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Friday, February 15, 2019

A single-arm, phase II trial in men with PSMA-positive metastatic, castration-resistant prostate cancer (mCRPC) that progressed despite standard therapies, found that in the majority of men, the cancers were responsive to treatment with a novel, targeted radiation therapy called Lutetium-177 PSMA-617 (LuPSMA), according to findings presented at the 2019 Genitourinary Cancers Symposium in San Francisco (Abstract 228).

This is the first prospective study of LuPSMA, part of a potential new class of treatments for men with metastatic prostate cancer. According to the researchers, men receiving the medication lived a median of 13.3 months after treatment, longer than the average 9-month survival time for men with this stage of disease.

"For men with localized prostate cancer, brachytherapy, or radioactive seeds implanted by needle directly into the tumor, as well as external beam radiotherapy, have been effective forms of treatment," said lead study author Michael Hofman, MBBS, Professor of Nuclear Medicine at the Peter MacCallum Cancer Centre, Melbourne, Australia. "However, for men in our trial, with cancer cells spread throughout the body, LuPSMA provides a new approach to a form of the disease that has been difficult to treat."

LuPSMA is composed of a small-molecule targeting ligand that selectively targets prostate-specific membrane antigen (PSMA)—a receptor common on prostate cancer cells—attached to Lutetium-177, a radioactive payload. With this approach, LuPSMA delivers high doses of radiation precisely to the cancer metastases, while avoiding delivery of potentially hazardous radiation to normal cells.

The half-life of the radioactive payload is 7 days. Additionally, LuPSMA emits low levels of gamma rays, which can be visualized with nuclear medicine imaging, which allows clinicians to see if the cancer is regressing.

Study Specifics

All patients enrolled in the trial were diagnosed with a form of mCRPC in which PSMA is present on the surface of the cancer cell, when scanned with positron emission tomography (PET).

Prior to enrollment, the men, ages 50 to 87, saw their PSA levels rapidly double after a median of 2.6 months. Because of the aggressiveness of the disease, most had previously been treated with docetaxel chemotherapy or antiandrogen therapy (abiraterone and/or enzalutamide). Forty-eight percent had also received second-line cabazitaxel chemotherapy.

In this trial, clinicians administered up to four IV cycles of LuPSMA in an outpatient setting every 6 weeks and tracked prostate-specific antigen (PSA) levels and imaging using CT, bone or PET scans. In some patients in whom the cancer responded but subsequently progressed, further cycles of LuPSMA were administered.

Key Findings

A PSA decline of 50 percent or more was seen in 32 of the 50 men in the study. In 22 of them, PSA declined 80 percent or more. Among men in which the cancer responded to LuPSMA therapy, PSA values did not increase for a median of 6.9 months, indicating that the disease was not progressing. Fourteen of the men in whom the cancer progressed received a median of two more cycles of LuPSMA. In nine of these men, PSA subsequently declined 50 percent or more; survival in this group of men was 33 months.

The most common side effects were nausea, fatigue, and dry mouth as PSMA is also present on cells in salivary and tear glands. Some of the more serious side effects of the drug, seen in about 10 percent of the men, were anemia and thrombocytopenia.

"In this trial, we treated men who would have otherwise been directed to palliative care," said Hofman. "It's exciting to see that LuPSMA can potentially offer benefits for many men with these very aggressive cancers, with few side effects and significant improvements in quality of life. Importantly, we saw continued benefits with LuPSMA retreatment in some men whose cancer progressed."

Based on positive early-stage results, two randomized trials have been launched to further evaluate LuPSMA. One trial compares LuPSMA with chemotherapy and the other with the standard of care, according to the study authors.

"Survival rates are low for patients with prostate cancer that has spread to distant parts of the body, and providing effective treatments for this type of cancer has been an ongoing challenge for physicians. For this group of patients in dire need of new options, using an entirely new approach, this study provides hope that we can start to change their outcomes," said ASCO Expert Robert Dreicer, MD, MS, MACP, FASCO, during a presscast prior to the conference.

Friday, February 15, 2019

Results from the randomized, phase III KEYNOTE-426 clinical trial show that first-line therapy with a combination of the PD-1 targeted immunotherapy pembrolizumab and the VEGF-targeted tyrosine kinase inhibitor axitinib extended both overall survival and progression-free survival for patients with clear-cell metastatic renal cell carcinoma (mRCC), compared with the current standard of care, sunitinib. Findings from this international study were presented at the 2019 Genitourinary Cancers Symposium in San Francisco (Abstract 543).

