Tuesday, February 7, 2023

First Line Treatment For Prostate Cancer

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Cancer That Clearly Has Spread

Changes in NCCN Guideline: Affecting First-Line

If the cancer has spread outside the prostate, it will most likely go to nearby lymph nodes first, and then to bones. Much less often the cancer will spread to the liver or other organs.

When prostate cancer has spread to other parts of the body , hormone therapy is probably the most effective treatment. But it isnt likely to cure the cancer, and at some point it might stop working. Usually the first treatment is a luteinizing hormone-releasing hormone agonist, LHRH antagonist, or orchiectomy, sometimes along with an anti-androgen drug or abiraterone. Another option might be to get chemotherapy along with the hormone therapy. Other treatments aimed at bone metastases might be used as well.

Clinical Outcomes After Abiraterone/enzalutamide Or Docetaxel According To Grade Group System

The median follow up at the time of analysis was 47 months . In patients receiving docetaxel as first-line treatment, the univariate analysis showed that GG did not significantly influence OS median OS was 37.6 months in patients with GG 24 and 29.8 months in GG 5. Similarly, median PFS was not significantly different for patients with GG 24 compared to GG 5 disease. Chemotherapy-naive mCRPC treated with abiraterone or enzalutamide presented no significantly difference for median OS and PFS depending on GG 24 and GG 5 . GG did not significantly affect PSA response rate in chemotherapy-naïve mCRPC patients treated with abiraterone or enzalutamide as well as in docetaxel-treated patients .

Table 2 Prostate-specific antigen response rate and progression-free survival and overall survival according to Grade Group 24 versus Grade Group 5 and treatment.

Patients With Diabetes Mellitus

Baseline Characteristics

At baseline, 121 , 47 , and 100 patients had diabetes mellitus in the abiraterone, enzalutamide, and docetaxel groups, respectively in each treatment group, a lower proportion of those with diabetes mellitus had diabetes mellitus type 1 than diabetes mellitus type 2 .

The median time from initial diagnosis to study start was 5.7 , 4.0 , and 5.4 years in the abiraterone, enzalutamide, and docetaxel groups, respectively. Median age at baseline was 77.0 , 77.0 , and 69.0 years, respectively . A Gleason score of 810 at diagnosis was reported in 47.7%, 55.8%, and 49.0% of these treatment groups, respectively . The following important concomitant co-morbidity types were reported in the diabetes mellitus group for patients receiving abiraterone, enzalutamide, and docetaxel, respectively: cardiovascular in 102 , 36 , and 85 patients neurologic in 13 , 4 , and 12 patients and renal in 10 , 12 , and 7 patients . Details regarding treatment history at study inclusion are presented in Supplementary Table S4B.

Treatment Exposure

Efficacy Outcomes

According to KaplanMeier estimates, the median time to progression was 12.0 , 10.3 , and 7.7 months with abiraterone, enzalutamide, and docetaxel, respectively . The median OS was 30.8 , 27.1 , and 24.3 months in these treatment groups, respectively .

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Radiation As Adjuvant Or Salvage Therapy After Surgery

Several randomized trials have evaluated the use of adjuvant radiation therapy to the prostatic bed following surgery for patients at high risk of recurrence . Those include EORTC 22911, SWOG 8794, ARO 96-02/AUO AP 09/95, and FinnProstataX, as well as the ongoing RAVES, GETUG-AFU 17, and RADICALS-RT studies. Recent research has further highlighted the role of early salvage radiation therapy with concomitant ADT for those with biochemical recurrence after prostatectomy, to avoid overtreatment associated with adjuvant radiotherapy. This is reflected in the current AUA/ASTRO guidelines.

Provenge For Advanced Prostate Cancer

First

Sipuleucel-T is a “vaccine” for advanced prostate cancer that helps prolong survival.

Provenge isn’t your everyday vaccine. It’s an immune therapy created by harvesting immune cells from a patient, genetically engineering them to fight prostate cancer, and then infusing them back into the patient.

It’s approved only for treatment of patients with few or no prostate cancer symptoms whose cancer has spread outside the prostate gland and is no longer responding to hormone therapy.

