Category: Treatment Information

According to Dr. William Oh,  Deputy Director of  the Tisch Cancer Institute, Chief of the Division of Hematology and Medical Oncology, and Professor of Medicine at the Icahn School of Medicine at Mount Sinai in New York, there are six myths about chemotherapy.

Some prostate cancer patients shy away from or choose not to utilize chemotherapy. Their hesitation may result from an outdated understanding of chemotherapy’s side effects and its effectiveness against prostate cancer. In this blog, Dr. Oh explores the myths driven by common misperceptions about chemotherapy and replaces them with some facts.

MYTH #1:  Chemotherapy is a last resort.

“Some patients believe that we use chemotherapy when we are out of options. Far from a last resort, there are currently promising studies utilizing chemotherapy earlier in the treatment of prostate cancer. For instance, in men with newly diagnosed metastatic disease, chemotherapy significantly improves survival.”

MYTH #2:  Chemotherapy is a single and outdated option.

“Chemotherapy is not a single drug. In fact there are many “chemotherapies”, both oral and intravenous, and new chemotherapies are being developed and approved regularly.

In prostate cancer, there have been continuous improvements over the past few years. In the past, an older drug called mitoxantrone was approved by the FDA to relieve cancer symptoms only. Then something important happened in 2004: docetaxel (taxotere) chemotherapy was shown to be the first drug to improve overall survival for men with metastatic prostate cancer that became resistant to hormone treatments. This was a critical milestone, as no drugs to that point could lengthen survival. In 2010, the FDA approved another chemotherapy drug for prostate cancer called cabazitaxel.

Far from being outdated, these advancements allow me as an oncologist to have a larger toolbox to treat cancers which adapt to different types of treatments. For instance, resistance often develops to drugs like abiraterone or enzalutamide, which target the androgen receptor.  Chemotherapy may more effectively kill those resistant cancer cells.

Finally, ongoing research will determine how best to combine chemotherapy with other drugs and radiation as well as use biomarkers to personalize treatment. We thought chemo might go away with newer treatments, but we use it as often as we did before as men are living longer and better lives with advanced prostate cancer.”

MYTH #3:  Chemotherapy has no role in an era of immunotherapy and precision medicine.

“Some people believe chemotherapy is a ‘shotgun’ approach. Patients want more targeted therapy specific to their cancer. The fact is we do have specific chemotherapy to kill prostate cancer cells called taxanes. Taxanes stop cancer cells from dividing and also may interfere with androgen receptor signaling in prostate cells as well.

In fact, when a patient stops responding to drugs such as abiraterone or enzalutamide, a blood test for a biomarker called ARV-7 predicts greater benefit from chemotherapy than to continue the androgen pathway drug. This test is now approved in the U.S.” (See a recent blog on this website describing AR-V7 testing.)

MYTH #4:  I’ll be nauseated and vomiting throughout my chemotherapy.  

“Chemotherapy induced nausea and vomiting (CINV) can be very scary and intimidating and many patients have known or heard about someone who has had it. Two things are really important to understand about CINV.

First, there are many types of chemotherapy and their ability to cause CINV varies widely.  In fact the drugs used in prostate cancer are unlikely to cause this. The American Society of Clinical Oncology (ASCO) Guidelines consider cabazitaxel, for instance, as a ‘low risk’ drug for causing CINV.

Second, modern antiemetics have revolutionized the treatment of CINV. Antiemetics are drugs used to prevent nausea and vomiting and there are a host of agents available to use. Typically I will incorporate one of these on the day of therapy and prescribe something for home, but most patients do not need it.”

MYTH #5:  I won’t be able to function day-to-day while on chemo.

“Some men believe their quality of life will drastically suffer while on chemotherapy. Fortunately, these newer drugs have much fewer side effects. The most common side effect in day-to-day life is fatigue. This is usually mild to moderate and I find that most patients are able to continue many of their regular activities. For instance, they may continue to work, spend time with family, and exercise.”

MYTH #6:  I’ll permanently lose all my hair after chemo.

“It is true that many prostate cancer patients experience temporary hair loss while undergoing chemotherapy. Some patients won’t lose their hair at all. Others will experience thinning hair.

In nearly all patients, the hair loss is reversible once chemotherapy is complete. If you experience hair loss, your hair should grow back several months following your chemotherapy treatment.”

FACT:  Chemotherapy is a key treatment in the fight against advanced prostate cancer.