"These results are exciting," said co-lead study author Thomas Powles, MD, Professor of Urology Oncology at Barts Cancer Institute in London, England. "By adding pembrolizumab to a VEGF-targeted therapy, we are seeing powerful anticancer responses, including improved survival – and importantly, the results are seen across broad subgroups of patients."

Pembrolizumab is an immune checkpoint inhibitor that blocks the PD-1 protein on the surface of immune cells, which allows the immune system to then recognize and attack tumor cells. Axitinib and sunitinib are antiangiogenic medicines that can block the growth of blood vessels to the tumor, therefore limiting its growth. 

It is estimated there will be 73,820 new cases and 14,770 deaths from kidney cancer in the U.S. in 2019, about 95 percent of which result from renal cell cancers. Metastatic RCC has a 5-year survival rate of 12 percent.

Study Details

In the study, 861 people with untreated clear-cell mRCC were randomly assigned to oral sunitinib once daily or to combination therapy, with pembrolizumab given intravenously every 3 weeks along with oral axitinib twice daily. Treatment continued until the disease progressed, patients developed high toxicity, or they dropped out of the study. The median patient age in the trial was 62, and 73 percent of the participants were male and 27 percent were female.

These results build on findings from an earlier phase Ib trial, which found pembrolizumab plus axitinib had a manageable safety profile and a high response rate (73%) among patients with mRCC. Following these positive results, investigators proceeded directly to this phase III trial.

"Both pembrolizumab and axitinib have shown efficacy against mRCC on their own," said Powles. "Antiangiogenic therapy such as axitinib facilitates immune T-cell infiltration." According to Powles, phase Ib study results indicated that axitinib was easier to combine with pembrolizumab than some other antiangiogenic drugs in the same class as sunitinib.

Key Findings

At a median follow-up of 12.8 months, a comparison of patients receiving combination therapy versus sunitinib showed that:

  • Overall survival: Combination therapy was associated with a 47 percent reduction in the risk of death compared with sunitinib (HR: 0.53); the 12-month overall survival rate was 89.9 percent in the combination group vs 78.3 percent in the sunitinib group. These benefits were seen irrespective of risk group or PD-L1 status.
  • Progression-free survival: With the combination patients lived a median of 15.1 months without disease progression versus 11.1 months with sunitinib.
  • Overall response rate: 59.3 percent with the combination versus 35.7 percent with sunitinib.
  • Duration of response: Longer in patients treated with combination therapy, with a median not yet reached versus 15.2 months with sunitinib.
  • Ongoing treatment: With the combination 59.0 percent of patients continue to be treated versus 43.1 percent with sunitinib.

Serious treatment-related side effects were seen in 62.9 percent of people on the combination therapy compared to 58.1 percent who received sunitinib. These side effects led to discontinuation of all treatment in 8.2 percent versus 10.1 percent of the groups, respectively.

Next Steps

"We have a number of unanswered questions at this point, particularly the absence of biomarkers to predict response. PD-L1 levels, which have been markers for immunotherapy success in other cancers, remain unproven in renal cancer. It is possible that by combining pembrolizumab with axitinib, the predictive value of PD-L1 is being masked," said Powles. "Overall, we have not previously seen a renal cancer study which has improved response, progression-free survival, and overall survival. This is therefore a major step forward in renal cancer."

Commenting on the findings during a presscast before the conference, ASCO Expert Robert Dreicer, MD, MS, MACP, FASCO said: "Metastatic kidney cancer has very low survival rates and there have been few significant advances in treating this advanced form of the disease. These findings may help provide an important new option for patients."

Friday, February 15, 2019

A large, retrospective study analyzing 5 years of data from the Veterans Health Administration (VHA) found that African-American men with metastatic castration-resistant prostate cancer (mCRPC) who were treated with newer prostate cancer drugs abiraterone acetate or enzalutamide—and who had not received prior chemotherapy—lived 20 percent longer compared with white men who received the same treatment, according to findings presented at the 2019 Genitourinary Cancers Symposium in San Francisco (Abstract 212).

"We've historically seen that prostate cancer is more common, more aggressive, and more lethal in African Americans, compared with men of other racial groups," said lead study author Megan McNamara, MD, Assistant Professor of Medicine at the Duke University School of Medicine in Durham, N.C. "Balancing against other health-related risks, we found that treatment with newer hormonal medicines led to a significantly greater survival for African-American men in this analysis, compared with white men.

