Tag: Prostate Cancer

Prostate Cancer Screening with Polygenic Risk Score

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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 313,780 new cases of prostate cancer will be diagnosed in 2025 and 35,770 men will die of the disease

PSA is one of the most widely used prostate cancer biomarkers, and the widespread use of PSA testing in the recent years has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer. PSA-based screening is widely debated due to false positives, overdiagnosis, and overtreatment.

The researchers in the present study hypothesized that Polygenic Risk Scores (PRS) based on aggregation of common genetic variants offer a promising way to stratify individual risk, independent of PSA or family history. Following completion of a pilot study, the BARCODE1 study was designed to prospectively test whether using a Polygenic Risk Score (PRS) could improve targeted screening effectiveness.

STUDY DESIGN:
BARCODE1 is a prospective, population-based, genetic risk-stratified screening study which included 6,393 men aged 55-69 yrs, with their Polygenic Risk Score calculated and recruited from 130 UK general practices. Germline DNA from saliva was used to calculate Polygenic Risk Score based on 130 known prostate cancer SNPs (Single Nucleotide Polymorphisms). Single Nucleotide Polymorphisms (SNPs “snips”) are variations in certain genes of a person’s DNA that can increase or decrease an individual’s risk of susceptibility to the disease. Men in the top 10% of the Polygenic Risk Score distribution (N=745) were invited for further screening with multiparametric MRI (mpMRI) and transperineal biopsy, regardless of PSA level.

KEY RESULTS:
MRI/biopsy was performed in 468 of these 745 men and 40% (N=187) were diagnosed with prostate cancer. Of the 187 participants, 103 men (55.1%) had clinically significant (Grade Group ≥2) cancer.

High-risk (Grade Group 3-5) cancer was found in 21.4% (N=40) of diagnosed men. These cancers typically qualify for radical therapy.

Current UK PSA thresholds (PSA >3.0 ng/mL) would have missed 71.8% of clinically significant cancers found through Polygenic Risk Score-based screening. Notably, 52% of all clinically significant cases had PSA <3.0 ng/mL, reinforcing the inadequacy of PSA-alone screening.

Estimated overdiagnosis (Grade Group 1 tumors) was 15.6–20.8%, comparable to, or lower than rates seen in PSA-based screening.

mpMRI-negative but Polygenic Risk Score-positive men still had a 6.4% clinically significant prostate cancer detection rate, underscoring Polygenic Risk Score value beyond imaging.

CONCLUSION:
Polygenic Risk Score-based screening detected more clinically significant prostate cancers than PSA or mpMRI alone. Combining Polygenic Risk Score with age and family history may help optimize risk-based screening strategies. One important limitation of this study is that participants were mostly educated men of European ancestry. These results may therefore not generalize to other ethnic groups or broader populations. Further research is needed to assess cost-effectiveness, utility across ancestries, and integration of genomics into national screening programs.

Polygenic Risk Score for Prostate Cancer Screening. McHugh JK, Bancroft EK, Saunders E, et al. for the BARCODE1 Steering Committee and Collaborators. N Engl J Med 2025;392:1406-1417

Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline

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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 313,780 new cases of prostate cancer will be diagnosed in 2025 and 35,770 men will die of the disease.

The five year survival among patients first diagnosed with metastatic prostate cancer is approximately 30%. Early detection and treatment may improve outcomes. Risk factors for prostate cancer include age, ethnicity, and family history of prostate cancer. In individuals with a family history of prostate cancer in one or more first-degree relatives, the Relative Risk of prostate cancer increases approximately 2-3 fold, and the risk increases with an increasing number of affected relatives, and is inversely related to the age at time of diagnosis among those relatives.

It is estimated that approximately 40% of all diagnosed prostate cancers are inherited and prostate cancer risk also has been implicated in other familial cancer syndromes such as Hereditary Breast and Ovarian Cancer (HBOC) syndrome and Lynch Syndrome (LS). HBOC syndrome typically is found in families with early onset cancer and multiple cancer diagnoses such as, breast, ovarian and pancreatic cancer. Tumor suppressor DNA repair genes BRCA1 and BRCA2, has been implicated in prostate cancer, particularly in HBOC families. Patients with a BRCA1 mutation have a nearly 2-fold Relative Risk of prostate cancer among men less than 65 years, whereas those with BRCA2 mutations have a more than 7 fold Relative Risk. Further, patients with BRCA2 mutations are also associated with clinically aggressive disease, progression, and higher rates of cancer-specific mortality. It is estimated that the frequency of BRCA2 mutations ranges from 1-3%.