Once a cancer grows beyond a certain point, the immune system has a hard time fighting it. One reason is that cancer cells look a lot to the immune system like normal cells. Another reason is that tumors may give off signals that manipulate the immune system into leaving them alone.

Provenge bypasses these problems. The treatment first removes a quantity of dendritic cells from a patient’s blood. Dendritic cells show pieces of tumor to immune cells, priming them to attack cells that carry those pieces.

The patient’s doctor ships the cells to Provenge’s manufacturer, Dendreon, which then exposes them to Provenge. Provenge is a molecule made inside genetically engineered insect cells.

Once these cells have been exposed to Provenge, they’re shipped back to the doctor who infuses them back into the patient. This is done three times in one month. The first infusion primes the immune system. The second and third doses spur an anticancer immune response.

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Radiation Therapy In Metastatic Disease

In a study of men with newly diagnosed metastatic prostate cancer, treatment with prostate radiation and ADT led to substantially longer survival compared with treatment with ADT alone. In the study, which included 6,382 men, combination therapy yield superior median survival and 5-year overall survival .

In patients with metastatic prostate cancer, radiation is also applied for palliative purposes. It is used in patients with castration-resistant prostate cancer with painful bone metastases, in patients at risk for fracture, and in patients with impending spinal cord compression.

A meta-analysis of the use of radioisotopes to relieve pain from bone metastases found that over 1-6 months, pain may be reduced without an increase in analgesic use however, severe effects such as leukocytopenia and thrombocytopenia frequently surface.

Radium-223 dichloride , formerly alpharadin, is an alpha particleemitting radioactive therapeutic agent that was approved by the FDA in 2013 for use in men with CRPC, symptomatic bone metastases, and no known visceral metastatic disease. Approval was based on the multinational ALSYMPCA trial , which is the first randomized phase III trial to demonstrate improved survival of CRPC with a bone-seeking radioisotope.

Immune Checkpoint Inhibitor Therapy

Immune checkpoint inhibitor therapy has shown clinical benefit in a number of solid tumors , but unfortunately these observations have not been replicated in patients with mCRPC . Factors such as low tumor mutational burden , loss of tumor suppressors , low prevalence of DDR genetic defects, and silencing of major histocompatibility complex-1 expression may all contribute to mCRPCs relative lack of response to ICI therapy . Two early phase-3 studies of the anti-cytotoxic T lymphocyte-associated protein-4 antibody ipilimumab both failed to meet their primary endpoint of improved OS however, recent studies investigating the efficacy of the programmed death-1 inhibitor pembrolizumab have shown promising responses in patients with mCRPC. In a single-site cohort of 48 patients with mCRPC treated with pembrolizumab, 17% had50% PSA decline with 8% having90% PSA decline as best response . These exceptional responders were found to have molecular changes , TMB-high, and mutation in LRP1b), which predispose to anti-PD-1 responses.

Completed and ongoing clinical trials investigating different ICI agents in patients with mPC have been summarized . Although monotherapy ICIs have not been successful, there are many ongoing trials to combine ICIs with standard chemotherapies or targeted therapies in order to improve clinical outcomes.

Table 3 Ongoing clinical trials investigating the administration of immune checkpoint inhibitor agents in patients with mPC

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There Are Three Ways That Cancer Spreads In The Body

Cancer can spread through tissue, the lymph system, and the blood:

  • Tissue. The cancer spreads from where it began by growing into nearby areas.
  • Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
  • Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.

Peer Review And Document Approval

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An integral part of the guideline development process at the AUA is external peer review. The AUA conducted a thorough peer review process to ensure that the document was reviewed by experts in the diagnosis and management of Advanced Prostate Cancer. In addition to reviewers from the AUA PGC, Science and Quality Council , and Board of Directors , the document was reviewed by representatives from ASTRO, SUO, and ASCO as well as external content experts. Additionally, a call for reviewers was placed on the AUA website from December 2-16, 2019 to allow any additional interested parties to request a copy of the document for review. The guideline was also sent to the Urology Care Foundation and representation from prostate cancer advocacy to open the document further to the patient perspective. The draft guideline document was distributed to 96 peer reviewers. All peer review comments were blinded and sent to the Panel for review. In total, 44 reviewers provided comments, including 34 external reviewers. At the end of the peer review process, a total of 522 comments were received. Following comment discussion, the Panel revised the draft as needed. Once finalized, the guideline was submitted for approval to the AUA PGC, SQC, and BOD as well as the governing bodies of ASTRO and SUO for final approval.

