Tag: Prostate Cancer

Late Breaking Abstract – ASCO 2026: Perioperative Apalutamide Plus ADT in High-Risk Localized and Locally Advanced 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 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 333,830 new cases of prostate cancer will be diagnosed in 2026 and 36,320 men will die of the disease. Androgen Deprivation Therapy (ADT) or testosterone suppression has been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention.

Background
Patients with high-risk localized prostate cancer and locally advanced prostate cancer remain at substantial risk for recurrence following definitive local therapy. Radical prostatectomy with pelvic lymph node dissection is a potentially curative treatment option. However, disease recurrence occurs in up to 50% of patients within five years of surgery. Long-term outcomes remain suboptimal despite advances in surgical techniques and patient selection.

The use of neoadjuvant systemic therapy before surgery is established in several solid tumors, but previous studies evaluating neoadjuvant approaches in prostate cancer have not resulted in changes to clinical practice. Earlier trials were limited by heterogeneous patient populations, including lower-risk disease, and by reliance on endpoints such as Prostate-Specific antigen (PSA) response rather than long-term oncologic outcomes.

Phase 2 studies investigating Androgen Receptor Pathway Inhibitors in the neoadjuvant setting demonstrated reductions in residual tumor burden and increased rates of pathological response, providing the rationale for larger randomized studies. Apalutamide (ERLEADA®) 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.

The Phase 3 PROTEUS trial was designed to determine whether perioperative treatment with Apalutamide plus Androgen Deprivation Therapy (ADT) could improve pathological and long-term clinical outcomes in patients with high-risk localized or locally advanced prostate cancer undergoing radical prostatectomy.

Study Design and Patient Population

PROTEUS was a Phase 3, randomized, double-blind, placebo-controlled trial that enrolled patients with newly diagnosed high-risk localized or locally advanced prostate cancer.

A total of 2,109 patients were randomized in a 1:1 ratio to receive either:

  • Apalutamide 240 mg daily plus ADT (N=1,057), or
  • Placebo plus ADT (N=1,052)

Treatment was administered for six 28-day cycles before surgery, followed by radical prostatectomy with pelvic lymph node dissection. After surgery, patients received an additional six cycles of their assigned treatment. A two-week treatment break was incorporated before surgery, followed by a four-week break after surgery before treatment resumed.

Eligible patients had high-risk localized or locally advanced disease based on histologic and clinical criteria, including PSA level and nodal status assessed by conventional imaging. The median age of enrolled patients was 66 years, and 95.8% had a Gleason score of 8 or higher. The median follow-up was 61.7 months.

Study Endpoints

The trial had two Primary endpoints:

  • Pathological Complete Response (pCR) or minimal residual disease, defined as pathological Stage ypT2 or lower with residual tumor measuring no more than 5 mm in greatest dimension.
  • Metastasis-Free Survival (MFS), assessed by Blinded Independent Central Review using conventional imaging and/or Prostate-Specific Membrane Antigen Positron Emission Tomography (PSMA PET).

Secondary endpoints included:

  • Event-Free Survival (EFS)
  • Time to first subsequent treatment
  • Time to distant metastasis
  • Safety

Exploratory analyses included assessment of residual cancer burden and investigator-assessed Metastasis-Free Survival.

Primary Endpoint: Pathological Response

The addition of Apalutamide to ADT resulted in higher rates of pathological Complete Response or minimal residual disease at the time of surgery.

Pathological Complete Response or minimal residual disease was achieved in 8.9% of patients receiving Apalutamide plus ADT versus 1.0% of patients receiving placebo plus ADT. This corresponded to an odds ratio of 10.17 (95% CI, 5.27–19.64; P<0.0001).

These findings indicate a substantially greater proportion of patients had limited or no residual tumor identified in the surgical specimen following neoadjuvant treatment with Apalutamide plus ADT.

Primary Endpoint: Metastasis-Free Survival (MFS)

The Second Primary endpoint, Metastasis-Free Survival, was also met.

Treatment with Apalutamide plus ADT was associated with a reduction in the risk of distant metastasis or death compared with placebo plus ADT (Hazard ratio: 0.80; 95% CI: 0.67–0.96; P=0.0169). At five years, MFS rates were 78.2% in the Apalutamide group and 73.5% in the placebo group. Median MFS was not reached in either treatment arm. Investigator-assessed MFS showed similar results, with a Hazard Ratio of 0.74 (95% CI, 0.62–0.87).

Secondary Efficacy Endpoints

All key secondary efficacy endpoints favored the Apalutamide-containing regimen.

