Tag: Prostate Cancer

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 299,010 new cases of prostate cancer will be diagnosed in 2024 and 35,250 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention.

Metastatic prostate cancer remains a significant concern in the United States, being the second leading cause of cancer-related deaths among men. Over recent years, the incidence of metastatic prostate cancer has notably increased. For men diagnosed with metastatic Hormone-Sensitive Prostate Cancer (mHSPC), survival rates have improved with the introduction of Androgen Receptor Signaling Inhibitors (ARSIs) and chemotherapy. These therapeutic advancements, used in conjunction with androgen suppression, have demonstrated survival benefits, though patient outcomes remain highly variable. In previous studies, treatment intensification has been deemed justified based on tumor histology and radiographic disease burden, but these criteria have not consistently predicted outcomes, underscoring the urgent need for robust new, noninvasive, prognostic biomarkers.

Liquid biopsy, a noninvasive method of analyzing blood-based biomarkers, has emerged as a promising tool for early cancer detection, prognosis, personalized treatment decisions, and disease monitoring. In particular, Circulating Tumor Cells (CTCs)-cancer cells shed from primary or metastatic tumors into the bloodstream-offer a dynamic snapshot of disease status and have shown promise as biomarkers for prognosis, disease monitoring, and personalized treatment decisions. While CTCs have been extensively studied in metastatic Castration-Resistant Prostate Cancer (mCRPC), their role in mHSPC remains underexplored.

The S1216 trial is a prospective, multicenter, Phase 3, randomized clinical trial, conducted by SWOG in collaboration with the National Cancer Institute (NCI) and other research groups, to determine whether incorporating baseline CTC enumeration could serve as a reliable biomarker for predicting long-term outcomes, aiding in the identification of patients who may benefit from treatment intensification or novel therapeutic regimens. The primary goal of this study is to evaluate the prognostic value of Circulating Tumor Cell (CTC) counts in men with mHSPC, particularly their association with Overall Survival (OS).

The S1216 trial included 1313 men with newly diagnosed mHSPC, randomized in a 1:1 ratio to receive Androgen Deprivation Therapy (ADT) combined with either Orteronel, a CYP17 inhibitor that blocks androgen biosynthesis, or Bicalutamide, a nonsteroidal anti-androgen. ADT was administered using a Luteinizing Hormone-Releasing Hormone agonist, and Bicalutamide was given at a dose of 50 mg once daily, while Orteronel was administered at 300 mg twice daily. Treatment allocation was stratified based on disease severity, timing of ADT initiation prior to or after enrollment, and Zubrod Performance Status.

A key component of the trial was the collection and analysis of liquid biopsy samples, particularly CTC enumeration, at baseline and at disease progression to mCRPC. These blood samples were processed using the CellSearch platform, the only FDA-cleared system for CTC enumeration. The platform employs immunomagnetic beads that bind to epithelial cell adhesion molecules (EpCAM) on the surface of CTCs, enriching the sample for CTCs. After isolation, the CTCs were stained with specific markers to distinguish them from non-tumor cells: Cytokeratins (CK) markers for epithelial cells, CD45, a leukocyte antigen, used to exclude non-cancerous white blood cells, and DAPI, a nuclear stain to identify cells with intact nuclei. CTC counts were categorized into three groups: 0, 1-4, and 5 or more CTCs per 7.5 mL of blood. This categorization was based on findings from prior research in mCRPC, where higher CTC counts were associated with worse clinical outcomes. The goal was to determine whether a similar association could be observed in men with mHSPC. The Primary outcome of the study was Overall Survival (OS), with secondary outcomes including Progression-Free Survival (PFS) and Prostate-Specific Antigen (PSA) levels at 7 months.

