In December 2020, the Food and Drug Administration (FDA) approved two treatments for prostate cancer.
Oral Hormone Therapy for Advanced Cancer
On Dec. 18, 2020, approval was granted for Orgovyx (relugolix), marking the first oral hormone therapy approved for advanced prostate cancer.3
The approval follows the HERO trial,4 a study comprising 930 patients with advanced prostate cancer (age range, 48-97 years) across 155 sites in the United States, Canada, and countries in South America, Europe, and the Asia Pacific region. Patients were randomized to receive either one 120 mg tablet of relugolix a day (following three tablets [totaling 360 mg] on the first day, n=622) or active control (leuprolide acetate, n=308) given as an injection every three months. Treatment duration was 48 weeks. The main outcome was medical castration rate, defined as achieving and maintaining serum testosterone suppression to castrate levels (< 50 ng/dL) through 48 weeks of treatment. Other outcomes included noninferiority regarding the main endpoint, castrate levels of testosterone on day four, and profound castrate levels (<20 ng/dL) on day 15.
A greater proportion of patients in the relugolix group maintained castration through 48 weeks (96.7%; 95% confidence interval [CI], 94.9-97.9) compared to the leuprolide group (88.8%; 95% CI, 84.6-91.8). The secondary endpoints also demonstrated that relugolix was superior to leuprolide (P<0.001). On day four, 56% of patients in the relugolix group and 0% in the leuprolide group had castrate levels of testosterone.
A subgroup analysis was performed in 184 patients who were followed for testosterone recovery; patients treated with relugolix, compared to those who received leuprolide, had a higher mean testosterone level 90 days after treatment discontinuation (288.4 ng/dL vs. 56.6 ng/dL).
The approval is even more significant because of its cardiovascular implications. More than 90% of patients who took part in the study had at least one cardiovascular risk factor across the three main categories assessed (lifestyle risk factors [i.e., tobacco use and obesity], cardiovascular risk factors [i.e., diabetes and hypertension], and history of a major adverse cardiovascular event); these patients were evenly distributed between the two treatment groups. The incidence of major cardiovascular events was lower in the relugolix group compared to the leuprolide group (2.9% vs 6.2%; hazard ratio, 0.46; 95% CI, 0.24-0.88).
As an oral therapy, relugolix is a convenient option for patients, which could in turn help increase adherence. The HERO trial measured treatment adherence, which was defined as the percentage of expected doses actually taken. Both the relugolix and leuprolide groups had more than 99% adherence; 90.2% of relugolix patients completed 48 weeks of treatment. This is perhaps of even greater significance in the COVID-19 era because it may reduce the number of clinic visits a patient needs.
Relugolix may cause serious side effects, including heart rhythm problems or harm to an unborn baby. Some of the most common side effects are hot flushes, increased blood sugar levels, increased triglyceride levels, muscle and joint pain, anemia, increased liver enzymes, tiredness, constipation, and diarrhea.
Gallium 68 PSMA-11
On Dec. 1, 2020, the FDA approved Gallium 68 PSMA- 11 (Ga 68 PSMA-11), which, according to the agency, is the first drug for PET imaging of PSMA positive lesions in men with prostate cancer.1 It is currently approved for patients who (1) have a newly diagnosed disease that could be cured with initial treatment, or (2) were treated for prostate cancer previously but have high levels of prostate-specific antigen (PSA) in their blood.
The approval followed two clinical trials encompassing a total of 960 patients.2
The first trial enrolled 325 men with recently diagnosed prostate cancer who had a high risk for metastasis and were eligible for surgery. All patients received one injection of Ga 68 PSMA-11 and underwent PET/CT or PET/MRI scans. The patients who opted for surgery and had positive readings in the pelvic lymph nodes per Ga 68 PSMA-11 all had metastatic disease.
In the second trial, 635 men who underwent prostate surgery or radiotherapy and subsequently had rising PSA levels underwent a Ga 68 PSMA-11 PET/CT scan or PET/ MR scan. The scans detected at least one positive lesion in 74% of patients.
“In patients with positive Ga 68 PSMA-11 PET readings who had correlative tissue pathology from biopsies, results from baseline or follow-up imaging by conventional methods, and serial PSA levels available for comparison, local recurrence or metastasis of prostate cancer was confirmed in an estimated 91% of cases,” the FDA summarized.
Both studies were able to provide information that could help guide treatment decisions. No differences in outcomes were observed by age, although most of the cohort was aged ≥65 years (72%). Ga 68 PSMA-11 PET was determined to be relatively safe. Among the total 960 patients evaluated in the two trials, the most common side effects were nausea, diarrhea, and dizziness, occurring at a rate of <1%.
Current Clinical Trials Evaluating mCRPC Treatments
Here’s what we’re following in the prostate cancer treatment pipeline, with a focus on metastatic castrate-resistant prostate cancer.
