Finding Smallest Traces of Recurrent Cancer. FDA Approves First PSMA-targeted PET Imaging Agent for Prostate Cancer

The U.S. Food and Drug Administration (FDA) has approved Gallium 68 PSMA-11 (Ga 68 PSMA-11) as a positron emission tomography or PET imaging agent for men with prostate cancer. The molecule is the first approved PET imaging agent that detects prostate cancer lesions by targeting the prostate-specific membrane antigen (PSMA) — a protein produced at high levels by prostate cancer cells.

It is approved for patients suspected of cancer recurrence, based on elevated blood levels of prostate-specific antigen (PSA), a prostate cancer biomarker. The agent also can be used for those with suspected prostate cancer metastasis — when the cancer spreads to distant regions in the body — who might be cured by surgery or radiation therapy. Other PET agents have been approved for detecting recurrent prostate cancer, but none for men whose cancer is suspected of spreading.

“With this first approval of a PSMA-targeted PET imaging drug for men with prostate cancer, providers now have a new imaging approach to detect whether or not the cancer has spread to other parts of the body,” Alex Gorovets, MD, acting deputy director of the office of specialty medicine in the FDA’s Center for Drug Evaluation and Research, said in a press release.

Ga 68 PSMA-11, developed by researchers at the University of California, Los Angeles and the University of California, San Francisco, is a radioactive agent meant to be given as an intravenous (into-the-bloodstream) injection prior to PET scanning. Once inside the body, it binds and accumulates inside prostate cancer lesions containing the PSMA protein, allowing clinicians to visualize these lesions in PET scans.

The decision to approve Ga 68 PSMA-11 was based, according to the researchers, on the results from two clinical studies involving 960 men with prostate cancer suspected of either cancer recurrence or metastasis.

The first was a Phase 3 trial involving 635 patients suspected of prostate cancer recurrence based on elevated PSA levels after initial prostate cancer surgery or radiation therapy. In this trial, Ga 68 PSMA-11 detected recurrent prostate cancer in 74% of participants, according to the researchers, and these lesions were proven as prostate cancer via other methods in 91% of cases.

The second Phase 3 trial included 325 patients with a confirmed prostate cancer diagnosis — either newly diagnosed or a confirmed recurrence — who were candidates for surgery, but considered at high risk for metastasis. Among those who had surgery, the men whose lymph nodes had signs of cancer on PET scans had a clinically important rate of metastatic cancer, which was confirmed by surgical pathology.

Having this information prior to treatment is expected to spare some patients from undergoing unnecessary surgery, the researchers said.

No serious adverse events, meaning undesirable side effects, occurred in either trial. The most common reactions included nausea, diarrhea, and dizziness.

The FDA noted that some risk for misdiagnosis exists, due to Ga 68 PSMA-11 binding to some other cancer types and to certain healthy tissues. There also is a degree of health risk from the compound’s radioactivity, which increases a patient’s long-term radiation exposure.

The preceding appeared in the Dec. 7th online edition of Prostate Cancer News Today by Forest Ray.

FoundationOne Liquid CDx “Liquid Biopsy” Blood Test Gets Expanded FDA Approval

Roseate spoonbill in southwest Florida; photo by Shutterstock

If you are considering genetic testing to identify whether a potential therapy might be useful against your prostate cancer, this article may be helpful to you. This test can help identify genetic changes such as BRCA1, BRCA2 and ATM mutations in which case a corresponding targeted drug, such as olaparib (Lynparza), may be useful.

The Food and Drug Administration (FDA) has expanded the approved uses for a blood test, known as a liquid biopsy, that can help doctors pick the best treatments for some people with cancer. The test identifies cancer-related genetic changes in DNA from tumor cells that have been released into the blood.

The test, called FoundationOne Liquid CDx, was approved by FDA earlier this year to identify patients with lung and prostate cancer who can receive specific targeted drugs. When the test is used in this way, it’s known as a companion diagnostic.

Under the expanded approvals, announced by FDA in late October and early November, the use of the test as a companion diagnostic has been broadened to people with other cancers and other drugs not covered by the original approval. (See table.)