“Battling prostate cancer may be the hardest fight you’ve encountered. Certainly, the side effects of some of the treatments you’ve received have been difficult. There is no question that chemotherapy comes with its own set of challenges.

However, it is critical to understand how important chemotherapies used to combat prostate cancer can be in extending and even improving your life. Many studies have shown that drugs such as docetaxel, cabazitaxel, and others can play a key role in treating metastatic prostate cancer, cancer that has spread beyond the prostate.

Please ask your oncology team about any specific concerns you may have before starting any treatment regimen. Knowledge is the most effective tool in the battle against prostate cancer.”

See the following link from Zero-the Fight to End Prostate Cancer, published Jan. 10, 2019.

Rubraca (rucaparib), Clovis Oncology‘s oral PARP inhibitor, shrank tumors in 44% of metastatic hormone-resistant prostate cancer (mCRPC) patients with BRCA mutations included in the Phase 2 TRITON2 clinical trial. The treatment, which is already approved for ovarian cancer, also reduced PSA levels — a biomarker of prostate cancer — in 51.1% of patients with BRCA mutations. The findings were presented recently at the European Society of Medical Oncology (ESMO) 2018 Congress  and other meetings by Wassim Abida, a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York, and principal investigator for the Phase 2 study.

About a quarter of advanced prostate cancers show mutations in BRCA1, BRCA2 or other genes encoding proteins that repair damaged DNA. These tumors are more sensitive to further DNA damage, and often respond well to treatments that block other proteins involved in aiding DNA repair. The PARP enzymes are more involved when BRCA proteins are not functioning properly, and PARP inhibitors have shown great promise in breast and ovarian cancer patients with BRCA mutations. Now, data from the TRITON2 Phase 2 trial (NCT02952534) shows that Rubraca also is effective in prostate cancer patients with such mutations.

The Phase 2 trial is testing the efficacy and safety of Rubraca (600 mg twice a day) in 85 mCRPC patients who have inherited or acquired BRCA mutations, or in one of the 13 DNA repair genes known to increase susceptibility to PARP inhibitors, and who were already treated with androgen receptor-directed therapy (e.g. Xtandi or Zytiga) and taxane-based chemotherapy (e.g. taxotere). Depending on their disease and mutation status, patients were divided in three groups: those with BRCA or ATM mutations and with measurable disease; those with BRCA or ATM mutations without measurable disease; and, those with mutations in other DNA repair genes, with or without measurable disease. The primary goal of the study is to determine the proportion of patients with measureable disease who respond to Rubraca, and those without measureable disease who achieve a significant lowering of their PSA levels. Secondary measures include duration of response, time to disease progression or death, overall survival and safety measures.

After a median follow-up of 5.7 months, 46 out of 85 patients were evaluable for responses. Among the 25 patients with BRCA mutations, 44% had seen their tumor shrink, after only a median of 3.7 months on treatment. At the time of the analysis, more than half of patients were still responding to Rubraca. The results also showed that 51.1% of patients with BRCA  mutations saw a reduction in their PSA levels. The most common adverse events were fatigue, nausea, anemia, and constipation. Five patients discontinued Rubraca due to a treatment-related adverse effect, and one patient died of disease progression.

Enrollment in TRITON2 is ongoing. The trial expects to evaluate about 160 patients from at least 100 worldwide locations, and to study other mutations besides BRCA1/2.

Findings from the trial have led the U.S. Food and Drug Administration to grant breakthrough therapy designation to Rubraca as a treatment for mCRPC patients with BRCA mutations, earlier this month.This FDA designation is given to speed the development of medications that might treat serious conditions and potentially provide an improvement on available therapies.  It has now been shown that PARP inhibitors are a validated therapeutic class in oncology in multiple tumor types, and these new data underscore the benefit that Rubraca may provide for men with advanced, BRCA-mutant castration-resistant prostate cancer.

This information represents a compilation of two articles published in the 10/24/18 Prostate Cancer News Today.

Immunotherapy with Keytruda (pembrolizumab) may be an effective way to treat some cases of advanced prostate cancer according to a preliminary study conducted at Oregon Health and Science University – Knight Cancer Institute. Findings were published in the journal Oncotarget in a paper entitled “Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer.” Keytruda is a monoclonal antibody that blocks the PD-1 receptor on the surface of immune T-cells, allowing them to recognize and destroy tumor cells. The FDA-approved drug has been shown to work well in melanoma and lung cancer but has so far not demonstrated much anti-tumor activity in prostate cancer.