Somatic genomic testing in metastatic prostate cancer can offer insights into both prognosis and potential treatment responses, helping guide clinical decisions. Germline genetic testing can also yield similar insights, with the added benefit of revealing inherited cancer risks that may be relevant to patients relatives, including risks for cancers such as breast, pancreatic, colon, and endometrial. As a result, research has focused on determining which germline and somatic genetic tests deliver the most valuable information for individual patient cases.

The present ASCO guideline was developed by a multidisciplinary Expert Panel, following review of evidence on germline and somatic genomic testing for patients with metastatic prostate cancer. A total of 1,713 papers were identified in the literature search, and the recommendations are based on evidence from eight systematic reviews and six trials. This guideline is applicable to a patient who has a life expectancy of more than 6 months, is a candidate for systemic treatment, and for whom appropriate germline and somatic testing, including expertise in interpretation, is readily available.

This guideline addresses the following questions:
1) Why germline and somatic genomic testing should be offered?
2) The criteria for which patients should be offered testing?
3) Which test(s) to use?
4) When in the disease course testing should be considered?
5) Which biospecimens should be used for testing?

RECOMMENDATIONS

Clinical Question: Who should receive germline testing with NGS technologies?

Recommendation: All patients with metastatic prostate cancer should undergo germline genetic testing with next-generation sequencing technologies.

Clinical Question: Who should receive somatic testing with NGS technologies?

Recommendation: Those patients with metastatic prostate cancer (both Castrate Sensitive and Castrate Resistant Prostate Cancer) who are being considered for biomarker-directed systemic treatment should undergo somatic testing with next-generation sequencing technologies. While there are no current FDA-approved biomarker-directed treatments following somatic testing for metastatic Castrate Sensitive Prostate Cancer, somatic testing may be warranted in the presence of high-volume disease, or where there is a high likelihood the patient’s disease will progress to Castrate Resistant Prostate Cancer, where the patient is a candidate for future treatment with a biomarker-directed therapy (PARP inhibitor or checkpoint inhibitor).

Clinical Question: Who should receive sequential somatic testing with NGS technologies?

Recommendation: The panel recommends that sequential somatic testing may be offered when there has been a meaningful change in the patient’s status or treatment plan, especially in cases where prior tests were negative or uninformative (eg, insufficient or low tumor content).

Clinical Question: What are the strengths and weaknesses of primary tumor archival tissue versus fresh metastatic biopsy tissue versus ctDNA testing for somatic testing?

Recommendation: Archival tissue samples are preferred in initial testing. ctDNA is preferred when there is no accessible metastatic site to biopsy or for sequential testing. In the setting of minimal disease burden associated with low ctDNA fraction, metastatic biopsy is preferred.

Clinical Question: What are the key therapeutic impacts of germline or somatic testing for single-gene genetic variants (eg, BRCA1, BRCA2)?

Recommendation: Patients with pathogenic germline variants or somatic alterations in BRCA1 and BRCA2 demonstrate poorer outcomes, but are candidates for treatment with PARP inhibitor monotherapy, PARP inhibitor with Androgen Receptor Pathway Inhibitor combination therapy, and platinum-based agents.

Clinical Question: What are the key prognostic impacts of germline or somatic testing?

Recommendation: Treatment recommendations should not be made based on prognostic only biomarkers. However, they may be considered for directing patients to clinical trials. Germline information may still be important for patient counseling, informing hereditary risk for patients and families.

Pre-Test Genetic Counseling for Germline Testing

Before conducting germline testing, clinicians should ensure patients understand the following essential aspects:

  • Purpose of Testing: Explain the goals and implications of germline genetic testing.
  • Hereditary Nature: Emphasize that the results can reveal inherited cancer risks.
  • Family Impact: Discuss how findings might indicate elevated cancer risks for relatives.
  • Testing Options: Inform patients about the availability of gene panel testing.
  • Possible Outcomes:
    • Pathogenic/Likely Pathogenic Variants (P/LPVs)
    • Variants of Uncertain Significance (VUS)
    • Negative or Inconclusive Results
  • Legal Protections: Outline patient protections under the Genetic Information Nondiscrimination Act (GINA).
  • Cascade Testing: Stress the importance of testing family members when a P/LPV is found.

Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline. Yu EY, Rumble RB, Agarwal N, et al. J Clin Oncol. 2025;43:748-758. DOI:10.1200/JCO-24-02608.

FDA Approves Radioligand Therapy with PLUVICTO® Before Chemotherapy in Castrate Resistant Prostate Cancer

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SUMMARY: The FDA on March 28, 2025, expanded the indication for Lutetium Lu 177 vipivotide tetraxetan (PLUVICTO&reg;) to include adults with Prostate-Specific Membrane Antigen (PSMA)-positive metastatic Castration-Resistant Prostate Cancer (mCRPC) who have been treated with Androgen Receptor Pathway Inhibitor (ARPI) therapy and are considered appropriate to delay taxane-based chemotherapy. Patients with previously treated mCRPC should be selected for PLUVICTO&reg; using LOCAMETZ&reg; (active ingredient Gallium Ga 68 gozetotide) or another approved PSMA Positron Emission Tomography (PET) product based on PSMA expression in tumors.

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 313,780 new cases of prostate cancer will be diagnosed in 2025 and 35,770 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.

Lutetium Lu 177 vipivotide tetraxetan (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 PLUVICTO® targets PSMA and releases its payload of lethal beta radiation into the prostate cancer cell.

The FDA in March 2022, approved PLUVICTO® 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 (ARPI) 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 PLUVICTO® in patients with metastatic Castration-Resistant Prostate Cancer who had progressed on ARPIs, 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 (N=468) with taxane-naive metastatic CRPC who had PSMA-positive disease on gallium-68–PSMA-11 PET/CT, and were candidates for an ARPI change after one progression on prior ARPI. Patients were randomized (1:1) to receive PLUVICTO® 7.4 GBq (200 mCi) IV every 6 weeks for 6 doses, or a change in ARPI (Abiraterone or Enzalutamide). The Primary endpoint was radiographic Progression Free Survival (rPFS). Secondary endpoints included Overall Survival (OS), 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 PLUVICTO® demonstrated a median rPFS of 9.3 months compared to 5.6 months in the ARPI change group, showing a statistically significant and clinically meaningful benefit (HR=0.41; P<0.0001).

In the updated exploratory analysis, performed with a median follow-up of 24 months, PLUVICTO® more than doubled median rPFS versus ARPI change group (11.6 months versus 5.6 months, HR=0.49), with a 51% reduction in the risk of radiographic progression or death with PLUVICTO® versus a change in ARPI. At the preplanned final analysis, Overall Survival (OS) numerically favored PLUVICTO® but was not statistically significant. The median OS was 24.5 months with PLUVICTO® and 23.1 months with a change in ARPI (HR=0.91 (95% CI, 0.72-1.14). High crossover rate may have confounded OS analysis. Approximately 60% of patients randomized to the change in ARPI group subsequently crossed over to receive PLUVICTO® following confirmed radiographic progression. The Objective Response Rate (ORR) in the PLUVICTO® group was 49% versus 14% in the change in ARPI group, with Complete Response Rates of 21% versus 2.8%, respectively. PSA50 response was 51% with PLUVICTO® and 17% with change in ARPI.

The most frequently reported all-grade adverse events for PLUVICTO® included dry mouth, fatigue, nausea, and constipation, and were primarily Grade 1-2. Further, PLUVICTO® did not impair the ability of patients to be treated with subsequent chemotherapy.

It was concluded that in the updated analysis of the PSMAfore trial, PLUVICTO® more than doubled median rPFS versus a change in ARPI, with favorable safety profile and proven tolerability. The findings from the PSMAfore study suggest that PLUVICTO® could provide a viable therapeutic option earlier in the disease course, potentially delaying or obviating the need for more toxic chemotherapy regimens.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-pluvictos-metastatic-castration-resistant-prostate-cancer-indication

Advancing Prostate Cancer Treatment: The Efficacy of Primary Partial-Gland Cryoablation

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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 by the American Cancer Society that in the United States, about 313,780 new cases of prostate cancer will be diagnosed in 2025 and 35,770 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.

