Novel Hormone Therapy For Prostate Cancer

Current Treatment Strategies For Advanced Prostate Cancer

Novel Hormonal Therapies for Prostate Cancer

The current hormonal therapeutic armamentarium for advanced prostate cancer is informed by 2 broad approaches: inhibition of conversion of extragonadal precursor steroids to testosterone and DHT with abiraterone and direct blockade of the AR to prevent binding to its ligands, testosterone, and DHT with next-generation AR antagonists such as apalutamide, darolutamide, or enzalutamide .

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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Heres What You Should Know About This Treatment Option

Men who get diagnosed with prostate cancer have several options to choose from for their next step. Many men with slow-growing, low-risk cancer follow active surveillance, a wait-and-see approach that monitors the cancer for changes.

But if the cancer shows higher risk or has already begun to spread, other treatments are recommended. There are two options: surgery to remove the prostate or radiation to destroy the cancer cells.

Studies comparing these two approaches demonstrate no advantage of one over the other with respect to cancer control. Your path will depend on factors like your current health, the specifics of your cancer, and personal preference. Yet for many men, radiation can be the better option.

Its much more precise than the traditional radiation used for other kinds of cancer, and research also has found that long-term quality of life is often better, with fewer adverse health effects compared to surgery, says Dr. Anthony DAmico, a radiation oncologist with Harvard-affiliated Dana-Farber Cancer Institute and Brigham and Womens Hospital.

There are two main ways to deliver radiation to the prostate: external beam radiation and brachytherapy.

What Are The Side Effects Of Hormone Therapy For Prostate Cancer

The Rationale for Optimal Combination Therapy With Sipuleucel

Because androgens affect many other organs besides the prostate, ADT can have a wide range of side effects , including:

loss of interest in sex

Studer UE, Whelan P, Albrecht W, et al. Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer Trial 30891. Journal of Clinical Oncology 2006 24:18681876.

Zelefsky MJ, Eastham JA, Sartor AO. Castration-Resistant Prostate Cancer. In: Vincent T. DeVita J, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology, 9e. Philadelphia, PA: Lippincott Williams & Wilkins 2011.

Smith MR, Saad F, Chowdhury S, et al. Apalutamide and overall survival in prostate cancer. European Urology 2021 79:150158.

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Establishing Candidacy For Treatment Intensification

Although mHSPC is generally considered an aggressive prostate cancer, it is still a heterogeneous disease that requires an individualized treatment approach to optimize outcomes. Patients who tend to do worse are those with high-volume, de novo metastatic disease, which is different from those who also have metastatic disease but happen to years later and theyve finished treatment, Pedro C. Barata, MD, MSc, said. He noted that patients who tend to do worse have been shown to benefit from treatment intensification approaches, such as a triplet regimen that adds docetaxel and an AR-targeted therapy to ADT, as well as strategies such as concomitant radiotherapy of the primary tumor.

To ensure he identifies patients who would benefit from treatment intensification, Barata said he sequences all patients up front. When I have an aggressive molecular profile, it makes me think about treatment intensification at that point, he said. Another trigger he noted is a low PSA level. Its not concurrent with the amount of disease that you see, he said.

Barata noted that the next step will be identifying all the patient subgroups who would benefit from treatment intensification approaches such as triplet therapy, as well as which intensification approach may be best suited to each subgroup. Ongoing studies are anticipated to help shed light on these areas.

What Is Hormonal Therapy For Prostate Cancer

Hormonal therapy for prostate cancer is a treatment to lower the levels of the hormone testosterone in the body. Prostate cancer needs testosterone to grow. Testosterone is mainly made by the testicles. Hormonal therapies reduce the amount of testosterone in the body, or stop it reaching the prostate cancer cells.

Testosterone is important for:

muscle development and bone strength.

Hormonal therapies are drugs that can be given as injections or as tablets.

Prostate Cancer: Surgical Castration Linked To Fewer Adverse Events Than Chemical Castration

Bilateral orchiectomy is as effective as treatment with gonadotropin-releasing hormone agonists in controlling prostate cancer and is associated with fewer clinically relevant adverse events, a population-based study has found.1

Androgen-deprivation therapy with surgical or pharmacological castration has long been a mainstay of treatment for metastatic prostate cancer.2 However, due to concerns about cosmetic and psychological effects of surgical castration, that practice has been nearly eliminated in favor of medical castration.