Of the 1313 trial participants, 503 men had evaluable blood samples for CTC analysis at baseline. The results of the study showed that higher baseline CTC counts were strongly associated with worse clinical outcomes. Patients with 5 or more CTCs had a median OS of 27.9 months, compared with 56.2 months for men with 1-4 CTCs, and median OS of more than 78 months for men with 0 CTCs (median not reached). A similar trend was observed for PFS, with men who had 5 or more CTCs showing a significantly higher risk of disease progression. After adjusting for baseline clinical covariates, men with 5 or more CTCs were 3.22 times more likely to die during the study period and 2.46 times more likely to have their cancer progress, and had a lower odds of achieving a complete PSA response, compared to men with 0 CTCs at baseline.

This study demonstrates that baseline CTC count is a powerful, independent prognostic biomarker for men with mHSPC. CTC enumeration at the start of therapy can help identify men at higher risk of poor survival, even before the disease progresses to mCRPC. This information is particularly valuable for selecting patients for clinical trials of more aggressive or novel therapies. By identifying high-risk patients early, clinicians can potentially intensify treatment upfront, before PSA levels or clinical symptoms worsen.

In summary, CTC count provides critical insights into the biological behavior of metastatic prostate cancer and offers a noninvasive method for stratifying patients based on their risk of poor outcomes. Future research may expand the role of liquid biopsy beyond CTC enumeration to include molecular profiling of CTCs and circulating tumor DNA (ctDNA), enabling even more precise and personalized treatment strategies.

Circulating Tumor Cell Count and Overall Survival in Patients With Metastatic Hormone-Sensitive Prostate Cancer. Goldkorn A, Tangen C, Plets M, et al. JAMA Netw Open. 2024;7(10):e2437871. doi:10.1001/jamanetworkopen.2024.37871

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 299,010 new cases of prostate cancer will be diagnosed in 2024 and 35,250 men will die of the disease.

The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second-generation Androgen-Receptor Pathway Inhibitors (ARPI), which include ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide) and ERLEADA® (Apalutamide). Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The estimated mean survival of patients with CRPC is 9-36 months, and there is therefore an unmet need for new effective therapies. Patients who progress on Androgen Deprivation Therapy are often switched to second line hormonal treatments that block testosterone with a different mechanism of action, and upon further progression, offered taxane based chemotherapy.

Prostate-Specific Membrane Antigen (PSMA) is a Type II cell membrane glycoprotein that is selectively expressed in prostate cells, with high levels of expression in prostatic adenocarcinoma. PSMA is a therefore an excellent target for molecular imaging and therapeutics, due to its high specificity for prostate cancer. Lu-177–PSMA-617 (PLUVICTO®) is a radiopharmaceutical that targets PSMA. It is comprised of Lutetium-177, a cytotoxic radionuclide, linked to the ligand PSMA-617, a small molecule designed to bind with high affinity to PSMA. Radioligand therapy with Lu-177–PSMA-617 targets PSMA and releases its payload of lethal beta radiation into the prostate cancer cell.

The FDA in March 2022, approved Lu-177–PSMA-617 for the treatment of adult patients with Prostate-Specific Membrane Antigen (PSMA)-positive metastatic Castration-Resistant Prostate Cancer (mCRPC), who had been treated with Androgen-Receptor Pathway Inhibitors such as Enzalutamide or Abiraterone acetate and 1 or 2 taxane based chemotherapy regimens. This approval was based on the VISION Phase III study.

PSMAfore is a Phase III trial conducted to assess the benefit of Lu-177–PSMA-617 in patients with metastatic Castration-Resistant Prostate Cancer who had progressed on Androgen-Receptor Pathway Inhibitors, but had not received taxane based chemotherapy, with the hope of making this promising therapy available to more patients earlier in the course of their treatment journey. This study enrolled 468 patients with taxane-naive metastatic CRPC who had PSMA-positive disease on gallium-68–PSMA-11 PET/CT, and were candidates for an Androgen-Receptor Pathway Inhibitor change after one progression on prior Androgen-Receptor Pathway Inhibitor. These patients were randomized to receive either Lu-177–PSMA-617 or a change in Androgen-Receptor Pathway Inhibitor therapy (Abiraterone or Enzalutamide). The Primary endpoint was radiographic Progression Free Survival (rPFS). Secondary endpoints included Overall Survival, Prostate-Specific Antigen (PSA) declines of 50% or more from baseline-known as a PSA50 response, Quality of Life measures, and Safety profiles.