FoundationOne Liquid CDx and another cancer liquid biopsy test, Guardant360 CDx, were initially approved by FDA earlier in 2020. Both approvals covered use of the tests as companion diagnostics for several targeted therapies. The initial approvals also covered the use of the tests for general tumor profiling, meaning they can be used to identify a large number of specific cancer-related genetic changes, any of which may influence patients’ treatment choices or make them eligible to participate in certain clinical trials.

According to FDA, the expanded approval of FoundationOne Liquid CDx was based on analyses of the test’s use on blood samples from patients participating in clinical trials evaluating the targeted drugs.

In instances where the blood test does not identify the specific genetic change that means a patient can receive a corresponding targeted therapy, the agency advised that the patient’s tumor tissue should be analyzed “to determine if the specific mutations and alterations are present.”

Most of the above was published by the National Cancer Institute (NCI) Current Contents Blog on November 30th, 2020.

Study Finds That Provenge Improves Survival in mCRPC Patients Over Xtandi, Zytiga.

Provenge (sipuleucel-T) by Dendreon Pharmaceuticals, is superior to Zytiga (abiraterone acetate) or Xtandi (enzalutamide) at prolonging the lives of men with metastatic castration (hormone)-resistant prostate cancer (mCRPC) when added at any point in a treatment regimen, according to a real-life study in the U.S.

The study, “A Retrospective Observational Analysis of Overall Survival with Sipuleucel-T in Medicare Beneficiaries Treated for Advanced Prostate Cancer,” was published in the journal Advances in Therapy.

“Men with mCRPC who received [Provenge] had a significant improvement in median overall survival and reduction in the risk of death at three years, regardless of line of use,” according to Rana R. McKay, MD, the study’s lead author at the University of California, San Diego.

“This analysis underscores the importance of using complementary mechanisms of action to maximize patient survival outcomes and highlights the critical role immunotherapy plays in the modern era of mCRPC treatment,” said Bruce A. Brown, MD, Dendreon’s chief medical officer. “Provenge continues to deliver on its promise of helping men with advanced prostate cancer live longer and should be considered when making treatment decisions in daily clinical practice,” Brown added.

Approved in the U.S. in 2010, Provenge is the only immunotherapy that uses a patient’s own immune cells to fight prostate cancer. It consists of an individual’s white blood cells that have been exposed to a prostate cancer protein, ultimately priming them to activate the remaining immune cells to fight cancer.

In the years since Provenge’s approval, the oral agents Zytiga and Xtandi — second-generation androgen-receptor signaling pathway inhibitors (ASPIs) — have become the standard-of-care treatment for men with mCRPC. Currently, both ASPIs and Provenge are recommended as a first-line treatment for the same indication. However, no study to date has compared the effectiveness of Provenge with that of the ASPIs. To fill this knowledge gap, Dendreon researchers and colleagues retrospectively analyzed the survival outcomes of 6,044 men with mCRPC who received either Provenge or ASPIs (Zytiga or Xtandi).

The current study explored differences in the survival outcomes, adjusted for multiple factors available in the dataset that could potentially influence the patients’ risk of death.

The results showed that men treated with first-line Provenge lived significantly longer (34.9 months; nearly three years) than those receiving ASPIs as first-line therapy (21 months; just less than two years), reflecting a 44% reduced risk of death at three years. Further, adding Provenge to either Zytiga or Xtandi at any point of the treatment regimen reduced the risk of death by 41% and prolonged median overall survival by 14.5 months (just over one year). Specifically, overall survival was 35.2 months with any-line Provenge versus 20.7 months without the immunotherapy.

These findings highlight that including Provenge at any point during treatment prolongs the life of men with mCRPC by more than one year and reduces their risk of death by more than 40%.

Moreover, exploratory analyses suggested that patients who received both Provenge and an ASPI during their treatments saw their risk of death reduced by 52% compared with only one ASPI or two sequential ASPIs.

“These findings support the need for further research to explore treatment sequences and therapeutic combinations,” the researchers wrote.

For additional details, see the October 26th issue of Prostate Cancer News Today by Marta Figueiredo.