Researchers administered Keytruda in ten (10) men with metastatic prostate cancer who had received androgen deprivation therapy or the androgen receptor antagonist Xtandi (enzalutamide) but failed to respond to it. Three of the 10 men who participated on the trial responded remarkably well to Keytruda treatment. Prostate-specific antigen (PSA) levels in their blood, an early measure of treatment response, dropped rapidly and dramatically from 46, 71, and 2,503 ng/ml respectively to less than 0.1 ng/ml. In addition, two of the three men saw their tumors shrink and reported a reduction in cancer-related pain to the point of not needing their opiate pain medication. Finally, the three patients who responded to Keytruda remained free of cancer progression at 30, 55 and 16 weeks of follow up, respectively.

It is still unclear why only three of the ten men who participated in the clinical trial responded to Keytruda while others showed no signs of clinical benefit. It is not yet possible to conclude that blocking PD-1 signaling can improve survival in men with metastatic prostate cancer, or to predict which patients will respond to treatment. More research is needed to better understand the mechanisms by which Keytruda reduces prostate cancer and which factors may influence the therapeutic effect of the drug. Additional patients have been enrolled in this clinical trial.

For a review of immunotherapy in prostate cancer, see the following link.

OncBioMune Pharmaceuticals will soon start a Phase 2 clinical trial of its investigational vaccine ProscaVax in men with early-stage prostate cancer under “active surveillance”. ProscaVax consists of a combination of the PSA protein produced by the prostate gland with the cytokines interleukin-2 (IL-2) and granulocyte-macrophage colony stimulating factor (GM-CSF). [Cytokines are molecules that participate in immune responses.] This will be the first time that prostate patients will be treated with a vaccine rather than waiting for disease progression or being exposed to more invasive treatment options that frequently are accompanied by unpleasant side effects such as incontinence and/or impotence. Scientists will evaluate whether the vaccine leads to a change in prostate cancer progression compared to patients on “active surveillance” in which disease progression is monitored before other strategies such as surgery or radiation therapy are considered. PSA doubling time and adverse effects will also be assessed.

Treatment arm-patients will start with a 4-month induction period, being given six (6) doses of ProscaVax at weeks 1, 2, 3, 7, 11, and 15. This period will be followed by maintenance injections once every month and alternating between low-dose IL-2 alone and the ProscaVax vaccine for six months.

OncBioMune reported results of a Phase 1a/1b study in January, 2018 showing that ProscaVax reduced tumor growth in 70% of recurrent prostate cancer patients after a minimum of 31 weeks of treatment. This result added to previously reported positive safety data. Trial results at 19 weeks of treatment also found that ProscaVax stopped disease progression in 80% of patients.

The single-site trial is expected to finish in August, 2022. It will be conducted at Beth Israel Deaconess Medical Center in Boston, MA and includes the Dana-Farber Cancer Institute. Information about this trial was published in the July 16th, on-line edition of Prostate Cancer News Today to which readers of this website are urged to subscribe.

In catching up on some news from a few months ago, I realized that much had been written recently about treating men with an early stage of advanced  prostate cancer. So here is some information in addition to the following posts; The FDA Approves Apalutamide for Some Men with Prostate Cancer; and  Xtandi Extends Metastasis-Free Survival in Hormone-Resistant Men with Rising PSA according to Phase 3 Study.

Over the course of prostate cancer progression, there can come a time during which the cancer is progressing, but there are no treatments known to improve survival.  One of these “empty spaces” is when men who are being treated with androgen deprivation therapy (ADT) see their PSA levels begin to rise (indicating the cancer has become resistant to ADT and is starting to grow again), but no metastases are visible yet on scans.  This clinical state is termed “non-metastatic hormone-resistant prostate cancer” (non-metastatic CRPC).  Many of these men will ultimately go on to develop metastases and lethal prostate cancer.  Until today, there were no other options and these men often just continued to receive ADT despite its diminishing benefit.

At the 2018 ASCO Genitourinary Cancers Symposium, held February 8-10 in San Francisco, California, results from two randomized phase 3 clinical trials, SPARTAN and PROSPER, may have filled this empty space.  Enzalutmide (Xtandi®) and Apalutamide (Erleada®; ARN-509) are two highly similar hormonal treatments that when added to ADT (or whatever treatments were already being used) were found to significantly delay the onset of metastases and several other measures of cancer progression in men with non-metastatic CRPC.