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Patients With Cardiovascular Disease

Baseline Characteristics

At baseline, cardiovascular disease was reported in 504 , 161 , and 351 patients in the abiraterone, enzalutamide, and docetaxel, groups, respectively the most common cardiovascular co-morbidity was hypertension in all three treatment groups , followed by specific cardiovascular co-morbidities of arrhythmia and history of myocardial infarction . This cardiovascular disease group also had important concomitant co-morbidities for patients receiving abiraterone, enzalutamide, and docetaxel: diabetes mellitus was reported in 101 , 36 , and 84 patients respiratory co-morbidities were reported in 46 , 23 , and 38 patients and neurologic co-morbidities were reported in 52 , 17 , and 37 patients, respectively .

Patients treated with abiraterone had a median time from initial prostate cancer diagnosis to study inclusion of 5.3 years versus 4.9 and 3.1 years for the enzalutamide and docetaxel groups, respectively. Median age at baseline was 77 , 77 , and 71 years, respectively , which was older than the ages reported in recent registration studies . At diagnosis, 49.8%, 59.0%, and 56.6% of patients in the abiraterone, enzalutamide, and docetaxel groups, respectively, had a Gleason score of 810 . Details regarding treatment history at study inclusion are presented in Supplementary Table S3B.

Treatment Exposure

Efficacy Outcomes

Biomarkers And Other Systemic Therapies

Given the dramatic increase in available therapies for advanced prostate cancer over the past 10 years, there is a renewed urgency to identify predictive biomarkers that can guide treatment selection. A number of promising molecular approaches continue to be investigated, but as of yet there is no assay that has been prospectively demonstrated to lead to improved oncologic outcomes.

In addition to PARP inhibitors, immunotherapies have also emerged as a key therapeutic modality in a large number of solid tumors. Aside from sipuleucil-T, these treatments have generally shown less efficacy in advanced prostate cancer compared to other malignancies, in part related to the relatively low tumor mutational burden of most prostate cancers.171 However, as described in guideline statement 34, there is likely to be a subset of prostate cancer patients who are uniquely sensitive to immunotherapy particularly those patients who have tumors that have a high mutational burden .172 Ongoing trials continue to explore whether immune checkpoint inhibitors, vaccine-based therapies, or oncolytic viruses may have broader utility in men with advanced prostate cancer.

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Drugs That Stop Androgens From Working

Anti-androgens

For most prostate cancer cells to grow, androgens have to attach to a protein in the prostate cancer cell called an androgen receptor. Anti-androgens are drugs that also connect to these receptors, keeping the androgens from causing tumor growth. Anti-androgens are also sometimes called androgen receptor antagonists.

Drugs of this type include:

They are taken daily as pills.

In the United States, anti-androgens are not often used by themselves:

  • An anti-androgen may be added to treatment if orchiectomy or an LHRH agonist or antagonist is no longer working by itself.
  • An anti-androgen is also sometimes given for a few weeks when an LHRH agonist is first started. This can help prevent a tumor flare.
  • An anti-androgen can also be combined with orchiectomy or an LHRH agonist as first-line hormone therapy. This is called combined androgen blockade . There is still some debate as to whether CAB is more effective in this setting than using orchiectomy or an LHRH agonist alone. If there is a benefit, it appears to be small.
  • In some men, if an anti-androgen is no longer working, simply stopping the anti-androgen can cause the cancer to stop growing for a short time. This is called the anti-androgen withdrawal effect, although it is not clear why it happens.

Newer anti-androgens

Enzalutamide , apalutamide and darolutamide are newer types of anti-androgens. They can sometimes be helpful even when older anti-androgens are not.

These drugs are taken as pills each day.