Targeted SBRT Radiation Reduces Pain From Metastases to the Spine

The following Nov. 24th article from the National Cancer Institute (NCI) of the National Institutes of Health (NIH) describes recent clinical trial findings that for some patients with painful spinal metastases from advanced cancer, a type of precise, high-dose radiation therapy (SBRT) may be a highly effective way to relieve that pain. About a third of people in the clinical trial who received this form of radiation therapy, called stereotactic body radiation therapy, or SBRT, for spinal metastases were pain-free up to 6 months after treatment compared with only about 15% of people who received conventional external beam radiation therapy to treat the pain.

This study included about 200 people with three or fewer spinal metastases in a concentrated area of the spine that were the sole source of their pain. None had measurable signs of instability in the bones of the spine, which would increase the risk of fracture and make it harder to assess pain.

The study’s principal investigator noted that “this isn’t for the patient who has pain everywhere in the spine, which is unfortunately the majority of patients. But if you have a defined region of metastatic disease in the spine, and you can pinpoint the pain to that region, that’s going to be who benefits.” See the entire article for details.

Feeling Overwhelmed?

Jesus calms any storms. Photo: Shutterstock

I hope today finds you all doing well and healthy. But, as cancer survivors, we all have had days wherein we were feeling overwhelmed either with the disease itself or our anxieties. So for those days, I pass along this message I recently received from YouVersion entitled “You Are Not Alone.”

If you are unsure of your personal relationship with God through Jesus Christ, see the following.

PyL Prostate Cancer Imaging Agent Submitted to FDA for Approval

Lantheus Holdings has submitted an application to the U.S. Food and Drug Administration (FDA) seeking approval of PyL, an investigational imaging agent used to locate prostate cancer lesions. The new drug application (NDA) sent to the FDA includes a request for priority review, which if granted may shorten PyL’s regulatory review process from the usual 10 months to six. Lantheus expects the FDA’s decision on this filing in early December.

PyL, also known as 18F-DCFPyl, is a tracing agent used in positron emission tomography or PET scans to visualize prostate cancer lesions in different types of tissues. It does this by targeting the prostate-specific membrane antigen (PSMA), a protein commonly found on the surface of prostate cancer cells. Once bound to these cells, PyL emits a radioactive signal that can be seen in PET scans, signaling where these lesions are located.

The company’s NDA submission was supported by data from two clinical trials — OSPREY (NCT02981368) and CONDOR (NCT03739684) — that showed PyL can detect local and distant prostate cancer lesions that conventional imaging methods sometimes miss. Such detection makes tracking disease recurrence and spread more accurate, enabling doctors to adjust treatment plans appropriately.

In the Phase 2/3 OSPREY trial, PyL showed good sensitivity and specificity at identifying cancer lesions among 385 men, split into two groups. Group A included men with high-risk locally advanced prostate cancer, while group B involved men with metastatic or recurrent disease. Of note, in this context, sensitivity refers to PyL’s ability to identify true cancer sites, and specificity to its ability to distinguish cancer sites from non-cancer (healthy) sites.

Among men from group A, PyL had a specificity of 96-99%, a sensitivity of 31-42%, and a positive predictive value (PPV) of 78-91% at identifying cancer lesions in pelvic lymph nodes. The PPV is the proportion of patients with positive results who truly have the disease. In the group B participants, PyL had a sensitivity of 93-99% and a PPV of 81-88% at detecting metastatic cancer lesions, meaning those found farther away from the prostate. Metastatic cancer is disease that has spread to other parts of the body.

The participants tolerated PyL well and reported no serious undesirable side effects. The most frequent side effects observed included altered or unpleasant taste sensations and headaches.

The Phase 3, open-label CONDOR study evaluated PyL’s ability to safely and accurately detect prostate cancer lesions in 208 men with suspected disease relapse. All of the patients enrolled in the study had high levels of prostate-specific antigen (PSA), a biomarker of prostate cancer, but had negative or ambiguous imaging results. The study met its main goal, with PyL correctly locating cancer lesions in 85-87% of the patients. As a result of these findings, nearly 64% of participants saw changes in their treatment management plans.

Dr. Istvan Molnar, MD, chief medical officer of Lantheus, stated “we believe that the demonstrated strong diagnostic performance of PyL, will assist in treatment decisions and, ultimately, may improve patient outcomes,”

Much of the above appeared in the Oct. 6th, 2020 Prostate Cancer News Today, by Forest Ray.