In the PROSPER trial, investigator Maha Hussain, MD (Northwestern University), tested the addition of enzalutamide vs. placebo in 1,401 non-metastatic CRPC patients who were continuing to receive ADT despite a rapidly rising PSA.  Enzalutamide was found to delay the time to metastatic disease by 22 months on average, compared with placebo.

In the SPARTAN trial, investigator Eric Small, MD (University of California, San Francisco), tested the addition of apalutamide vs. placebo in 1,207 non-metastatic CRPC patients with rapidly rising PSA,  in addition to whatever treatment the men were already receiving (mostly ADT). Apalutamide was found to delay the time to metastatic disease by over 24 months on average.   The full results from the SPARTAN study were simultaneously published in the New England Journal of Medicine.

This could be amazing news for patients with CRPC. “We don’t yet know if either apalutamide or enzalutamide increases the survival duration in these patients, although early indication is in that they will,” said Philip Kantoff, MD, Chairman of the Department of Medicine at Memorial Sloan Kettering Cancer Center, who led the discussion on the trials at the Symposium.  “Patients do need to be aware that these treatments when used early, can cause greater treatment exposure and greater chance for toxicity including a small chance of unexplained death.  Nonetheless these trials may change practice patterns in a major way and provide treatment opportunities for men with no current effective therapies.”

These two treatments are highly similar oral medications, differing chemically by only a single atom.  They have since been separately licensed and developed by different pharmaceutical companies, namely Astellas Pharma (enzalutamide) and Janssen (apalutamide).  Apalutamide is a new medicine, whereas enzalutamide is already FDA-approved for metastatic CRPC.  Both of these treatments are now under review by the FDA for use in non-metastatic CRPC, and decisions – and the change in practice that will accompany an FDA approval — are expected very soon.

For additional information, see the Prostate Cancer Foundation Feb. 28th Newsletter.

I realize this is somewhat old news but I’d like to share it anyway. On February 14, the Food and Drug Administration (FDA) approved apalutamide (Erleada) for men with prostate cancer that has not spread (non-metastatic) and is resistant to standard hormone therapy, also called androgen deprivation therapy (ADT). In the clinical trial that led to its approval, treatment with apalutamide decreased the risk of metastasis or death by more than 70% compared with placebo.

In the phase 3 trial (dubbed SPARTAN) that led to the FDA approval, men with hormone-resistant prostate cancer and no metastatic disease detectable by standard imaging tests were randomly assigned to receive apalutamide or placebo in addition to ongoing ADT. All participants were at high risk of metastasis based on rapidly rising prostate-specific antigen (PSA) levels. The study was sponsored by Janssen Pharmaceutical Companies, the manufacturer of apalutamide.

The median length of time from the start of treatment to when tumors spread (metastasis-free survival) or the patient died was 16 months in the placebo group and 40 months in the apalutamide group. Men treated with apalutamide also went longer without worsening symptoms of cancer progression. Even when their cancer progressed on apalutamide and they went on to receive another therapy, these men had longer time to progression with the subsequent treatment than men in the placebo group. The median length of time patients were alive after the start of treatment (overall survival) was 39 months for those who received placebo and had not been reached at the time of the study analysis for those who received apalutamide. An early analysis suggests that apalutamide may reduce the risk of death from prostate cancer, but longer patient follow-up is needed before the researchers can confirm this.

Apalutamide is the first drug to be approved by FDA based on an improvement in metastasis-free survival. Traditionally, most approvals are based on an improvement in progression-free survival or overall survival.

“These are very dramatic results and, in many ways, exceeded our expectations,” said lead investigator Matthew Smith, M.D., Ph.D., of Massachusetts General Hospital Cancer Center.  “We’re learning that using hormone therapy earlier in men with prostate cancer can delay metastasis and probably improve survival. But the balance of benefits and potential side effects will need to be evaluated on a patient-by-patient basis,” said William Dahut, M.D., head of the Prostate Cancer Clinical Research Section of National Cancer Institute’s Center for Cancer Research (NCI-CCR).

While apalutamide—and, potentially, enzalutamide (Xtandi)—gives men with non-metastatic hormone resistant disease a new treatment option, this patient population may decrease in the future, Dr. Dahut noted. That’s because traditional imaging techniques such as a CAT scan may not be able to detect tiny metastatic tumors, he explained. But a technique being used in research studies called molecular imaging  can catch smaller tumors. If molecular imaging tests become part of clinical care, more men with prostate cancer might be classified as having metastatic disease. “It’s highly likely that apalutamide would be active in men with metastatic hormone-resistant prostate cancer, Dr. Dahut speculated. Trials to evaluate apalutamide in this patient population are already underway, Dr. Smith noted.