Prostate cancer treatment has traditionally revolved around whole-gland procedures, primarily radical prostatectomy, which, while effective in cancer eradication, is often associated with significant adverse effects, including urinary incontinence, erectile dysfunction, and the absence of semen. However, advancements in focal therapy, particularly Primary Partial-Gland CryoAblation (PPGCA), present a promising alternative that mitigates these consequences while maintaining efficacy. Primary Partial-Gland Cryoablation is a minimally invasive treatment for prostate cancer that involves the focal application of ultra‐cold temperature that destroys only the cancerous part of the prostate gland by freezing and thawing the cancerous cells.

The introduction of multiparametric Magnetic Resonance Imaging (mpMRI) has significantly improved our ability to determine the size, location, and aggressiveness of prostate cancer, enabling better candidate selection for focal therapy.

To rigorously assess the effectiveness of PPGCA, a study conducted at NYU Langone Health between May 2017 and March 2024, enrolled 313 men diagnosed with intermediate-risk prostate cancer, with no out-of-field Gleason grade group 2 or more, gross extracapsular extension, or extreme apical disease on pre-treatment mpMRI. Of these, 91 patients were followed for at least five years to evaluate the long-term efficacy of PPGCA. An intensive follow-up regimen was implemented. Patients underwent PSA testing every six months and received mpMRIs at 6-12, 24, 42, and 60 months post-treatment. Initially, protocol biopsies were conducted at 6-12 and 24 months; however, these were discontinued after interim analysis revealed a low incidence of clinically significant Prostate Cancer (csPCa) recurrence, defined as Gleason grade group 2 or more disease. The Primary end point was Freedom-from-failure, defined as no prostate cancer-specific mortality, metastatic disease, or whole-gland salvage treatment.

Key Findings

Among the 91 patients monitored for at least five years:

  • Clinically significant Prostate Cancer (csPCa) was detected in 33 (10.5%) patients.
  • The freedom-from-recurrence rates at five years were:
    • In-field csPCa: 86%
    • Out-of-field csPCa: 85%
    • Overall csPCa: 70%
  • The overall freedom-from-failure rate at five years was 89%.
  • No patient succumbed to prostate cancer during the study period.
  • One patient (1%) developed metastatic disease.
  • 15 patients (16.5%) underwent whole-gland salvage treatment.
  • 15 patients (16.5%) received salvage focal therapy.
  • Patient compliance with the five-year surveillance protocol was exceptionally high, with only three patients (3.3%) deviating from scheduled monitoring.

Clinical Implications and Future Directions
The researchers emphasized that intermediate-risk patients were selected because, under conventional treatment paradigms, they would have been recommended for immediate whole-gland removal. The study suggests that 80% of men diagnosed with intermediate-risk prostate cancer may opt for focal cryotherapy over prostatectomy if given the choice, based on the effectiveness of treatment and reduced side effects.

The authors highlighted the comprehensive nature of this research, marking it as the largest prospective study of intermediate-risk prostate cancer treated with PPGCA. They reiterated the importance of rigorous follow-up and high patient compliance in ensuring accurate outcome assessment. As the study cohort matures, researchers aim to expand their evaluations to include lower-risk patients, who may not qualify for active surveillance but could benefit from less invasive alternatives to whole-gland treatment.

In conclusion, the current study demonstrated that PPGCA can effectively prevent cancer recurrence while avoiding the significant functional side effects of whole-gland removal. This study underscores the efficacy and feasibility of PPGCA as a viable alternative to prostatectomy, demonstrating very encouraging intermediate-term oncological outcomes. The high compliance rate with a rigorous surveillance protocol reinforces the potential of focal therapy in preserving quality of life while maintaining robust cancer control. Future research will focus on refining patient selection criteria and further validating long-term oncological and functional outcomes.

Five-year Oncologic Outcomes Following Primary Partial Gland Cryo-ablation Prospective Cohort Study of Men With Intermediate-risk Prostate Cancer. Lepor H, Rapoport E, Tafa M, et al. Urology. 2025 Feb;196:189-195. 

Late Breaking Abstract – 2025 ASCO GU Cancers Symposium: Talazoparib Plus Enzalutamide Improves Overall Survival in mCRPC

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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 Bicalutamide (CASODEX®), Nilutamide (NILANDRON®) and Flutamide (EULEXIN®) or with second-generation Androgen-Receptor Pathway Inhibitors (ARPIs), which include Abiraterone (ZYTIGA®), Enzalutamide (XTANDI®), Apalutamide (ERLEADA®) and Darolutamide (NUBEQA®).