Event-Free Survival (EFS) was prolonged with Apalutamide plus ADT (Hazard ratio: 0.71; 95% CI: 0.63–0.80; P<0.0001). Median EFS was 57.1 months with Apalutamide plus ADT versus 38.4 months with placebo plus ADT

The addition of Apalutamide delayed the need for additional local, regional, or systemic therapy, including re-initiation of ADT (Hazard Ratio: 0.65; 95% CI: 0.57–0.73; P<0.0001). Median time to first subsequent treatment was 74.2 months in the Apalutamide arm and 41.5 months in the placebo arm.

Time to distant metastasis also favored Apalutamide plus ADT (Hazard Ratio: 0.68; 95% CI: 0.55–0.83; P=0.0002). Median time to distant metastasis was not reached in either treatment group.

Residual Cancer Burden Analysis

Exploratory analyses evaluating residual cancer burden also demonstrated lower residual disease following treatment with Apalutamide. Minimal residual disease based on residual cancer burden criteria was observed in 30.6% of patients receiving Apalutamide plus ADT versus 11.7% of patients receiving placebo plus ADT. The odds ratio was 3.36 (95% CI, 2.67–4.23; P<0.0001). These findings support the association between intensified Androgen Receptor Pathway Inhibition and reduction in residual tumor burden at surgery.

Role of PSMA PET Imaging

PROTEUS incorporated both conventional imaging and PSMA PET imaging in the assessment of Metastasis-Free Survival. The inclusion of PSMA PET reflects changes in prostate cancer staging and recurrence assessment during the conduct of the trial. PSMA PET has greater sensitivity than conventional imaging, particularly at low PSA levels, and is increasingly incorporated into routine clinical practice. The study authors noted that increasing use of PSMA PET may influence assessment of disease recurrence and should be considered in future clinical trial designs evaluating localized prostate cancer.

Safety

The safety profile of Apalutamide plus ADT was consistent with previous studies of Apalutamide. Grade 3 or 4 treatment-emergent adverse events occurred in 39.6% of patients receiving apalutamide plus ADT and 31.0% of patients receiving placebo plus ADT. The difference was primarily attributable to a higher incidence of rash in the Apalutamide arm. Treatment discontinuation due to adverse events occurred in 7.4% of patients receiving Apalutamide and 2.7% of patients receiving placebo. No new safety signals were identified during the study.

Clinical Implications

PROTEUS is the first Phase 3 trial to demonstrate improvements in both pathological response and Metastasis-Free Survival with perioperative Androgen Receptor Pathway Inhibition in patients undergoing radical prostatectomy for high-risk localized or locally advanced prostate cancer.

Treatment with Apalutamide plus ADT before and after surgery resulted in higher rates of pathological Complete Response or minimal residual disease, improved Metastasis-Free Survival, prolonged Event-Free Survival, delayed need for subsequent treatment, and longer time to distant metastasis compared with ADT alone.

These findings provide evidence supporting perioperative treatment intensification with Apalutamide plus ADT in patients with high-risk localized or locally advanced prostate cancer who are candidates for radical prostatectomy.

Perioperative (neoadjuvant and adjuvant) apalutamide (APA) + androgen deprivation therapy (ADT) vs placebo (PBO) + ADT with radical prostatectomy (RP) in high-risk localized or locally advanced prostate cancer (HR LPC/LAPC): Final analysis of the PROTEUS phase 3 study. Mary-Ellen Taplin M-E, Gleave M, Shore ND, et al. J Clin Oncol 44, 2026 (suppl 17; abstr LBA1)

Final Overall Survival Results from the EMBARK trial: Practice-Changing Evidence in High-Risk Biochemical Recurrence

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SUMMARY: 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 333,830 new cases of Prostate cancer will be diagnosed in 2026 and 36,320 men will die of the disease. Androgen Deprivation Therapy (ADT) or testosterone suppression has 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 (XTANDI®) is a potent oral Androgen Receptor Pathway Inhibitor with demonstrated efficacy in patients with both localized and advanced prostate cancer.

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 IM 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. Secondary end points included MFS in the Enzalutamide monotherapy group, as compared with the Leuprolide-alone group, Overall Survival (OS), 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% with Leuprolide alone (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 Leuprolide alone among patients with biochemically recurrent prostate cancer. At the time of this analysis, Overall Survival data were immature.

In this publication, the final Overall Survival (OS) analysis of the Phase 3 EMBARK trial provided compelling long-term evidence supporting intensified Androgen-Receptor Pathway Inhibition in patients with high-risk biochemical recurrence of prostate cancer and no evidence of metastasis on conventional imaging. At the time of this final analysis, 277 deaths had occurred: 73 in the combination arm, 111 in the Leuprolide-alone arm, and 93 in the Enzalutamide monotherapy arm. Median follow-up exceeded 93 months across all treatment groups, offering a robust long-term perspective on survival outcomes.

