Achieving Testosterone Suppression in Advanced Prostate Cancer

Neal Shore, MD, FACS, is the medical director of the Carolina Urologic Research Center, Myrtle Beach, South Carolina. He practices with Atlantic Urology Clinics in Myrtle Beach. Dr Shore is an internationally recognized expert in systemic therapy for advanced urologic cancers and has conducted more than 250 clinical trials.

How is advanced prostate cancer defined?

Advanced prostate cancer exists in a spectrum. There is no single, universally accepted definition.

Some might describe patients with advanced prostate cancer as those who have high-grade disease that is spreading outside the prostate into the seminal vesicles and pelvic lymph nodes. But then there are patients who present with what is described as de novo metastatic disease, in which, in addition to their prostate cancer, they also have disease in lymph nodes above the pelvic rim or in bones or viscera — for example, the lungs and liver.

Advanced prostate cancer can also be what some would describe as recurrent metastatic. A patient may have had surgery or radiation with curative intent but did not have imaging-positive metastatic disease when the condition was initially diagnosed; however, when he returns for evaluation, he presents with metastatic disease in the lymph nodes, bone, liver, or lungs. That would be recurrent or primary-progressive, metastatic, castration-sensitive disease.

There is also another form of advanced cancer, in which a patient may have had radiation to his prostate or surgery and later exhibits a rising prostate-specific antigen [PSA] level. Although imaging does not demonstrate positive findings for cancer, the rising PSA level now suggests micrometastatic disease.

The more advanced form of prostate cancer would be castration-resistant prostate cancer, in which the PSA level is rising despite testosterone suppression having been instituted. We then repeat imaging; if there is no imaging positivity on conventional computed tomography scan or bone scan, we say that’s nonmetastatic, castration-resistant prostate cancer. It is nonmetastatic based on conventional imaging, but if the imaging is positive then we say that the patient has metastatic castration-resistant prostate cancer [mCRPC].

For which types of advanced prostate cancer that you just outlined is androgen-deprivation therapy (ADT) recommended?

There is a potential role for ADT for all of these patients. For patients who have obvious metastatic disease, whether they are castration-sensitive or castration-resistant, ADT is the mainstay of treatment and is usually continuous. In patients who have biochemical relapse (PSA relapse), some urologic oncologists will use intermittent, as opposed to continuous, ADT. ADT can also be considered for patients who have intermediate-risk or high-risk localized disease who choose radiation therapy and, usually, are selecting a more limited duration of ADT.

How does ADT help control prostate cancer?

There is probably no other cancer that is more hormonally sensitive to endocrine manipulation than prostate cancer, which Charles Huggins and Clarence Hodges discovered in the 1940s and for which Huggins won the Nobel Prize in Physiology or Medicine in 1966. So, patients with any one of the disease states that I described — 95% to 99% of them — initially respond in the castration-sensitive milieu. Castration resistance develops when we add new therapies. Since 2010, we have 10 life-prolonging therapies for men with advanced prostate cancer who have either metastatic castration-sensitive prostate cancer or mCRPC. Prior to 2010, we only had 1 treatment, docetaxel, which was approved in 2004.¹

Please discuss these therapies and how they differ.

In 2004, docetaxel was approved for patients with mCRPC.¹ Docetaxel is a taxane-based treatment that works on microtubule inhibition. In 2010, we had the approval, in the United States only, of sipuleucel-T, an autologous cellular immunotherapy that works on antigen-presenting cells and increases the stimulation of dendritic cells to attack tumor cells.² This is the first immune-based therapy to be approved for treating a solid tumor.

Following that, we had approvals for androgen receptor-pathway inhibitors. The first was abiraterone acetate in conjunction with prednisone, which was approved for patients with mCRPC who had experienced progression on docetaxel. Soon after that, abiraterone acetate was approved, after another large phase 3 trial, for patients with mCRPC before they receive docetaxel.³ Similarly, about a year later, enzalutamide, a direct androgen-receptor inhibitor, was approved for mCRPC following treatment with docetaxel; a couple of years later, enzalutamide received approval for mCRPC prior to treatment with docetaxel.^4,5 Similarly, we received approval of cabazitaxel, another taxane, for patients with mCRPC who experienced progression after receiving docetaxel.⁶

Close in time to these approvals, we saw approval of a radiopharmaceutical, radium-223 dichloride. This agent has a unique mechanism of action: It causes double-stranded DNA breaks because of the use of this very potent alpha isotope that specifically goes to sites of bone metastasis but not to soft tissue or viscera.⁷ Radium-223 dichloride is approved for patients with mCRPC with bone metastases.