For men diagnosed with metastatic Hormone-Sensitive Prostate Cancer (mHSPC), survival rates have improved with the introduction of Androgen Receptor Pathway Inhibitors (ARPIs) and chemotherapy. These therapeutic advancements, used in conjunction with androgen suppression, have demonstrated survival benefits, though patient outcomes remain highly variable. 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.

DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 genes recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HRR pathway. At least 15 genes are involved in the HRR pathway including BRCA1, BRCA2 and ATM genes. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. BRCA1 and BRCA2 are tumor suppressor genes and functional BRCA proteins repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Recently published data has shown that deleterious Germline and/or Somatic mutations in BRCA1, BRCA2, ATM, or other Homologous Recombination DNA-repair genes, are present in about 30% of patients with advanced prostate cancer, including metastatic CRPC. Patients with metastatic CRPC harboring BRCA alterations and other HRR gene alterations have poor outcomes, and earlier resistance to commonly used systemic therapies.

The PARP (Poly ADP Ribose Polymerase), family of enzymes include, PARP1and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. PARP inhibitors trap PARP onto DNA at sites of single-strand breaks, preventing their repair and generating double-strand breaks that cannot be repaired accurately in tumors harboring defects in HRR genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death. PARP inhibitors have demonstrated significant activity in patients with prostate cancer and HRR gene alterations, with the greatest clinical benefit noted in BRCA1/2 mutation carriers.

Talazoparib (TALZENNA®) is a PARP inhibitor presently approved for HRR Gene-Mutated CRPC and for Germline BRCA- mutated advanced breast cancer.

TALAPRO-2 trial is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study that enrolled 1,035 unique patients with mCRPC (who had not received new life-prolonging systemic treatments after documentation of mCRPC) at sites in the U.S., Canada, Europe, South America, and the Asia-Pacific region. The study included two patient cohorts: Cohort 1 included all comers (N=805, of whom 169 had HRR mutations and 636 did not) and Cohort 2 included those with HRR gene mutations (N=399, including 169 patients from Cohort 1 and 230 enrolled in Cohort 2). A total of 805 patients in Cohort 1 were randomized in a 1:1 ratio to receive either Talazoparib 0.5 mg daily plus Enzalutamide 160 mg daily (N=402) or placebo plus Enzalutamide (N= 403). Randomization was stratified based on HRR gene alteration status and prior Abiraterone or Docetaxel (yes/no) for castration-sensitive prostate cancer. Eligible patients had asymptomatic or mildly symptomatic mCRPC, ECOG PS 1 or less, ongoing Androgen Deprivation Therapy, and no prior life-prolonging therapy for CRPC. All patients underwent tumor tissue testing before enrollment, and approximately 20% were found to have HRR alterations. Specific gene mutations, including BRCA1, BRCA2, ATM, and CDK12, were evenly distributed across treatment arms, with BRCA1 and BRCA2 alterations found in approximately 7% of patients. The Primary endpoint of the study was radiographic Progression-Free Survival (rPFS), and Overall Survival (OS) was a key Secondary endpoint. The researchers had previously reported that TALAPRO-2 trial met its Primary endpoint, showing improved radiographic PFS for Talazoparib plus Enzalutamide compared to placebo plus Enzalutamide as first line treatment in patients with mCRPC unselected for HRR gene alterations (Cohort 1). The final OS data, updated rPFS, and extended safety follow-up in Cohort 1 was reported in this publication

The final OS analysis demonstrated a statistically significant and clinically meaningful improvement in survival for patients treated with Talazoparib plus Enzalutamide compared to Enzalutamide alone. The median OS in the Talazoparib plus Enzalutamide group was 45.8 months versus 37.0 months in the placebo arm, representing a 20% reduction in the risk of death (HR=0.796; P=0.0155). Patients with HRR-deficient tumors had a greater reduction in the risk of death (38%), with a median OS improvement of 14 months (HR=0.622; P=0.0005). The median OS with Talazoparib plus Enzalutamide was 45.1 months and 31.1 months in the placebo plus Enzalutamide group. Patients without HRR mutations still benefited from an approximate 9-month OS gain.

