Lethal Prostate Cancer Treatment May Benefit from Combination Immunotherapy

Excerpt:

“Researchers at the Johns Hopkins Kimmel Cancer Center and the Bloomberg~Kimmel Institute for Cancer Immunotherapy (BKI) released a study investigating the use of combination checkpoint immunotherapy in the treatment of a lethal form of advanced prostate cancer. The study suggested a genetic subset of prostate cancer may benefit from this form of immunotherapy.

“The study targeted AR-V7+ prostate cancer with a combination of two checkpoint blockers, ipilimumab and nivolumab, in 15 patients with this aggressive variant, first discovered at Johns Hopkins in 2014.”

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AR-V7+ CTCs Predicted Worse PFS, OS in mCRPC

Excerpt:

“Detection of circulating tumor cells (CTCs) positive for the nuclear-specific AR-V7 protein was an independent predictor of shortened progression-free survival (PFS) and overall survival (OS) when treating metastatic castration-resistant prostate cancer (mCRPC) with abiraterone or enzalutamide, according to results of the PROPHECY study (abstract 5004). The findings were presented at the 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO), held June 1–5 in Chicago.

“’Men with AR-V7–positive CTCs have a very low probability of benefit from abiraterone or enzalutamide, ranging from 0% to 11%,’ said Andrew J. Armstrong, MD, of Duke Cancer Institute. ‘However, a lack of AR-V7 detection does not guarantee response or benefit’ where these therapies are concerned, he added.”

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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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Test Aids Prostate Cancer Treatment

Excerpt:

“Genomic Health Inc. has struck a deal to commercialize a new blood test that can help advanced prostate cancer patients decide whether to try costly new-generation drugs or rely on much cheaper traditional chemotherapy to improve their chances for survival.

“The test, developed by closely held Epic Sciences Inc., San Diego, detects a mutation associated with a poor response to two new drugs, Xtandi from Medivation Inc. and Astellas Pharma Inc. of Japan, and Zytiga from Johnson & Johnson.

“The two blockbuster drugs have significantly extended survival for many patients with advanced prostate cancer. But in a study published last month, patients who tested positive for the anomaly—a variant of the androgen receptor called AR-V7—lived substantially longer if they were treated with chemotherapy than those given the two new drugs. The receptor is the target of the new drugs.”

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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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Men with AR-V7 Variant May Benefit from Taxanes for Advanced Prostate Cancer

“Men with advanced prostate cancer who have the androgen receptor splice variant-7 respond to chemotherapy equally as well as those who do not have the variant, according to findings from a small clinical trial.

“Further, taxane chemotherapy may be more effective than hormone therapy for men with the androgen receptor splice variant-7 (AR-V7).

” ‘The key finding from this study is that men with detectable AR-V7 in their circulating tumor cells may respond more favorably to chemotherapy (docetaxel or cabazitaxel [Jevtana, Sanofi]) compared to novel hormonal therapies (abiraterone and enzalutamide),’ Emmanuel S. Antonarakis, MBBCh, assistant professor of oncology and assistant professor of urology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, told HemOnc Today. ‘This finding was quite a relief because AR-V7–positive prostate cancer can be very lethal, and now we have at least one class of drugs that may work for these patients.’ ”


Chemo May Be Preferred Option for Some with Advanced Prostate Cancer

“In a small clinical trial, scientists at Johns Hopkins’ Kimmel Cancer Center and James Buchanan Brady Urological Institute found that men with advanced prostate cancer and detection of androgen receptor splice variant-7 (AR-V7) respond to chemotherapy just as well as men who lack the variant.

“The findings, the researchers say, may be significant for patients who carry the AR-V7 variant, because they are more likely to develop resistance to one of two hormone drugs routinely used to treat their disease. Results of the trial are published online in the June 4 issue of JAMA Oncology.

” ‘Our study shows that men who have the AR-V7 gene variant and usually don’t respond to either abiraterone or enzalutamide, are not at a disadvantage when given chemotherapy drugs,’ says Emmanuel Antonarakis, M.D., an oncologist at the Kimmel Cancer Center. Seven of the 17 men in the trial who carried the AR-V7 variant and received chemotherapy experienced a 50 percent reduction in their prostate-specific antigen (PSA) level.”


AR-V7 Biomarker Could Guide Treatment in mCRPC Patients

“In men with metastatic castration-resistant prostate cancer (mCRPC), the presence of androgen receptor V7 (AR-V7) in circulating tumor cells did not significantly affect response to treatment with taxane therapy, according to the results of a small prospective study (Abstract 138) presented at a press conference held in advance of the 2015 ASCO Genitourinary Cancers Symposium.

“In fact, researchers led by Emmanuel Antonarakis, MD, assistant professor of oncology and urology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, found that men who had AR-V7 detected in circulating tumor cells (AR-V7–positive) may retain their sensitivity to taxane-based treatment.

“An earlier study by Antonarakis and colleagues found that AR-V7–positive mCRPC patients treated with either enzalutamide or abiraterone fared worse than AR-V7–negative patients.

“AR-V7 is a truncated form of the androgen receptor that is detected in about one-third of patients with CRPC. AR-V7 lacks the ligand-binding domain of the androgen receptor, the target of enzalutamide and abiraterone.”


Galeterone Shows Activity in a Variant Form of Castration-Resistant Prostate Cancer

The gist: A drug called galeterone might help lower PSA levels in certain men with castration-resistant prostate cancer (CRPC). A clinical trial recently tested the treatment in volunteer patients.

“Results from a trial of the anti-cancer drug galeterone show that it is successful in lowering prostate-specific antigen (PSA) levels in men with a form of prostate cancer that is resistant to treatment with hormone therapy (castration-resistant prostate cancer or CRPC).

“Associate professor Mary-Ellen Taplin, of the Dana-Farber Cancer Institute, Boston, USA, will tell the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, today (Wednesday) that galeterone was well tolerated by patients in the ARMOR2 trial, and also lowered PSA levels in a subset of men with CRPC that was resistant to other drugs that target the cancer, such as enzalutamide and abiraterone.

” ‘Recent data have shown that a variant of the androgen receptor called AR-V7, found in tumour cells circulating in the blood of patients with metastatic CRPC, predicted resistance to treatment with enzalutamide and abiraterone,’ she will say. ‘Indeed, we believe AR-V7 and other, related variants are a mechanism of resistance in this disease and patients who have them may have a poorer prognosis.’ ”