The Promise of Peace

Wooden Stave church built in the 12th century in western Norway

Philippians 4:6-7 states as follows: “Be anxious for nothing, but in everything by prayer and supplication (asking humbly and earnestly), with thanksgiving, let your requests be made known to God; and the peace of God, which surpasses all understanding, will guard your hearts and minds through Christ Jesus.”

Earlier this month, I needed to undergo a CT scan and a bone scan in order to identify and locate any sites of prostate cancer metastasis. Tests such as these always seem to be accompanied by apprehension and to some degree, anxiety. I also had to be alone for the entire day at Moffitt Cancer Center in Tampa as my wife and her support were not permitted to be there due to COVID-19. I sat alone with my thoughts and the oft-accompanying “what-ifs.” What if sites of metastatic cancer were revealed? How would they be treated? How would it all affect my life and life span? However, I also experienced periods of strong inner peace especially as my mind focused on the words of Philippians 4:6-7. I literally presented my thoughts, anxiety and requests to God who in turn promised that “the peace of God, which transcends all understanding, will guard your (my) heart and mind in Christ Jesus.” As if God wanted to punctuate this message with an exclamation point, I had briefly verbalized my trust in Jesus to the technician who performed one of the scans. Immediately, he responded enthusiastically that he also had put his faith in Jesus earlier in his life and the two of us formed a brotherly bond as the scanner passed over my body.

Are you, my reader, facing a similar situation with an unknown result and no apparent solution? Then, like a soothing salve to your anxious heart, the same promise of Philippians 4 is for you as well.

Unfortunately, anxiety does not come with an automatic “off” switch. One of the most complex human emotions, anxiety warns us that something could be wrong and may need attention. But anxiety may not inheritantly be a bad thing, especially if it drives us to prayer. Yet submission in prayer can often be the last thing we think to do.

Through a relationship with God through Jesus, we have access to the very throne room of heaven. God’s spirit intercedes for us there with “groaning too deep for words” (Romans 8:26). Even when we don’t know how to pray, we are not hindered. And remember, God would not invite us to bring our cares and requests before Him if He did not plan to act.

His promise is not that all our requests will be granted in the way we would hope or anticipate. But He promises the peace of Jesus Christ which will guard our hearts….and that is better by far! If you have never been introduced to a personal relationship with God through Jesus Christ, see the following link.

By the way, neither of my scans revealed any metastatic sites, for which I humbly but fervently give God the glory and thanks.

A portion of the above is an excerpt from the Sept. 2nd, 2020 devotional from Haven Ministries.

ExoDx Urine Prostate Test to Evaluate Risk of Aggressive Prostate Cancer Prior to First Biopsy.

The ExoDx Prostate Test is a non-invasive, non-digital rectal exam, urine test used as a risk assessment tool to provide risk probabilities for aggressive prostate cancer.

The technology relies on cancer-specific genomic biomarkers found in the urine. The test analyzes three cancer-specific biomarkers found in the urine associated with aggressive prostate cancer: ERG, PCA and SPDEF. It purposefully does not analyze prostate specific antigen (PSA). Patients below the cut-point of 15.6 are considered at low risk of having high-grade prostate cancer. Patients above the cut-point of 15.6 are considered to have higher risk of high-grade prostate cancer.

The test is intended for men over 50 with PSA’s from 2-10 ng/mL and considering an initial biopsy. The doctor and the patient should discuss the patients’ ExoDx Prostate score in a shared decision-making process including all relevant factors and make a decision as to whether or not to proceed with a prostate biopsy.

This urine-exosome, pre-biopsy risk stratification technology is now commercialized. See the following link.

With Two New FDA Approvals, Prostate Cancer Treatment Enters the PARP Era.

Two recent approvals by the Food and Drug Administration (FDA) have opened a new avenue of treatment for some men with prostate cancer: an expanded role for targeted therapies.

The approvals are for the drugs olaparib (Lynparza) and rucaparib (Rubraca). They cover the use of the drugs in men whose prostate cancer has spread, or metastasized, and whose disease has stopped responding to standard hormone treatments, often called castration-resistant disease. To receive either drug, men must also have specific genetic alterations that prevent their cells from repairing damage to their DNA.