In patients with BRCA1/2 alterations, the median OS was not reached in the Talazoparib plus Enzalutamide group versus 28.5 months in the placebo plus Enzalutamide group (HR=0.497; P =0.0017). For those with non-BRCA1/2 HRR alterations, the median OS was 42.4 versus 32.6 months (HR=0.727; P=0.0665).

The updated rPFS data continued to favor Talazoparib plus Enzalutamide. The median rPFS was 33.1 months versus 19.5 months in the placebo arm (HR=0.667; P<0.0001). In the HRR-deficient cohort, median rPFS was 30.7 months versus 12.3 months (HR=0.468; P <0 .0001).

No new safety signals emerged with extended follow-up. The most common adverse event was anemia. Grade 3-4 anemia occurred in 49% of the unselected population and 43.4% of the HRR-deficient population. Talazoparib discontinuation due to adverse events was 21.6% in the unselected population and 13.1% in the HRR-deficient cohort. Anemia-related discontinuations were 8.5% in the unselected population and 4.5% in the HRR-deficient group.

It was concluded from this study that Talazoparib plus Enzalutamide significantly improved OS and rPFS compared to Enzalutamide alone in both HRR-deficient and non-deficient populations. The findings support the broad use of this combination as a new standard of care for treatment-naïve patients with mCRPC.

Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line treatment in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial. Agarwal N, Azad A, Carles J, et al. J Clin Oncol. 2025,43(suppl 5):LBA141. doi:10.1200/JCO.2024.42.4_suppl.LBA18.

Stockholm3 Blood Test Identifies Aggressive Prostate Cancer

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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.

PSA (Prostate Specific Antigen) is one of the most widely used prostate cancer biomarkers, and the widespread use of PSA testing in the recent years has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer. The management of clinically localized prostate cancer that is detected based on PSA levels remains controversial, and management strategies for these patients have included Surgery, Radiotherapy or Active Monitoring. However, it has been proposed that given the indolent nature of prostate cancer in general, majority of the patients do not benefit from treatment intervention and many patients die of competing causes. PSA test CANNOT distinguish between aggressive and benign cancer. As a result, many men have to undergo unnecessary follow-ups with a biopsy of the prostate. Further, treatment intervention can result in adverse effects on sexual, urinary, or bowel function. PSA test is also difficult to interpret, and PSA elevation can be associated with several non-malignant conditions such as older age, infection, inflammation and Benign Prostatic Hypertrophy. The U.S. Preventive Services Task Force (USPSTF) has recommended that population screening for prostate cancer with PSA should not be adopted as a public health policy, because the risks appeared to outweigh benefits, from detecting and treating PSA-detected prostate cancer.

Stockholm3 is a blood test that combines 5 protein biomarkers, 101 genetic markers, and clinical data with an advanced algorithm, in order to detect almost 100% of aggressive prostate cancers at an early stage. The Stockholm3 test provides an answer that can be negative or positive. A negative answer represents low or normal risk of developing prostate cancer, whereas referral to an urologist is recommended if the test is positive. The Stockholm3 test has been validated in over 75, 000 men and has been used in health systems in Sweden, Norway, Finland, Germany, Switzerland, UK and Turkey, and results have been published in international peer-reviewed journals. Evidence suggests that Stockholm3 is more effective at predicting risk than PSA testing alone, for men aged 45-74 with PSA of at least 1.5ng/ml. Several studies have shown that the application of this test can reduce the number of biopsies by 32%, without compromising the diagnostic capacity of intermediate grade prostate cancers (Gleason 7 or higher), in comparison with the use of the PSA value 3 ng/ mL as cut-off value for biopsy recommendation. However, none of the validation studies included ethnically diverse population.

SEPTA is a prospective trial conducted to validate Stockholm3 in an ethnically diverse population, for prostate cancer risk stratification, and determine whether it could achieve noninferior sensitivity and superior specificity in this diverse population. This trial included men who were referred for prostate biopsy at North American sites from 2019 to 2023. Study participants had no previous diagnosis of prostate cancer. This study also used bio-banked specimens from 2008 to 2020. The cohort comprised 912 enrolled men and 1,217 with bio-banked blood. The median age was 63 years, 46% were White, 24% Black, 16% Asian and 14% were Hispanic.