Following that, we had approval of 2 more androgen receptor-pathway inhibitors, apalutamide and darolutamide; together with enzalutamide, the 3 were approved for patients who have nonmetastatic castration-resistant prostate cancer. They were originally approved on the basis of demonstrating a primary endpoint of metastasis-free survival, which primarily consisted of radiographic progression or death.^8-10 The initial analysis showed the benefit of metastasis-free survival; then, in 2020, subsequent additional analyses of all 3 drugs, in 3 separate trials, demonstrated a survival benefit.

Last, pembrolizumab was approved for patients who have microsatellite instability-high findings on genomic profiling.¹¹ That approval is a tumor-agnostic approval for pembrolizumab, so patients with any tumor with microsatellite instability-high findings can get pembrolizumab. This is the second immuno-oncologic approved for treating prostate cancer.

In May of 2020, we also saw approval of olaparib and rucaparib, two poly (ADP-ribose) polymerase (PARP) inhibitors that work by trapping the PARP enzyme and inhibiting the replication fork of double-stranded DNA amplification. Olaparib was approved for patients with mCRPC who have DNA damage repair mutations — 14 such mutations are listed on product labeling — and have experienced progression on either abiraterone or enzalutamide.¹²

Rucaparib was approved for patients with mCRPC and BRCA-1 and BRCA-2 mutations who have experienced progression on abiraterone or enzalutamide, including those who have also received docetaxel.¹³

On December 18, 2020, the FDA approved relugolix for the treatment of adult patients with advanced prostate cancer. How will this new agent influence management of patients with advanced prostate cancer?

Relugolix is the first approved oral ADT agent; other ADT agents, which were approved in the 1980s, are administered parenterally, so they’re given intramuscularly or subcutaneously. Most of them are luteinizing hormone-releasing hormone (LHRH) agonists (except for degarelix, an LHRH antagonist approved in 2008), so their mechanisms of action differ, but they are all administered by injection. Relugolix is an antagonist, which is, I think, a more effective biologic concept for lowering testosterone because the drug produces its effect directly — as opposed to agonists, which lower testosterone indirectly and are associated with a temporary surge in levels of follicle-stimulating hormone, luteinizing hormone, and testosterone.

On what data was approval of this agent based?

The phase 3 HERO trial (ClinicalTrials.gov Identifier: NCT03085095) enrolled more than 900 patients globally and compared relugolix to the LHRH agonist leuprolide, with the primary endpoint being testosterone suppression.¹⁴ We met the noninferiority endpoint, and we actually surpassed it and achieved superiority in terms of evaluating testosterone beginning at Day 29 through Week 48. A lot of secondary endpoints — looking at profound testosterone suppression, T values less than 20, and immediate PSA responses at Days 4 and 15 — were all highly statistically significantly in favor of relugolix. So, now you have the convenience of a once-a-day pill that can be taken with or without food.

Did relugolix demonstrate other advantages?

To me, the most important aspect of this study¹⁴ was the prespecified safety analysis looking at cardiovascular adverse effects. There was 54% less of a likelihood of developing a cardiovascular adverse effect with relugolix than with leuprolide.

Also, in a subset of 184 patients who stopped relugolix and leuprolide at Week 48, 53% of patients in the relugolix arm returned to a normal testosterone level by Day 90, as opposed to only 3% of the leuprolide patients, so relugolix demonstrated faster testosterone recovery, which might be nice for patients who are on a short-term, limited course of testosterone suppression and are not going to be on it continuously. That might be good for radiation patients or patients being treated with a strategy of intermittent testosterone suppression.

I think that the real novelty of relugolix is clearly 4-fold: once-daily oral dosing, antagonist as opposed to agonist action, more rapid return of the testosterone level when the drug is stopped, and, most important, an enhanced cardiovascular safety profile.

Is relugolix suitable for patients who need long-term testosterone control?

In our study,¹⁴ roughly 50% of patients were started on treatment for biochemical relapse; 25% had metastatic disease, and another 25% had locally advanced disease that was unsuitable for surgery or radiation.

Are there specific considerations that clinicians should take into account when prescribing ADT?

The decision to start ADT is an important and powerful patient–physician decision, because there are many attendant adverse effects of therapy. We describe it as the mainstay of treatment because 95% or more of patients respond to testosterone suppression, but it can cause myriad adverse effects, including hot flushes, loss of energy, fatigue, sometimes depression, loss of libido, bone demineralization, and unwanted cardiovascular effects.¹⁵ So, a risk–benefit analysis has to be done vis-a-vis the patient’s age, comorbidities, and concomitant medications and the extent of tumor burden and the actuarial survival estimate.