About the Study

Researchers analyzed VHA data from April 2013 to March 2018, focusing on men with prostate cancer who were age 18 or older, whose only prior treatment was surgical or medical castration. Among men with disease that had progressed, researchers included only those who had been treated with either abiraterone acetate or enzalutamide. These medications were approved in 2013 and 2014, respectively, for use in men with mCRPC who had not received chemotherapy. Investigators monitored patients' health outcomes until they either disenrolled from the VHA or died.

Altogether, the analysis included data from 2,123 white and 787 African-American men with mCRPC, with mean ages of 74 and 71, respectively. Higher rates of hypertension, type II diabetes, and liver damage or abnormality, were seen among African-American men in the study as compared with white men in the study.

After adjusting for demographic and clinical characteristics available in the VHA database, researchers found that African-American men treated with either hormone therapy lived for a median of 30 months, compared with 26 months for white men.

Next Steps

This research group conducted a prospective clinical trial--called Abi Race – exploring prostate cancer outcomes in African-American men and white men treated with abiraterone acetate. Initial findings from the Abi Race trial were presented at the 2018 ASCO Annual Meeting, demonstrating better PSA response among African-American men with mCRPC treated with abiraterone acetate, compared with white men (Abstract LBA5009).

Additional analyses of blood samples from that trial are ongoing to investigate whether variations in key genes involved in androgen metabolism and transport may help explain some of the biology behind racial differences in treatment response. It is hoped that these results will lead to a better understanding of why African-American men live longer than white men when treated with certain medicines for prostate cancer and why African-American men have a higher incidence of prostate cancer than white men.

"An important goal of the study is to understand why some men respond better to certain treatments for prostate cancer than others so that we can tailor treatments more effectively," said McNamara. "Finding biomarkers that can guide development of targeted therapies is the ultimate goal."

"When it comes to cancer treatments, it's important to understand how different groups respond to different therapies. Mining historic records in large databases can often help researchers home in on the patients who are more likely to benefit from certain medications. These findings provide important evidence that African-American men with metastatic prostate cancer, who have long had among the highest incidence and poorest outcomes of this disease, may now have better survival when treated with newer prostate cancer medications as compared with other men," commented ASCO Expert Robert Dreicer, MD, MS, MACP, FASCO, during a presscast prior to the conference.

Friday, February 15, 2019

The American Society or Breast Surgeons (ASBrS) announced new genetic testing guidelines for hereditary breast cancer, calling for genetic testing to be available to all patients diagnosed with breast cancer. These new recommendations expand on common restrictions which recommend testing only for certain age groups and types of cancer.

The new ASBrS Consensus guidelines follow a recent study published in the Journal of Clinical Oncology that found a similar rate of pathogenic genetic variants in breast cancer patients who did not qualify for testing under National Comprehensive Cancer Network (NCCN) criteria and those who did. They also are based on an extensive ASBrS review of current related literature that likewise suggests that if NCCN criteria are followed, many patients harboring breast cancer-related mutations will not have the opportunity to be tested. As a result, a large number of patients with pathogenic variants remain undetected and some patients and their family members may develop cancers that could have been prevented with testing under the new broader guidelines.

Genetics Drive Treatment, Identify Family Members at Risk

Identification of specific genetic anomalies in breast cancer patients often provides crucial guidance for more effective disease management. Additionally, relatives of mutation carriers, who have a high potential of carrying the same pathogenic genes, also could be tested, offered risk-reducing strategies as appropriate, and followed carefully for early stage diagnosis. Currently, NCCN guidelines allow for testing of family members of patients with identified pathogenic variants but only identify ~50 percent of breast cancer patients with these pathogenic variants.

Dated Testing Guidelines

"As medical science identifies a growing number of genetic anomalies linked to cancer and other diseases, genetic testing guidelines must evolve," stated Walton Taylor, MD, ASBrS President, who helped spearhead the new ASBrS guideline effort. "When these guidelines were established, the long-recognized BRCA 1/2 variants were the only mutations with a known association to breast cancer. Genetic testing was extremely costly and limited in availability.

"But today, the list of actionable genetic disorders related to breast cancer has grown tremendously. At the same time, testing has often become significantly less costly. Instead of helping to identify patients who might benefit from genetic assessment, these guidelines now often drive denial of testing for those who would benefit."