At the primary analysis conducted at 7.3 months, patients treated with Lu-177–PSMA-617 demonstrated a median rPFS of 9.3 months compared to 5.55 months in the Androgen-Receptor Pathway Inhibitor change group, showing a statistically significant and clinically meaningful benefit (HR=0.41; 95% confidence interval [CI] = 0.29-0.56). The positive outcomes persisted at the second interim analysis at 15.9 months, where Lu-177–PSMA-617 continued to show superiority in rPFS, PSA50 response rates (57.6% versus 20.4%), Objective Response Rates (50.7% versus 14.9%), and time to PSA progression (10.55 months versus 4.24 months). Moreover, the safety profile of Lu-177–PSMA-617 was manageable and consistent with previous observations from the VISION trial, with fewer Grade or more adverse events compared to the Androgen-Receptor Pathway Inhibitor change group. Common treatment-related adverse events included dry mouth and myelosuppression.

It was concluded that Lu-177–PSMA-617 represents a promising advancement in the armamentarium against advanced prostate cancer, and Lu-177–PSMA-617 has the potential to redefine treatment paradigms for patients with advanced prostate cancer, particularly in the pretaxane setting. The findings from the PSMAfore study suggest that Lu-177–PSMA-617 could provide a viable therapeutic option earlier in the disease course, potentially delaying or obviating the need for more toxic chemotherapy regimens.

Phase 3 trial of [177Lu]Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (PSMAfore). Sartor O, Herrmann K, Castellano D, et al. Presented at the Society of Nuclear Medicine and Molecular Imaging. June 9, 2024; Toronto, ON, Canada.

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 299,010 new cases of prostate cancer will be diagnosed in 2024 and 35,250 men will die of the disease.

The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. Treatment options for patients with intermediate and high risk prostate cancer include Radical Prostatectomy and External Beam Radiation Therapy. Three Phase III randomized studies have previously assessed the addition of Androgen Deprivation Therapy (ADT) to postoperative radiotherapy after Radical Prostatectomy, but none of these studies compared different durations of ADT and the optimal duration of Androgen Deprivation Therapy has remained unclear.

RADICALS was a multicenter, international, open-label, randomized, controlled, Phase III trial in prostate cancer.
This study addressed two important questions:
1) Which is the best way to use radiotherapy after surgery?
2) Which is the best way to use hormone treatment with any radiotherapy given after surgery?

The full background and other details related to the RADICALS trial is published elsewhere.

RADICALS-HD is a component of the RADICALS trial and the researchers hypothesized that long-course ADT would be more effective than short-course ADT in patients receiving postoperative radiotherapy. They therefore designed a prospective, international, randomized controlled trial to compare long-course versus short-course use of ADT in this setting. In the RADICALS-HD trial, 1523 patients were randomly assigned 1:1 to receive short-course ADT (N=761) or long-course ADT (N=762) in addition to postoperative radiotherapy at 138 centers in Canada, Denmark, Ireland, and the UK. Radiotherapy was started approximately 2 months after the start of hormone treatment, and patients received either 52.5 Gy in 20 fractions over 4 weeks or 66.0 Gy in 33 fractions over 6.5 weeks. Radiotherapy was given in the adjuvant setting for 43% of patients, and in the early salvage setting for 57% patients. Androgen Deprivation Therapy (ADT) consisted of Gonadotropin Releasing-Hormone analog given subcutaneously monthly for 6 months in the short-course ADT group and every 3 months for 24 months in the long-course ADT group. Outside Canada, Bicalutamide monotherapy 150 mg daily or monthly subcutaneous Degarelix were acceptable alternatives. Randomization was stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT. The two treatment groups were well balanced. The median age was 65 years, 93% of patients had Gleason score of 7 or higher and 30% had Stage T3b disease or higher. The Primary outcome measure was Metastasis-Free Survival, defined as metastasis arising from prostate cancer or death from any cause.