For additional information, see the March 8th, 2018 NCI Cancer Currents blog.

Related blogs describing apalutamide were published on this website. See February 16th, 2018 and  November 10th, 2017 posts.

 

Men with nonmetastatic, castration (hormone)-resistant prostate cancer (CRPC) and a rapidly rising prostate-specific antigen (PSA) level are at high risk for metastasis. Currently, only one recently approved treatment, Erleada® (apalutamide), is available to these patients. Xtandi®, an androgen receptor inhibitor, is an approved treatment for metastatic CRPC patients. It has been shown to delay disease progression and prolong these patients’ overall survival.  In a recent article published in the June 28th, 2018 issue of the New England Journal of Medicine, researchers hypothesized that enzalutamide (Xtandi®), which prolongs overall survival among patients with metastatic, hormone-resistant prostate cancer, could also delay metastasis in men with nonmetastatic, hormone-resistant prostate cancer and a rapidly rising PSA level. In this double-blind, phase 3 PROSPER trial, asymptomatic men with nonmetastatic, hormone-resistant prostate cancer and a PSA doubling time of 10 months or less and who were continuing androgen-deprivation (hormone) therapy received enzalutamide (at a dose of 160 mg) while men receiving only placebo and standard hormone therapy were randomized in a 2:1 ratio. The primary end point of the study was metastasis-free survival, the length of time a patient lives without cancer spreading or until death from any cause. Secondary goals included extension of the time to PSA progression and to the first use of a subsequent anticancer chemotherapy, patients’ overall survival, and safety.

A total of 1401 patients (median PSA doubling time, 3.7 months) were enrolled. As of June 28, 2017, a total of 219 of 933 patients (23%) in the enzalutamide group had metastasis or had died, as compared with 228 of 468 (49%) in the placebo group. The median metastasis-free survival was 36.6 months in the enzalutamide group versus 14.7 months in the placebo group. The time to the first use of subsequent chemotherapy was longer with enzalutamide treatment than with placebo (such therapy was used in 15% vs. 48% of patients) as was the time to PSA progression (37.2 vs. 3.9 months.) At the first interim analysis of overall survival, 103 patients (11%) receiving enzalutamide and 62 (13%) receiving placebo had died. So median overall survival had not been reached. However, the researchers noted that more patients receiving the combination therapy died without detectable development of metastasis than was seen in the placebo group. In these patients, no trend regarding the cause of death was found, and only two deaths were considered to be related to Xtandi treatment. The researchers noted that these patients were elderly, with a median age of 80 years in the Xtandi group and 81 years in the placebo group, and they had a high burden of other coexisting conditions. Subsequent follow-up and additional interim analysis are expected to clarify the benefits of Xtandi® in patients’ overall survival in the PROSPER study.

Conclusions from this PROSPER clinical trial indicated that in men receiving the combination therapy the time a patient remained alive and metastasis-free was significantly extended by nearly two years (21.9 months), the time to PSA progression by almost three years (33.3 months), and the time to the first use of chemotherapy by nearly two years (21.9 months), compared to single standard therapy. In men with nonmetastatic, hormone-resistant prostate cancer with a rapidly rising PSA level, enzalutamide treatment led to a clinically meaningful and significant 71% lower risk of metastasis or death than placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, (NCT02003924).

As mentioned above, these findings were recently published (“Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer”) in the New England Journal of Medicine and also summarized in the July 5th Prostate Cancer News Today. (I strongly encourage readers to subscribe to this valuable email resource.)

 

The National Cancer Institute (NCI), the largest institute of the National Institutes of Health (NIH), recently posted a short (3-4 minute) but very illustrative video showing and describing three ways how our immune system fights cancer. These methods include: a) non-specific immune stimulation, as illustrated in bladder cancer; b) T-cell transfer therapy, somewhat similar to how Provenge works against prostate cancer; and, c) immune checkpoint inhibitors, such as Keytruda and Opdivo, currently the subject of many combinatorial clinical trials against several types of cancer including prostate cancer. This video appeared in the July 11th, 2018 e mail edition of Cancer Information Highlights from the National Cancer Institute, nci@updates.cancer.gov to which one can subscribe at www.cancer.gov.