Given that these are 2 accepted alternative means to achieve testosterone blockade, it is important to understand the differences in side effects to properly counsel patients about their choices, said Quoc-Dien Trinh, MD, of Brigham and Womens Hospital and Dana-Farber Cancer Institute in Boston, MA, in an interview with Cancer Therapy Advisor.

A total of 3295 men with metastatic prostate cancer 66 years or older were selected using the Surveillance, Epidemiology and End Results database between January 1995 and December 2009. The men either were treated with GnRHa or underwent bilateral orchiectomy .

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Men who underwent surgical castration had significantly lower risks of experiencing any fractures, peripheral arterial disease, and cardiac-related complications than those who were treated with GnRHa.

Patient Demographics And Clinical Characteristics

Prostate Cancer: Clinical Guidelines, Novel Therapies, and Therapeutic Uncertainty

Patient demographics and clinical characteristics are presented in Table . Pairwise analyses revealed several significant differences between treatment groups , including for most recent PSA level, risk status and disease volume . Men treated with NHA or chemotherapy vs ADT alone had significantly higher PSA levels . Similarly, significantly higher proportions of patients receiving NHAs or chemotherapy vs ADT alone had high-risk status and high disease volume .

Table 3 Patient demographics and clinical characteristics

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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.

Breaking News: Fda Approves Darolutamide For Metastatic Hormone

Today, the FDA approved darolutamide in combination with docetaxel chemotherapy for patients with metastatic hormone-sensitive prostate cancer . This means that patients with mHSPC have an additional treatment option.

Darolutamide is a novel hormone therapy that works by blocking the androgen receptor. Androgens are the hormones that act as prostate cancers fuel. The approval is based on the results of a large Phase 3 clinical trial called ARASENS. This trial compared outcomes among 1300 patients who received docetaxel + standard ADT + darolutamide vs. patients who received docetaxel + standard ADT + placebo. 86% of the patients were newly diagnosed with prostate cancer that had metastasized to the bones or other organs.

Patients treated with the addition of darolutamide were 32% less likely to die during the study follow-up period compared to patients treated with docetaxel + ADT alone. These patients also had improved time to castration resistance , time to pain progression, time to symptomatic skeletal related events , and time to next cancer therapy. Importantly, these improved outcomes of triplet therapy intensification were associated with only a modest increase in adverse events.

Read more about treatment intensification in mHSPC here.

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How To Tell If Hormone Therapy Is Working

If you are taking hormone therapy for prostate cancer, you will have regular PSA tests. If hormone therapy is working, your PSA levels will stay the same or may even go down. But, if your PSA levels go up, this may be a sign that the treatment is no longer working. If this happens, your doctor will discuss treatment options with you.

If you are taking hormone therapy for breast cancer, you will have regular check-ups. Checkups usually include an exam of the neck, underarm, chest, and breast areas. You will have regular mammograms, though you probably wont need a mammogram of a reconstructed breast. Your doctor may also order other imaging procedures or lab tests.

Concerns When Selecting A Novel Hormonal Agent For Crpc

FDA Approves Relugolix for Advanced Prostate Cancer

During a live virtual event, Alicia Morgans, MD, MPH, discussed the choice of novel hormonal agents to combine with androgen-deprivation therapy in nonmetastatic castrate-resistant prostate cancer.

CASE SUMMARY

In October 2016, a 57-year-old black man was referred to the urology department with a PSA of 6.8 ng/mL. His medical history included seizures that were controlled with oxcarbazepine. His mother and sister had a history of breast cancer, and his brother had a history of pancreatic cancer. A multiparametric MRI scan showed a 58 cc index lesion to his left prostate zone, and prostate imaging reporting and data system showed it to be 4/5, 1.8 cm. Three months later, he had a robotically assisted radical prostatectomy and extended lymph node dissection. Six weeks post operation, the patient had a PSA of 0.15 ng/mL and baseline serum testosterone of 420 ng/mL.

Androgen deprivation therapy was initiated with leuprolide depot at 45 mg. The patient returned in August 2019. His PSA doubling time was 8.6 months with a PSA of 1.2 ng/mL. In October 2019 he was restaged, and bone scans showed he was negative for metastatic disease with an ECOG performance score of 0. In October 2020, the patients PSA was 3.81 ng/mL.

A decision to add a novel hormonal agent was made. Which therapy would you most likely recommend?