Aim Study Design And Setting

First

This prospective, noninterventional analysis of patient record data from the multicenter PCR of men with mCRPC was conducted to gain a greater understanding of real-world outcomes in a broad group of patients treated for mCRPC to optimize future treatment of patients with this disease. We focused on the characteristics and clinical outcomes of patients, including subgroups with baseline cardiac disease, diabetes mellitus, or visceral metastases, who received their first treatment for mCRPC during participation in the PCR. The data for the PCR were collected at 199 centers specializing in the treatment of prostate cancer by both oncologists and urologists in a range of settings in 16 countries: Austria, Belgium, France, Germany, Israel, Italy, Luxembourg, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, Turkey, and the UK. Patient enrollment took place between 2013 and 2016. At the start of the PCR, abiraterone acetate and enzalutamide were not routinely available in the mCRPC setting in all 16 countries. The study duration was 5.5 years, with a maximum patient follow-up of 3 years, and was designed specifically to include more than one line of therapy where applicable. The study end date was 9 July 2018.

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Intermittent Versus Continuous Hormone Therapy

Most prostate cancers treated with hormone therapy become resistant to this treatment over a period of months or years. Some doctors believe that constant androgen suppression might not be needed, so they advise intermittent treatment. This can allow for a break from side effects like decreased energy, sexual problems, and hot flashes.

In one form of intermittent hormone therapy, treatment is stopped once the PSA drops to a very low level. If the PSA level begins to rise, the drugs are started again. Another form of intermittent therapy uses hormone therapy for fixed periods of time for example, 6 months on followed by 6 months off.

At this time, it isnt clear how this approach compares to continuous hormone therapy. Some studies have found that continuous therapy might help men live longer, but other studies have not found such a difference.

The Grade Group And Psa Level Are Used To Stage Prostate Cancer

The stage of the cancer is based on the results of the staging and diagnostic tests, including the prostate-specific antigen test and the Grade Group. The tissue samples removed during the biopsy are used to find out the Gleason score. The Gleason score ranges from 2 to 10 and describes how different the cancer cells look from normal cells under a microscope and how likely it is that the tumor will spread. The lower the number, the more cancer cells look like normal cells and are likely to grow and spread slowly.

The Grade Group depends on the Gleason score. See the General Information section for more information about the Gleason score.

  • Grade Group 1 is a Gleason score of 6 or less.
  • Grade Group 2 or 3 is a Gleason score of 7.
  • Grade Group 4 is a Gleason score 8.
  • Grade Group 5 is a Gleason score of 9 or 10.

The PSA test measures the level of PSA in the blood. PSA is a substance made by the prostate that may be found in an increased amount in the blood of men who have prostate cancer.

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It Can Vary For The Same Cancer

Every cancer is different, and it is important to keep this in mind if you hear about another treatment for your type of cancer. First-line treatment for one cancer of a particular type and stage may be different than the first-line treatment of another person’s cancer of the same type and stage but a different molecular profile. In addition to this, other factors such as age, general health, and co-existing conditions may make what is a first-line treatment for one person a second-line therapy for another.

First Parp Inhibitor To Demonstrate Clinical Benefit In Combination With A New Hormonal Agent In This Setting

Dr. Motzer on First-Line Treatment of Metastatic RCC

AstraZeneca and MSDs Lynparza in combination with abiraterone and prednisone or prednisolone has been recommended for marketing authorisation in the European Union for the treatment of adult patients with metastatic castration-resistant prostate cancer for whom chemotherapy is not clinically indicated.

The Committee for Medicinal Products for Human Use of the European Medicines Agency based its positive opinion on results from the PROpel Phase III trial which were published in NEJM Evidencein June 2022.

In the trial, Lynparza in combination with abiraterone and prednisone or prednisolone, reduced the risk of disease progression or death by 34% versus abiraterone alone . Median radiographic progression-free survival was 24.8 months for Lynparza plus abiraterone versus 16.6 months for abiraterone alone. Results also showed that Lynparza in combination with abiraterone extended median rPFS by almost one year, with a median rPFS of 27.6 months versus 16.4 with abiraterone alone, as assessed by blinded independent central review .

Updated results also showed a favourable trend in improved overall survival with Lynparza plus abiraterone versus abiraterone alone, however the difference did not reach statistical significance at the time of this data cut-off .

Notes

Despite the advances in mCRPC treatment in the past decade with taxane and new hormonal agent treatment, there is high unmet need in this population.5,7,8,12

References

Adrian Kemp

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