This trial had 2 prespecified Primary goals: 1) Demonstrate noninferiority of the test in detecting Clinically Significant Prostate Cancer (defined as Gleason Grade group 2 or more), compared to PSA testing. 2) Prove superior specificity of the test versus PSA testing, thereby reducing the number of biopsies in men with benign or Gleason Grade group 1 biopsies. A Secondary goal was to evaluate Stockholm3 and PSA across ethnic subgroups. The study assessed Stockholm3 performance using prespecified thresholds and compared it to PSA across different ethnic subgroups. Statistical analysis plans were established before data analysis.

It was noted that the median PSA and Stockholm3 values among the participants were 6.1 ng/mL and 17, respectively. A total of 16% underwent MRI-targeted biopsies, and 20% had a prior benign biopsy. On biopsy, 29% were diagnosed with Clinically Significant Prostate Cancer, 14% with Gleason Grade group 1 cancer, and 57% with benign findings. The detection rate for Clinically Significant Prostate Cancer varied across ethnic groups: African American/Black (37%), White/Caucasian (28%), Hispanic/Latino (29%), and Asian (21%).

Overall, Stockholm3 value 15 or higher demonstrated noninferiority to a PSA value of 4 ng/mL or higher and nearly three times superior specificity. These results were consistent across ethnic subgroups. The researchers noted that using a Stockholm3 value of 15 or higher would have reduced benign and Gleason Grade group 1 biopsies by 45% overall and between 42-52% across ethnic subgroups, compared to PSA of 4 ng/ml or higher.

The study concluded that in an ethnically diverse population, Stockholm3 could significantly reduce unnecessary biopsies and diagnoses of low-grade tumors, while maintaining similar sensitivity to PSA, for detecting Clinically Significant Prostate Cancer. The results suggest that
Stockholm3 could improve risk stratification and reduce harms associated with prostate cancer screening in diverse populations.

Stockholm3 in a Multiethnic Cohort for Prostate Cancer Detection (SEPTA): A Prospective Multicentered Trial. Vigneswaran HT, Eklund M, Discacciati A, et al. on behalf of the SEPTA STHLM3 Study Group. J Clin Oncol. 2024;42:3806-3816. DOI:10.1200/JCO.24.00152.

Late Breaking Abstract – ESMO 2024: Addition of XTANDI® to XOFIGO® Significantly Improved Survival in Metastatic Castrate Resistant Prostate cancer

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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 Bicalutamide (CASODEX®), Nilutamide (NILANDRON®) and Flutamide (EULEXIN®) or with second-generation Androgen-Receptor Pathway Inhibitors (ARPIs), which include Abiraterone (ZYTIGA®), Enzalutamide (XTANDI®), Apalutamide (ERLEADA®) and Darolutamide (NUBEQA®).

For men diagnosed with metastatic Hormone-Sensitive Prostate Cancer (mHSPC), survival rates have improved with the introduction of Androgen Receptor Pathway Inhibitors (ARPIs) and chemotherapy. These therapeutic advancements, used in conjunction with androgen suppression, have demonstrated survival benefits, though patient outcomes remain highly variable. 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.

Radium Ra 223 dichloride (XOFIGO®) is a bone seeking alpha particle emitter, and by virtue of its chemical similarity to calcium is preferentially taken up by the bone and forms complexes with bone mineral hydroxyapatite, in areas where there is increased bone turnover such as bone metastases. Ra-223 induces double stranded DNA breaks resulting in antitumor effects and has a very short range in tissues (around 2 and 10 cells), quickly losing energy, compared to beta or gamma radiation. The end result is less damage to the adjacent healthy tissues. Further, unlike its historical counterpart Ra-226 which was first isolated by Madame Curie, Ra-223 has a short half life of 11.4 days and rapidly decays, preventing significant radiation exposure. Ra-223 in a randomized, double-blind, Phase III trial (ALSYMPCA study) improved Overall Survival in patients with CRPC with bone metastases (mCRPC).

Enzalutamide is an orally administered, second-generation, anti-androgen, with no reported agonistic effects. It competitively inhibits androgens and AR binding to androgens as well as AR nuclear translocation and interaction with DNA. It thus inhibits several steps in the AR signaling pathway and was designed to overcome acquired resistance to first-generation nonsteroidal anti-androgens.