Overall Survival: Durable and Clinically Meaningful Benefit

The combination of Enzalutamide plus Leuprolide demonstrated a statistically and clinically significant improvement in OS compared with Leuprolide alone:

  • 8-year OS:
    • 78.9% (95% CI, 73.9–83.1) with combination therapy
    • 69.5% (95% CI, 64.0–74.3) with Leuprolide alone
  • Hazard ratio for death: 0.60 (95% CI, 0.44–0.80; P<0.001)

This 40% relative reduction in mortality risk translates into an absolute improvement of nearly 10% at 8 years, a notable achievement in a population historically managed with Androgen Deprivation Therapy (ADT) alone.

By contrast, Enzalutamide monotherapy did not significantly improve OS relative to Leuprolide alone:

  • 8-year OS: 73.1% (95% CI, 67.6–77.9)
  • Hazard ratio: 0.83 (95% CI, 0.63–1.10; P=0.19)

While monotherapy previously demonstrated improvements in key Secondary endpoints, including Metastasis-Free Survival, it did not confer a statistically significant survival advantage in this final OS analysis.

Descriptive updates of Secondary endpoints were consistent with earlier reports. Time to first use of new antineoplastic therapy and time to first symptomatic skeletal event continued to favor combination therapy.

Although fractures were numerically more frequent in the combination arm, this reflected a broader category of bone and joint injuries. Importantly, the time to first symptomatic skeletal event was prolonged with Enzalutamide plus Leuprolide compared with Leuprolide alone, suggesting lower clinically meaningful skeletal morbidity despite the higher overall reporting of fractures.

Safety Profile: No New Signals

The long-term safety data remained consistent with earlier analyses. No new safety signals emerged, and the adverse-event profile of Enzalutamide, whether used in combination or as monotherapy, aligned with prior experience in metastatic castration-resistant and metastatic castration-sensitive prostate cancer settings.

Clinical Context: Imaging Evolution and Treatment Implications

Interpretation of these results must consider the evolving imaging landscape. At the time of trial enrollment, staging relied on CT or MRI for soft-tissue assessment and radionuclide bone scans for osseous disease. With the increasing use of PSMA PET imaging, it is likely that a proportion of patients categorized as nonmetastatic in the trial may have harbored occult locoregional or oligometastatic disease detectable by more sensitive modalities. Nevertheless, the study reflects real-world practice standards at the time and provides a pragmatic framework for treatment decision-making in high-risk biochemical recurrence.

Treatment Suspension Strategy: A Unique Feature

An important protocol component was treatment suspension at week 37 for patients achieving undetectable PSA (<0.2 ng/mL), with reinitiation upon PSA rise to predefined thresholds. This strategy aimed to mitigate toxicity and preserve quality of life. Notably, the OS benefit of combination therapy was achieved despite these mandated treatment interruptions.

Future research should clarify:

  • Which patients may safely undergo treatment suspension,
  • Whether continuous therapy could further optimize outcomes in select populations,
  • And how molecular imaging findings should inform early intensification strategies.

Positioning in the Treatment Paradigm

The final OS data reinforce earlier MFS findings and establish Enzalutamide plus ADT as a preferred standard of care for patients with Castration-Sensitive Prostate Cancer and high-risk biochemical recurrence without conventional radiographic metastases.

Although Enzalutamide monotherapy remains a reasonable option, particularly for patients prioritizing preservation of sexual function based on patient-reported outcomes, shared decision-making remains essential, balancing efficacy, toxicity, and quality-of-life considerations.

Conclusion

With nearly eight years of follow-up, the EMBARK trial confirms that intensification of Androgen-Receptor Pathway Inhibition with Enzalutamide plus Leuprolide delivers a durable Overall Survival advantage in high-risk biochemical recurrence. These findings extend the survival benefits observed with Enzalutamide across earlier disease states and further reshape management strategies in this evolving therapeutic space.

Improved Survival with Enzalutamide in Biochemically Recurrent Prostate Cancer. Shore ND, Luz MA, Giorgi UD, et al. N Engl J Med 2026;394:563-575.

Final Overall Survival Results from the EMBARK trial: Practice-Changing Evidence in High-Risk Biochemical Recurrence

RR

SUMMARY: 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 333,830 new cases of Prostate cancer will be diagnosed in 2026 and 36,320 men will die of the disease. Androgen Deprivation Therapy (ADT) or testosterone suppression has 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 (XTANDI®) is a potent oral Androgen Receptor Pathway Inhibitor with demonstrated efficacy in patients with both localized and advanced prostate cancer.