With a median follow-up of 8.9 years, the long-course ADT for 24 months resulted in a superior Metastasis-Free Survival compared to short-course ADT for 6 months. The 10-year Metastasis-Free Survival was 78.1% in the long-course ADT group compared to 71.9% in the short-course ADT group (HR=0.77; P=0.029). This finding was consistent across all prespecified subgroups, including baseline PSA. Grade 3 or higher toxicity was reported in 19% of patients in the long-course ADT group, and in 14% of patients receiving short-course ADT (P=0.025).

It was concluded that compared to adding 6 months of ADT, adding 24 months of ADT to patients receiving postoperative radiotherapy after radical prostatectomy for prostate cancer, significantly improved Metastasis-Free Survival. Long-course ADT should therefore be offered in addition to postoperative radiotherapy to individuals who are willing to accept the additional duration of adverse effects. The researchers added that this is the first trial to compare different durations of ADT with postoperative radiotherapy after Radical Prostatectomy in prostate cancer.

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial. Parker CC, Kynaston H, Cook AD, et al. The Lancet. 2024;403:2416-2425

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 299,010 new cases of prostate cancer will be diagnosed in 2024 and 35,250 men will die of the disease.

The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. The major source of PSA (Prostate Specific Antigen) is the prostate gland, and the PSA levels are therefore undetectable within 6 weeks after Radical Prostatectomy. Similarly, following Radiation Therapy there is a gradual decline in PSA, before reaching a post treatment nadir. A detectable PSA level after Radical Prostatectomy, or a rising PSA level following Radiation Therapy is considered PSA failure or biochemical recurrence. The American Urological Association suggested that a PSA of 0.2 ng/mL or higher after Radical Prostatectomy, defines PSA failure or relapse. A PSA rise 2 ng/ml or more above post Radiation Therapy nadir is considered PSA failure or relapse. Approximately 35% of the patients with prostate cancer will experience PSA only relapse within 10 years of their primary treatment and a third of these patients will develop documented metastatic disease within 8 years following PSA only relapse. Rising PSA is therefore a sign of recurrent disease. Patients with biochemically relapsed prostate cancer following local therapy, and a short PSA doubling time, are at risk for distant metastases.

It is estimated that approximately 15-20% of prostate cancer patients are classified as high-risk (PSA 20 ng/mL or more; or Gleason score 8-10; or clinical stage T3 or more). Approximately, 45-65% of patients with high-risk disease have recurrent disease within five years of undergoing Radical Prostatectomy.

ERLEADA® (Apalutamide) is an orally administered Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription. Apalutamide is presently approved for the treatment of patients with metastatic Castration Sensitive Prostate Cancer and non-metastatic Castration Resistant Prostate Cancer

Apa-RP is a multicenter, open-label, single-arm, Phase II study, which included 108 patients across 32 U.S. community urologic practices, and investigated the benefit of Apalutamide plus ADT adjuvant to Radical Prostatectomy, in patients with high-risk localized prostate cancer. Key inclusion criteria were high risk localized prostate cancer with a post-radical prostatectomy PSA of 0.2 ng/mL or less. Patients were treatment-naïve, had undergone Radical Prostatectomy, and were treated with Apalutamide 240 mg, orally once daily, every 28 days for 12 cycles along with ADT for 12 months. The median age was 66 years, 14% were African American and about 60% of patients had prostate cancer with a Gleason Score 9-10. The median preoperative PSA was 7.6 ng/mL and median testosterone level was 340 ng/dL. The Primary endpoint evaluated Biochemical Recurrence (BCR)-free rate, defined as two sequential PSA levels of 0.2 ng/mL or less, at 24 months. The Secondary endpoints included testosterone recovery rate to 150 ng/dL or more at 18 and 24 months, as well as Safety.

