetate (Zytiga) or enzalutamide (Xtandi). The open-label, phase IIa study is accruing patients with metastatic castration-resistant prostate cancer (mCRPC). The primary endpoint of the trial, which hopes to enroll 68 patients, is patient bone scan response rate (NCT02034552).”

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Enzalutamide Shows Efficacy in Prostate Cancer With Visceral Mets

Excerpt:

“Patients with metastatic castration-resistant prostate cancer (mCRPC) and visceral metastases (liver and lung) fare better with the androgen receptor inhibitor enzalutamide than placebo, according to a new analysis from the phase III AFFIRM trial. There were differences in response based on which of those two sites had metastases, suggesting they should be considered differently for treatment.

” ‘Visceral metastases are identified in approximately 22% to 30% of patients with mCRPC and are associated with unfavorable outcomes,’ wrote study authors led by Yohann Loriot, MD, PhD, of Université Paris-Saclay in Villejuif, France.”

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Pivotal ARMOR 3-SV Prostate Cancer Trial Discontinued After PFS Rates Miss the Mark

Excerpt:

“The pivotal phase III prostate cancer trial ARMOR 3-SV will be discontinued based on recommendations made by the trial’s independent data monitoring committee (DMC), according to the manufacturer Tokai Pharmaceuticals. The DMC concluded that ARMOR 3-SV would unlikely meet its primary endpoint of demonstrating improved radiographic progression-free survival (PFS) based on its review of all safety and efficacy data. Top-line data from the trial is not expected until next year.

“It’s a big setback for the company, which was seeking the right niche for the agent in a crowded prostate cancer treatment market. ARMOR 3-SV compared galeterone with enzalutamide (Xtandi) in patients with treatment-naïve metastatic castration-resistant prostate cancer (mCRPC), particularly in patients whose prostate tumors expressed AR-V7. These truncated ARs are missing the C-terminal end of the AR that contains the ligand-binding domain, which is known as C-terminal loss. AR-V7 is the most common form of C-terminal loss of androgen receptors (ARs), a key target in resistance. This form of AR-V7 is also thought to make patients unlikely to respond to either enzalutamide or abiraterone acetate (Zytiga).”

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ASCO: Combo Tx Fails in Local High-Risk Prostate Ca

Excerpt:

“Neoadjuvant enzalutamide (ENZA) and abiraterone acetate (AA) plus 5 mg prednisone daily can be given safely for 6 months in men with localized high-risk prostate cancer prior to prostatectomy, a neoadjuvant study showed.

“However, the findings did not favor adding ENZA to augment AA plus leuprolide acetate (LHRHa) efficacy in localized high-risk prostate cancer, Eleni Efstathiou, MD, PhD, of the University of Texas MD Anderson Cancer Center, in Houston, said during a presentation at the American Society of Clinical Oncology.

“Pathologic downstaging (≤ pT2N0) occurred in 30% of patients treated with the combination therapy (AA+ENZA+ LHRHa) versus 52% of patients who received AA plus LHRHa alone (P=0.07), the study showed. Despite universal PSA depletion (≤ 0.1), a wide range of viable tumor was observed (volume 0-8.64 cc, cellularity 0-90%, and a tumor epithelial volume [TEV] 0-5.58 cc). TEV and stage were aligned.”

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Presence of AR-V7 in Circulating Tumor Cells Validated as Predictive Biomarker for Advanced Prostate Cancer Treatment by Memorial Sloan Kettering and Epic Sciences

Excerpt:

“Detecting AR-V7 positive tumor cells circulating in the blood of an advanced prostate cancer patient predicts that he will not only fail the commonly-prescribed androgen receptor signaling inhibitors (ARSI), abiraterone and enzalutamide, but that he will survive significantly longer if treated with a taxane based chemotherapy regimen.

“This discovery, published today in JAMA Oncology, emerged from a study of 161 progressing metastatic castration-resistant prostate cancer (mCRPC) patients about to start an FDA approved ARSIs or taxane as a first, second or third line treatment at Memorial Sloan Kettering Cancer Center (MSK). Blood samples taken along with those routinely collected from the patients were analyzed on the Epic Sciences’ liquid biopsy platform for circulating tumor cells (CTCs) with the AR-V7 biomarker. Overall, almost 20% of patients had AR-V7 positive CTCs.

” ‘The percentage of men that responds to ARSIs is highest in the first line setting, decreasing steadily as more treatments are given. We found that a novel liquid biopsy for AR-V7 was able to identify, with specificity, patients who will not benefit from these therapies and should instead start chemotherapy independent of the line of therapy being administered,’ said Howard Scher, M.D., chief of the genitourinary oncology services at MSK and corresponding author for the study.”

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Enzalutamide Superior to Bicalutamide for Castration-Resistant Prostate Cancer

“The oral androgen receptor inhibitor enzalutamide significantly reduced the risk for prostate cancer progression or death compared with bicalutamide in patients with castration-resistant prostate cancer, according to findings from the STRIVE trial.

“Enzalutamide (Xtandi, Astellas) has been found to improve survival in men with castration-resistant prostate cancer prior to and following chemotherapy. It binds the androgen receptor in the same way as bicalutamide does, but with greater affinity, according to researchers.

“Since bicalutamide is the standard treatment for this population of patients, researchers conducted this phase 2 trial to compare the two treatments.”


FDA Grants Olaparib Breakthrough Designation in mCRPC

“Olaparib (Lynparza) has received an FDA breakthrough therapy designation as a treatment for patients with BRCA1/2 or ATM-mutated metastatic castration-resistant prostate cancer (mCRPC) in those who have received a prior taxane-based chemotherapy and at least either hormonal agent enzalutamide (Xtandi) or abiraterone acetate (Zytiga).

“The designation, which will accelerate the development and review of the first-in-class oral PARP inhibitor, is based on data from the phase II TOPARP-A trial that demonstrated that olaparib monotherapy had an overall response rate (ORR) of nearly 90% in a biomarker-defined subgroup of patients who had DNA-repair defects.


Multiple Trials Explore Radium-223 Combinations for mCRPC

“Clinical trials are now assessing how to best use radium-223 (Xofigo) in combination with androgen inhibitors, following the rapid approval of several agents for men with castration-resistant prostate cancer (CRPC).

“In the first of these studies, a phase III being conducted by the European Organisation for Research and Treatment of Cancer (EORTC), single-agent enzalutamide (Xtandi) is being compared with radium-223 plus enzalutamide for men with asymptomatic or mildly symptomatic bone metastatic CRPC (NCT02194842). Additionally, this same approach is being examined in a phase II study conducted by the All Ireland Cooperative Oncology Research Group (NCT02225704).”


Phase 1 Results Point to Larger Trial of Enzalutamide and Fulvestrant in Breast Cancer

“Results of a multicenter phase 1 clinical trial presented today at the 2015 San Antonio Breast Cancer Symposium show that the anti-androgen agent enzalutamide is active and well-tolerated alone and with fulvestrant in patients with advanced breast cancer. The study takes another important step toward larger clinical trials targeting androgen receptors in breast cancer.

” ‘We’ve known for years that prostate cancer is driven by androgens and now it’s increasingly clear that androgens and androgen receptors can influence many breast cancers as well. AR is actually even more prevalent in breast cancer than estrogen or progesterone receptors. Targeting androgen receptors in breast cancer gives us a new way to attack the disease,’ says Jennifer Richer, PhD, investigator at the University of Colorado Cancer Center. Results represent collaboration with CU Cancer Center clinical collaborator Anthony Elias, MD, Memorial Sloan Kettering, Medivation, Inc. and Astellas Pharma Global Development.”