Many treatments of metastatic prostate cancer are centered around therapies that block the ability of hormones to fuel the cancer’s growth and spread. But olaparib and rucaparib, which are taken as pills, work differently. They block the activity of a protein known as PARP, which helps cells mend specific types of damage to DNA. PARP inhibitors work in part by blocking the ability of PARP proteins to repair damaged DNA, which includes recruiting other DNA repair proteins.

Studies have shown that 20%–30% of men with metastatic prostate cancer have genetic alterations that impair cells’ DNA repair mechanisms. So, to now have two new approved therapies for these men, and in such rapid succession, “is good news for patients,” said Oliver Sartor, M.D., medical director of the Tulane Cancer Center and a prostate cancer expert. The past decade has seen a boom in new treatments for prostate cancer. But few of them are genomic targeted therapies, those intended to work on cells with specific genetic alterations, which are now commonly used to treat other types of cancer.

PARP: Prime Treatment Target for Prostate Cancer
Over the past decade, olaparib and rucaparib have become important treatments for women with ovarian and breast cancer, in whom genetic alterations that affect DNA repair processes are common. Among the most frequent such alterations are those in the BRCA1 and BRCA2 genes.

It’s no accident that researchers have identified people who have alterations in BRCA genes as ideal candidates for treatment with PARP inhibitors. BRCA proteins and some PARP proteins are both integral components of cells’ response to DNA damage. If that response is already dysfunctional because of BRCA1 or BRCA2 mutations, then researchers reasoned that blocking the activity of PARP proteins could further hamper any chance of repair—akin to punching a hole in a tire that already has a slow leak. If the cancer cells can’t fix the DNA damage, they will die.

Prostate cancer emerged as another strong candidate for PARP inhibitors after studies suggested that alterations in BRCA1 and BRCA2, as well as other genes involved in a cell’s ability to respond to DNA damage, may be present in approximately one-quarter of men with the disease. Other studies linked these genetic changes to an increased risk of prostate cancer, as well as more aggressive disease. Those findings, led to a series of clinical trials of PARP inhibitors in men with metastatic prostate cancer, laying the foundation for the new FDA approvals.

PROFOUND Trial: Most Benefit Seen in Men with BRCA2 Alterations
Olaparib’s approval, announced on May 19, was based on the results of a large clinical trial called PROFOUND. The trial enrolled men with mutations in DNA repair genes and divided them into two cohorts. Cohort A included men with alterations in the BRCA1, BRCA2, or ATM genes, each of which plays an important role in DNA repair. Cohort B included men who had alterations in a group of 12 other genes that have some involvement in repairing DNA.

All of the men in the trial had cancer that had worsened despite treatment with either abiraterone (Zytiga) or enzalutamide (Xtandi), which work in different ways to block hormones in prostate cancer cells. The 387 men in the trial were randomly assigned to either the treatment group, which received olaparib, or the control group, which received either abiraterone or enzalutamide (as selected by each patient’s oncologist).

In cohort A, men treated with olaparib lived more than twice as long without evidence of their cancer getting worse (as measured by standard imaging procedures) than men treated with abiraterone or enzalutamide: a median of 7.4 months versus 3.6 months. The treatment group in cohort A also lived longer overall, with olaparib improving survival by more than 4 months (19.1 months versus 14.7 months). In addition, men treated with olaparib were far more likely to see their tumors shrink (a tumor response) than men treated with one of the other two drugs (33% versus 2%).

Prostate cancer tends to spread to the bones, so reducing the size of those particular tumors can have a meaningful impact on patients, according to the trial’s lead investigator, Maha Hussain, M.D., of Northwestern Medicine. Metastases that are poorly controlled in the bone can be quite painful.

FDA’s approval covers the use of the drug in men with alterations in any of the DNA repair genes analyzed in the trial. But Dr. Sartor, who also was an investigator on the trial, noted that men with alterations in BRCA2 seemed to respond best to the treatment, experiencing the largest improvement in progression-free survival. And these men accounted for about one-third of trial participants. Men with ATM alterations, on the other hand, didn’t do any better than those in the control group.

FDA also simultaneously approved two tests, BRACAnalysis CDx and FoundationOne CDx, for identifying patients with metastatic castration-resistant prostate cancer who have the appropriate genetic alterations to receive olaparib.