The study met its Primary endpoint, showing that patients who received 12 months of Apalutamide plus ADT adjuvant to Radical Prostatectomy experienced 100% biochemical recurrence-free survival (RFS) rate at 24 months, with no confirmed biochemical recurrence at 2 plus years following Radical Prostatectomy. The treatment regimen demonstrated a serum testosterone recovery (150 ng/dL or more) rate of 76.4% at 12 months following treatment completion. The safety profile of Apalutamide with ADT was consistent with previous reports and Adverse Events were reported by 99.1% of patients. Adverse Events led to treatment discontinuation in 10.2% of patients and dose reduction or interruption in 13%.

Based on the results of this study, it was concluded that treatment intensification with 12 cycles of Apalutamide and Androgen Deprivation Therapy following Radical Prostatectomy could become an option for patients with high-risk localized prostate cancer.

Apalutamide for high-risk localized prostate cancer following radical prostatectomy (Apa-RP): a multicenter, open-label, single-arm phase 2 study. Shore N, Hafron J, Saltzstein D, et al. Presented at: 2024 American Urological Association Meeting; May 3-May 6, 2022; San Antonio, TX. Abstract P2-07.

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 299,010 new cases of Prostate cancer will be diagnosed in 2024 and 32,250 men will die of the disease. There are however significant racial disparities, and for Black men, 1 in 6 will develop prostate cancer and are more than twice likely, to die from the disease. Black men are more likely to be diagnosed with prostate cancer at a younger age and with more aggressive disease. Nonetheless, there are very few guidelines that have outlined specific recommendations for Prostate Specific Antigen (PSA)-based prostate cancer screening among Black men.

A multidisciplinary panel of experts in Primary Care, Urology, Medical and Radiation Oncology conducted a comprehensive literature search in PubMed and Embase and after reviewing 265 relevant studies, developed six new guideline statements addressing screening for Black men, reaching a consensus, with 80% or higher agreement rate among these experts.

Prostate Cancer Foundation (PCF) Statements of Recommendations

Question 1. Should Black men be screened for prostate cancer?
Yes. Since Black men are at a high risk for prostate cancer, the benefits of screening generally outweigh the risks.

Question 2. What should Black men know about how screening for prostate cancer is conducted?
Prostate-Specific-Antigen (PSA) is a blood test that should be considered first-line for prostate cancer screening. Some providers may recommend an optional Digital Rectal Exam (DRE) in addition to the PSA test.

Question 3. What information should Black men obtain to make an informed decision about PSA screening and early detection of prostate cancer?
Decisions about PSA testing depend on individual preferences. Black men should engage in shared decision-making with their health care providers and other trusted sources of information to learn about the pros and cons of screening.

Question 4. When should Black men obtain their first PSA test and how often should they be screened for prostate cancer?
For Black men who elect screening, a baseline PSA test should be done between ages 40 and 45. Depending on the PSA value and the individuals health status, annual PSA screening should be strongly considered.

Question 5. At what age should Black men consider stopping PSA screening?
Black men over the age of 70 who have been undergoing prostate cancer screening should talk with their health care provider about whether to continue PSA testing and make an informed decision based on their age, life expectancy, health status, family history, and prior PSA levels.

Question 6. How should family history and genetic risk be taken into consideration when screening Black men for prostate cancer?
Black men who are at even higher risk due to a strong family history and/or known carriers of high-risk genetic variants should consider initiating annual PSA screening as early as age 40.

The PCF expert panel concluded that based on the best available evidence, risk-adapted PSA screening in US Black men can reduce the rate of metastasis and death from prostate cancer. They added that although additional studies can elucidate the impact of PSA screening on Black men, based on the current evidence, other national guideline groups should consider revising current recommendations for early prostate cancer detection in Black men.

Prostate Cancer Foundation (PCF) screening guidelines for prostate cancer in Black men in the United States. Garraway I, Carlsson SV, Nyame YA, et al. https://doi.org/10.1200/JCO.2024.42.4_suppl.264

SUMMARY: The FDA on November 16, 2023, approved Enzalutamide (XTANDI®) for non-metastatic Castration-Sensitive Prostate Cancer (nmCSPC) with biochemical recurrence, at high risk for metastasis. Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 288,300 new cases of Prostate cancer will be diagnosed in 2023 and 34,700 men will die of the disease. The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer, and is the first treatment intervention.