VISION Trial Studying 177Lu-PSMA-617
The VISION study5 is a phase III, randomized, prospective, open-label trial comparing 177Lu-PSMA-617 plus best supportive/standard of care versus best supportive/standard of care alone in patients with metastatic castrate-resistant prostate cancer (mCRPC). The main outcomes are overall survival (OS) and radiographic progression-free survival (rPFS).
Eligibility criteria were prostate-specific membrane antigen (PSMA)-expressing tumor, per PSMA positron emission tomography (PET) imaging, and prior exposure to a taxane and a novel androgen axis inhibitor. The study began on May 23, 2018, and is expected to be completed on Dec. 30, 2021.6
According to an update published in the Journal of Clinical Oncology,7 the study met its enrollment goal at 814 patients. Median OS on active treatment is assumed to be 13.7 months (hazard ratio [HR], 0.7306), and rPFS, six months (HR, 0.67).
Another study is examining the effectiveness of ipatasertib in patients with mild or asymptomatic, previously untreated mCRPC.8 In this phase III, randomized, double-blind, placebo-controlled, multicenter trial, patients are randomly assigned to either ipatasertib (400 mg once daily, oral) plus abiraterone (1000 mg once daily, oral) and prednisone/prednisolone (5 mg twice daily) or placebo plus abiraterone and prednisone/prednisolone. The main outcome is rPFS. The study has enrolled 1,101 patients. The trial kicked off on June 30, 2017, and is expected to be completed by November 17, 2023.
Phase 1 Study of BiTE AMG 160
A phase 1, first-in-human trial is set to assess the safety and tolerability of AMG 160, a half-life extended (HLE) bispecific T-cell engager (BiTE®) antibody construct, alone and in combination with pembrolizumab in patients with mCRPC9.
The study will have six parts:
- Patients will receive intravenous (IV) AMG 160 at different dose levels
- Patients will receive IV AMG 160 at different dose levels, as well as IV pembrolizumab
- Patients will receive IV AMG 160 at the recommend- ed phase 2 dose (RP2D) or maximum tolerated dose (MTD), as well as etanercept, administered subcutane- ously in cycle 1 only
- Patients will receive IV AMG 160 at RP2D/MTD with 24-hour monitoring
- Patients will receive IV AMG 160 at RP2D/MTD in an outpatient setting with eight-hour monitoring
- Patients will receive IV AMG 160 at RP2D/MTD levels, as well as an oral immunomodulating agent
As of Feb. 3, the study was still recruiting participants. Study completion is currently projected for January 17, 2025.
- U.S. Food and Drug Administration. (2020, December 1). FDA Approves First PSMA-Targeted PET Imaging Drug for Men with Prostate Cancer [Press release]. www.fda.gov/news-events/press-announcements/fda-approves-first-psma-targeted-pet-imaging-drug- men-prostate-cancer
- U.S. Food and Drug Administration. (2020, December 9). Drug Trials Snapshot: Ga 68 PSMA-11. www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshot-ga-68-psma-11
- U.S. Food and Drug Administration. (2020, December 18). FDA Approves First Oral Hormone Therapy for Treating Advanced Prostate Cancer [Press release]. https://www. fda.gov/news-events/press-announcements/fda-approves-first-oral-hormone-therapy- treating-advanced-prostate-cancer
- Shore ND, Saad F, Cookson MS, et al: Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. N Engl J Med 2020;382, 2187-2196. https://doi.org/10.1056/ NEJMoa2004325
- Sartor AO, Morris MJ, Krause BJ: VISION: An international, prospective, open-label, multicenter, randomized phase 3 study of 177Lu-PSMA-617 in the treatment of patients with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). J Clinc Oncol 2019;37(15). https://doi.org/10.1200/JCO.2019.37.15_suppl.TPS5099
- ClinicalTrials.gov. (2018) Study of 177Lu-PSMA-617 In Metastatic Castrate-Resistant Prostate Cancer (VISION). U.S. National Institute of Health, National Library of Medicine. https://clinicaltrials.gov/ct2/show/NCT03511664
- Sartor AO, Morris MJ, Krause BJ: VISION: An international, prospective, open-label, multicenter, randomized phase III study of 177Lu-PSMA-617 in the treatment of patients with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). J Clinc Oncol 2020;38(6). https://doi.org/10.1200/JCO.2020.38.6_suppl.TPS259
- ClinicalTrials.gov. (2017) Ipatasertib Plus Abiraterone Plus Prednisone/Prednisolone, Relative to Placebo Plus Abiraterone Plus Prednisone/Prednisolone in Adult Male Patients With Metastatic Castrate-Resistant Prostate Cancer (IPATential150). U.S. National Institute of Health, National Library of Medicine. https://clinicaltrials.gov/ct2/show/ NCT03072238?term=03072238&draw=2&rank=1
- ClinicalTrials.gov. (2019) Safety, Tolerability, Pharmacokinetics, and Efficacy of AMG 160 in Subjects With mCRPC. U.S. National Institute of Health, National Library of Medicine. https://clinicaltrials.gov/ct2/show/NCT03792841?term=03792841&draw=2&rank=1