TRITON2 Leads to Accelerated Approval for Rucaparib
FDA’s approval for rucaparib, announced on May 15, is slightly different than what was granted to olaparib.

To begin with, it was an accelerated approval. That means the approval was granted based on results from a clinical trial that strongly suggests rucaparib could be beneficial for patients—such as an improvement in progression-free survival—although that level of proof is not yet available. In addition, the approved use is only for men with mutations in BRCA1 or BRCA2 and only for cancer that has progressed despite earlier treatment with both a hormone-blocking treatment as well as chemotherapy.

The approval was based on the results of a 115-patient clinical trial, called TRITON2. Similar to the PROFOUND trial, TRITON2 enrolled men with alterations in a host of DNA repair genes, the largest group of which was those with BRCA2 mutations. All the men in the trial were treated with rucaparib.

According to data presented last year—and similar to what was seen in PROFOUND—men with BRCA2 alterations were most likely to respond to the PARP inhibitor. Of the 62 men with BRCA2 alterations, nearly 45% had a tumor response. And, in more than half of these men, the response lasted for at least 6 months.

Overall, Dr. Karzai said, it does appear that BRCA2 alterations “really do drive the benefit” of PARP inhibitors among men with metastatic prostate cancer. “I think we’re really seeing that in these trials.”

Making Treatment Choices: Olaparib or Rucaparib?
Often, when multiple drugs are approved for the same—or in this case, a very similar—use, the side effects associated with each drug can help doctors decide which therapy is best for each patient. Overall, Dr. Sartor explained, there aren’t notable differences in the types or severity of the side effects caused by olaparib and rucaparib.

And although most patients seem to handle the side effects caused by both drugs relatively well, he continued, they can cause substantial problems, including anemia, severe drops in white blood cell count, nausea, and vomiting. Dr. Karzai also pointed to the risk of myelodysplastic syndrome, a disorder that affects the formation of blood cells in the bone marrow and that has been seen in a very small percentage of patients treated with PARP inhibitors. “These drugs definitely require close monitoring [of patients],” Dr. Sartor said.

One potential advantage of rucaparib over olaparib could be the eventual availability of a blood test, called a liquid biopsy, that can identify men with BRCA1 or BRCA2 alterations (as well as other genetic alterations) who are candidates for the drug. This liquid biopsy, called FoundationOne Liquid CDx, is currently being evaluated by FDA and a decision on its approval is expected soon, according to a spokesperson for Foundation Medicine, which manufactures the test.

One reason that’s important, Dr. Karzai explained, also comes back to the fact that prostate cancer so often spreads to the bones. Because bone metastases are often hard and dense, she said, biopsies of these sites are “notorious for not having enough tissue to do standard genetic sequencing.” In addition to tissue quantity, there are also issues with the type of tissue that comes from the biopsy and its quality. “There a lot of variables that can make it difficult,” she added.

The PROFOUND trial provides a case in point: In nearly one-third of tissue samples collected from more than 4,000 men screened as possible participants for the trial, the genetic test used wasn’t able to determine whether the specific genetic alterations were present in 31% of patients. Even with a liquid biopsy, ensuring the routine testing of patients for the presence of alterations in DNA repair genes will likely be the biggest barrier to oncologists’ adoption of these drugs in everyday patient care, Dr. Sartor believes.

The above was received in a National Cancer Institute (NCI) Post dated June 12th.

New Guidelines for Care of Advanced Prostate Cancer

The American Urological Association (AUA), American Society for Radiation Oncology (ASTRO), and Society of Urologic Oncology (SUO) have released new guidelines for the diagnosis and treatment of advanced prostate cancer, developed by a panel of experts. In addition to their own expertise and experience, panel members assessed data from 264 prostate cancer studies in developing these recommendations for clinical practice.

In total, the panel released 38 individual guidelines, grouped into six overarching themes. These are early evaluation and counseling, recurrence without metastatic disease (local treatment exhausted), metastatic hormone-sensitive cancer, non-metastatic castration-resistant disease, metastatic castration-resistant cancer, and bone health. For the entire July 29th article from Prostate Cancer News Today, see the following link.