The PEACE-3 trial is a pivotal double-blind, randomized Phase III study exploring whether combining Enzalutamide with Ra-223 dichloride provides enhanced efficacy over Enzalutamide monotherapy in mCRPC with bone metastases. As a cooperative effort led by EORTC, CTI, CUOG, LACOG, and UNICANCER, the trial enrolled 426 mCRPC patients (N=426) from 12 countries between 2015 and 2023. Participants were required to have bone metastases, be asymptomatic or mildly symptomatic, and be naïve to prior treatments with Enzalutamide, Ra-223, or other specific anti-androgen therapies (Apalutamide or Darolutamide). Patients were randomized in a 1:1 to receive either Enzalutamide monotherapy (Standard of Care) at 160 mg taken orally once daily, or a combination of Enzalutamide 160 mg daily plus Ra-223 administered at 55 kBq/kg IV every four weeks, for six cycles. Patients were stratified by factors including country, baseline pain scores, prior use of Docetaxel, previous treatment with Abiraterone, and use of bone-protecting agents (which became mandatory after an early protocol amendment). The decision to require bone-protecting agents was driven by fracture rate concerns seen in the ERA-223 study, which had paired Ra-223 with Abiraterone and showed increased fracture risks without these bone-protecting agents. The median age of patients was 70 years and both treatment groups were well balanced. About 30% had received Docetaxel, with fewer than 5% previously treated with Abiraterone. About 42-44% of patients had ten or more bone lesions, and about 37% had elevated alkaline phosphatase levels, an indicator of high bone turnover. The Primary endpoint was radiological Progression-Free Survival (rPFS). Secondary endpoints include Overall Survival (OS), Time to subsequent systemic anti-neoplastic therapy, Time to pain progression, and Time to first symptomatic skeletal event. The median follow-up duration was 42.2 months.

The combination of Enzalutamide and Ra-223 showed a statistically significant improvement in rPFS. Patients in the combination arm had a median rPFS of 19.4 months, compared to 16.4 months for enzalutamide alone (HR=0.69; P=0.0009). Interim results demonstrated a 31% reduction in mortality risk in the combination arm, with median OS extending from 35 months with Enzalutamide alone to 42.3 months with the combination (HR=0.69; P=0.0031). Although nonproportional hazards were observed, necessitating a continued final OS analysis, these interim findings strongly suggest the potential survival benefit with this combination therapy.

Patients on the combination therapy had a significantly longer period before needing subsequent systemic treatments, with a 43% lower risk of starting a new therapy compared to those on Enzalutamide alone (HR=0.57; P< 0.0001). At the two-year mark, 51% of patients in the Enzalutamide-only group required additional treatments, compared to 30% in the combination group. There were no significant differences between the groups in time to pain progression or the onset of Symptomatic Skeletal Events (SSEs), which include fractures and spinal cord compression.

The combination of Enzalutamide plus Ra-223 was well tolerated, although it led to a slight increase in Grade 3 or higher adverse events (28%) compared to 19% in the Enzalutamide monotherapy group. Approximately 30% of patients in both groups experienced hypertension, though severe cases were more frequent in the combination arm. Other common side effects included fatigue and cytopenias. The safety protocol of the study was adjusted to include mandatory bone-protecting agents such as Denosumab or Zoledronate and baseline DEXA scans, contributing to fewer symptomatic skeletal events. Over 80% of patients received these agents during the trial, likely mitigating the risk of fractures and other bone-related adverse effects seen in similar trials.

It was concluded from the PEACE-3 trial that adding 6 cycles of Ra223 to Enzalutamide as first-line therapy for mCRPC patients, significantly improved radiological Progression-Free Survival. A preplanned interim analysis showed a statistically significant Overall Survival benefit favoring the Enzalutamide plus Ra-223 combination, although further analysis will address long-term survival and Quality of Life outcomes.

A randomized multicenter open label phase III trial comparing enzalutamide vs a combination of Radium-223 (Ra223) and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic castration-resistant prostate cancer (mCRPC): First results of EORTC-GUCG 1333/PEACE-3. Gillessen S, Choudhury A, Saad F, et al. Annals of Oncology, Volume 35, S1254. September 2024.

Liquid Biopsy May Predict Survival in Metastatic Prostate Cancer

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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

Radioligand Therapy before Chemotherapy in Castrate Resistant Prostate Cancer

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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.

Duration of Androgen Deprivation Therapy with Postoperative Radiotherapy for Prostate Cancer: 24 Months versus 6 Months

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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