Cancer Risk Multi-Factorial

Taylor stresses that genetics are not the only predictor of lifetime breast cancer risk. Factors such as age, lifestyle, and family history play a role. The new ASBrS guidelines also recommend that these issues, along with genetic test results, be discussed carefully with all patients. Affected family members who are cancer-free can be offered risk reduction strategies ranging from more frequent imaging procedures and chemoprevention to prophylactic mastectomies based on the specifics of their unique situation. All patients must understand that the implications of some genetic anomalies on cancer risk are still unknown and others do not dictate any alteration in disease or risk management strategies. The more testing that is done, the more we will learn and the more management recommendations we can put forth.

Role of Breast Surgeons

"Breast surgeons are often the first physicians who interact with patients after they are diagnosed with breast cancer, and they can guide patients through the testing and interpretation process," Taylor stated. "Genetic counselors also are a valuable resource that can help breast care physicians and their patients make the best decisions for themselves and their families."

In addition to advocating for testing of all diagnosed breast cancer patients, other new ASBrS genetic testing guidelines cover re-evaluation of those tested in the past to take advantage of advances in genetic research, as well as testing of all patients unaffected by breast cancer who meet current NCCN guidelines.

Sunday, January 27, 2019

Regular use of a common type of medication, such as aspirin and ibuprofen, significantly improves survival for a third or more patients with head and neck cancer, a new study led by UC San Francisco has found. The paper was published January 25 in the Journal of Experimental Medicine (2019; doi:10.1084/jem.20181936).

Non-steroidal anti-inflammatory drugs, or NSAIDs, improved the overall 5-year survival rate from 25 percent to 78 percent for patients whose cancer contained a specific altered gene, known as PIK3CA, the researchers reported. The survival for patients whose gene was not altered in their tumor, was unaffected by NSAID use.

This is the first study to show a strong clinical advantage of regular NSAID use for head and neck cancer patients with mutations in the PIK3CA gene and may indicate a clear, biological reason to implement NSAID therapy in certain cases of the disease, said the authors.

"Our results suggest that the use of NSAIDs could significantly improve outcomes for not only head and neck cancer patients, but also patients with other cancers that contained the PIK3CA mutation," said Jennifer R. Grandis, MD, UCSF Professor of Otolaryngology, Head and Neck Surgery, and senior author of the paper. "The magnitude of the apparent advantage is strong, and could potentially have a positive impact on human health."

Within head and neck squamous cell carcinoma, PIK3CA is the most commonly altered oncogene, with 34 percent of all tumors carrying mutations that activate the PIK3CA gene. In head and neck cancer associated with the human papillomavirus (HPV), PIK3CA is mutated in more than half of tumors.

Head and neck squamous cell carcinoma is a complex malignancy that carries a poor prognosis: the 5-year survival rate is about 45 percent. According to the American Cancer Society, head and neck cancer accounts for approximately 4 percent of all cancers in the U.S., with an estimated 65,000 people developing it annually.

While the disease can occur in the young, most patients are above age 50 when diagnosed. Primary risk factors include smoking, alcohol use, and HPV infection.

In the new research, 266 patients from the University of Pittsburgh Medical Center whose tumors were surgically removed were investigated by the study authors. The majority (84%) smoked and 67 percent received post-surgery chemotherapy and/or radiotherapy. Median overall survival was 66 months.

Altogether, 75 tumors (28%) in the study had an activating alteration of the PIK3CA gene.

Among the patients who regularly used NSAIDs, 93 percent used aspirin as a component of the NSAID regiment, and 73 percent took aspirin exclusively. Most of the regular users started on the aspirin therapy following their head and neck cancer diagnosis.

The investigators learned that regular use of NSAIDs for at least 6 months provided "markedly prolonged" improved survival compared to non-use for patients whose PIK3CA gene was mutated or amplified -- in these patients, NSAIDs raised overall 5-year survival from 25-78 percent. However, patients without alterations in their PIK3CA gene were no better off by taking NSAIDs.

Through analysis of both cell line and mouse studies, the researchers speculated that NSAIDs likely blocked tumor growth by reducing the production of an inflammatory molecule called prostaglandin E2.

The researchers pointed out that their results need to be corroborated in a prospective trial. Additionally, they noted limitations, including the small size of the study group, as well as the type, timing, and dosages of NSAIDs taken by patients.

"NSAID use likely confers a statistically and clinically significant advantage in overall survival in PIK3CA-altered head and neck cancer through direct interaction between the PI3K and COX pathways," said Grandis, a member of the UCSF Helen Diller Family Comprehensive Cancer Center.

"Given the marked mortality of this disease," she said, "the researchers have designed a prospective, randomized clinical trial to address the initial study's limitations and assess the clinical significance of this therapeutic use."