Reference:

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How Hormone Therapy Is Given

Hormone therapy may be given in many ways:

Oral. Hormone therapy comes in pills that you swallow.
Injection. The hormone therapy is given by a shot in a muscle in your arm, thigh, or hip, or right under the skin in the fatty part of your arm, leg, or belly.
Surgery. You may have surgery to remove organs that produce hormones. In women, the ovaries are removed. In men, the testicles are removed.

How The Study Was Performed

During the study, scientists randomized 1,071 men with intermediate- or high-risk localized prostate cancer into four groups. One group received radiation and six months of an anti-testosterone drug called leuporelin, and the second group received radiation plus 18 months of leuporelin therapy. Two other groups were treated with the same regimens of either radiation plus six or 18 months of leuporelin therapy, along with another drug called zoledronic acid, which helps to limit skeletal pain and related complications should cancer spread to the bones. Study enrollment occurred between 2003 and 2007 at 23 treatment centers across New Zealand and Australia.

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Key Factors Associated With Chemotherapy Use: Chemotherapy Vs Adt Alone

Patients receiving chemotherapy were significantly younger than patients receiving ADT alone . Examining the key clinical reasons for treatment choice revealed that physicians prescribed chemotherapy vs ADT alone to significantly higher proportions of patients who were younger: , who had good performance status , whose top priority was OS , whose top priority was maximal PFS , for whom a rapid onset of action was required , who had high disease burden , or who had visceral metastases . All key clinical reasons for treatment choice for chemotherapy vs ADT alone are presented in Fig. .

Availability Of Data And Materials

Overview of Treatment for Advanced Prostate Cancer, including Metastatic Disease – Novel Treatment

The data reported in this study were derived from an independent survey . All data, i.e. methodology, materials, data and data analysis, supporting the study are the intellectual property of Adelphi Real World. The data that support the findings of this study are available from Adelphi Real World but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Adelphi Real World. All requests for access should be addressed directly to Andrea Leith at [email protected].

Advancements In The Treatment Of Metastatic Hormone

Department of Urology, Gansu Provincial Hospital, Lanzhou, China

In the last decade, there have been substantial improvements in the outcome of the management of metastatic hormone-sensitive prostate cancer following the development of several novel agents as well as by combining several therapeutic strategies. Although the overall survival of mHSPC is shown to improve with intense androgen deprivation therapy , combined with docetaxel, as well as other novel hormonal therapy agents, or alongside local intervention to the primary neoplasm. Notably, luteinizing hormone-releasing hormone antagonists are known to cause fewer cardiovascular side effects compared with LHRH agonists. Thus, in this mini review, we explore the different approaches in the management of mHSPC, with the aim that we may provide useful information for both basic scientists and clinicians when managing relevant clinical situations.

How Is Hormone Therapy Used To Treat Hormone

Hormone therapy may be used in several ways to treat hormone-sensitive prostate cancer, including:

Early-stage prostate cancer with an intermediate or high risk of recurrence. Men with early-stage prostate cancer that has an intermediate or high risk of recurrence often receive hormone therapy before, during, and/or after radiation therapy, or after prostatectomy . Factors that are used to determine the risk of prostate cancer recurrence include the grade of the tumor , the extent to which the tumor has spread into surrounding tissue, and whether tumor cells are found in nearby lymph nodes during surgery.

The use of hormone therapy before prostatectomy has not been shown to be of benefit and is not a standard treatment. More intensive androgen blockade prior to prostatectomy is being studied in clinical trials.

Relapsed/recurrent prostate cancer. Hormone therapy used alone is the standard treatment for men who have a prostate cancer recurrence as documented by CT, MRI, or bone scan after treatment with radiation therapy or prostatectomy.

Hormone therapy is sometimes recommended for men who have a “biochemical” recurrencea rise in prostate-specific antigen level following primary local treatment with surgery or radiationespecially if the PSA level doubles in fewer than 3 months.

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How Does Hormone Therapy Work Against Prostate Cancer

Early in their development, prostate cancers need androgens to grow. Hormone therapies, which are treatments that decrease androgen levels or block androgen action, can inhibit the growth of such prostate cancers, which are therefore called castration sensitive, androgen dependent, or androgen sensitive.

Most prostate cancers eventually stop responding to hormone therapy and become castration resistant. That is, they continue to grow even when androgen levels in the body are extremely low or undetectable. In the past, these tumors were also called hormone resistant, androgen independent, or hormone refractory however, these terms are rarely used now because the tumors are not truly independent of androgens for their growth. In fact, some newer hormone therapies have become available that can be used to treat tumors that have become castration resistant.