The major source of PSA (Prostate Specific Antigen) is the prostate gland, and the PSA levels are therefore undetectable within 6 weeks after Radical Prostatectomy. Similarly, following Radiation Therapy there is a gradual decline in PSA, before reaching a post treatment nadir. A detectable PSA level after Radical Prostatectomy, or a rising PSA level following Radiation Therapy, is considered PSA failure or biochemical recurrence. Approximately 35% of the patients with prostate cancer will experience PSA only relapse within 10 years of their primary treatment, and a third of these patients will develop documented metastatic disease within 8 years following PSA only relapse. Rising PSA is therefore a sign of recurrent disease. Patients with biochemically relapsed prostate cancer following local therapy, and a short PSA doubling time, are at risk for distant metastases.

Enzalutamide is a potent oral Androgen Receptor signaling inhibitor with demonstrated efficacy in patients with both localized and advanced prostate cancer. The present FDA approval is based on results from the EMBARK trial.

EMBARK is a randomized, double-blind, placebo-controlled, multi-national, Phase III trial, conducted to evaluate the efficacy and safety of Enzalutamide plus Leuprolide and Enzalutamide monotherapy, as compared with Leuprolide alone, in patients with non-metastatic Hormone/Castration-Sensitive Prostate Cancer (nmHSPC or nmCSPC) prostate cancer, who have had high-risk biochemical recurrence. In this study, a total of 1068 eligible patients were randomly assigned 1:1:1 to receive Enzalutamide at 160 mg orally once daily plus Leuprolide every 12 weeks (N=355), single agent Enzalutamide at 160 mg orally once daily (N=355) or Leuprolide alone (N=358). All patients had received prior definitive therapy with radical prostatectomy and/or radiotherapy with curative intent. High risk disease was defined as a PSA doubling time of 9 months or less and a PSA level of 2 ng/ml above nadir after radiation therapy, or 1 ng/ml or more after radical prostatectomy with or without postoperative radiation therapy. The baseline characteristics were well balanced among the treatment groups. The median age was 69 years, the median PSA doubling time was 4.9 months and the median PSA level was 5.2 ng/ml. The Primary end point was Metastasis-Free Survival (MFS), as assessed by Blinded Independent Central Review (BICR) in the combination group, as compared with the Leuprolide-alone group. MFS is defined as the duration of time in months between randomization and the earliest objective evidence of radiographic progression by central imaging or death due to any cause, whichever occurred first. A key Secondary end point was Metastasis-Free Survival in the Enzalutamide monotherapy group, as compared with the Leuprolide-alone group. Other Secondary end points were Patient-Reported Outcomes and Safety.

At a median follow up 60.7 months, the 5 year MFS was 87.3% in the Enzalutamide combination group and 71.4% in the Leuprolide-alone group (HR for metastasis or death 0.42; P<0.001). This represented a 58% lower risk of metastasis or death in the combination group than in the leuprolide-alone group. The 5 year MFS with Enzalutamide monotherapy versus Leuprolide alone was 80% versus 71.4% respectively (HR=0.63; P=0.005), suggesting a 37% lower risk of metastasis or death in the Enzalutamide monotherapy group than in the Leuprolide-alone group. At the time of this analysis, Overall Survival data were immature. No new safety signals were reported, and there was no substantial difference in Quality of Life measures between the treatment groups.

It was concluded that in patients with prostate cancer with high-risk biochemical recurrence, both Enzalutamide plus Leuprolide and Enzalutamide monotherapy resulted in significantly longer Metastasis-Free Survival and a longer time to PSA progression and receipt of next antineoplastic therapy, compared to Leuprolide alone, while maintaining overall Quality of Life.

Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer. Freedland SJ, de Almeida Luz M, De Giorgi U, et al. N Engl J Med. 2023;389:1453-1465.