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 IM 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. Secondary end points included MFS in the Enzalutamide monotherapy group, as compared with the Leuprolide-alone group, Overall Survival (OS), 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% with Leuprolide alone (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 Leuprolide alone among patients with biochemically recurrent prostate cancer. At the time of this analysis, Overall Survival data were immature.

In this publication, the final Overall Survival (OS) analysis of the Phase 3 EMBARK trial provided compelling long-term evidence supporting intensified Androgen-Receptor Pathway Inhibition in patients with high-risk biochemical recurrence of prostate cancer and no evidence of metastasis on conventional imaging. At the time of this final analysis, 277 deaths had occurred: 73 in the combination arm, 111 in the Leuprolide-alone arm, and 93 in the Enzalutamide monotherapy arm. Median follow-up exceeded 93 months across all treatment groups, offering a robust long-term perspective on survival outcomes.

Overall Survival: Durable and Clinically Meaningful Benefit

The combination of Enzalutamide plus Leuprolide demonstrated a statistically and clinically significant improvement in OS compared with Leuprolide alone:

  • 8-year OS:
    • 78.9% (95% CI, 73.9–83.1) with combination therapy
    • 69.5% (95% CI, 64.0–74.3) with Leuprolide alone
  • Hazard ratio for death: 0.60 (95% CI, 0.44–0.80; P<0.001)

This 40% relative reduction in mortality risk translates into an absolute improvement of nearly 10% at 8 years, a notable achievement in a population historically managed with Androgen Deprivation Therapy (ADT) alone.

By contrast, Enzalutamide monotherapy did not significantly improve OS relative to Leuprolide alone:

  • 8-year OS: 73.1% (95% CI, 67.6–77.9)
  • Hazard ratio: 0.83 (95% CI, 0.63–1.10; P=0.19)

While monotherapy previously demonstrated improvements in key Secondary endpoints, including Metastasis-Free Survival, it did not confer a statistically significant survival advantage in this final OS analysis.

Descriptive updates of Secondary endpoints were consistent with earlier reports. Time to first use of new antineoplastic therapy and time to first symptomatic skeletal event continued to favor combination therapy.

Although fractures were numerically more frequent in the combination arm, this reflected a broader category of bone and joint injuries. Importantly, the time to first symptomatic skeletal event was prolonged with Enzalutamide plus Leuprolide compared with Leuprolide alone, suggesting lower clinically meaningful skeletal morbidity despite the higher overall reporting of fractures.

Safety Profile: No New Signals

The long-term safety data remained consistent with earlier analyses. No new safety signals emerged, and the adverse-event profile of Enzalutamide, whether used in combination or as monotherapy, aligned with prior experience in metastatic castration-resistant and metastatic castration-sensitive prostate cancer settings.

Clinical Context: Imaging Evolution and Treatment Implications

Interpretation of these results must consider the evolving imaging landscape. At the time of trial enrollment, staging relied on CT or MRI for soft-tissue assessment and radionuclide bone scans for osseous disease. With the increasing use of PSMA PET imaging, it is likely that a proportion of patients categorized as nonmetastatic in the trial may have harbored occult locoregional or oligometastatic disease detectable by more sensitive modalities. Nevertheless, the study reflects real-world practice standards at the time and provides a pragmatic framework for treatment decision-making in high-risk biochemical recurrence.

Treatment Suspension Strategy: A Unique Feature

An important protocol component was treatment suspension at week 37 for patients achieving undetectable PSA (<0.2 ng/mL), with reinitiation upon PSA rise to predefined thresholds. This strategy aimed to mitigate toxicity and preserve quality of life. Notably, the OS benefit of combination therapy was achieved despite these mandated treatment interruptions.

Future research should clarify:

  • Which patients may safely undergo treatment suspension,
  • Whether continuous therapy could further optimize outcomes in select populations,
  • And how molecular imaging findings should inform early intensification strategies.

Positioning in the Treatment Paradigm

The final OS data reinforce earlier MFS findings and establish Enzalutamide plus ADT as a preferred standard of care for patients with Castration-Sensitive Prostate Cancer and high-risk biochemical recurrence without conventional radiographic metastases.

Although Enzalutamide monotherapy remains a reasonable option, particularly for patients prioritizing preservation of sexual function based on patient-reported outcomes, shared decision-making remains essential, balancing efficacy, toxicity, and quality-of-life considerations.

Conclusion

With nearly eight years of follow-up, the EMBARK trial confirms that intensification of Androgen-Receptor Pathway Inhibition with Enzalutamide plus Leuprolide delivers a durable Overall Survival advantage in high-risk biochemical recurrence. These findings extend the survival benefits observed with Enzalutamide across earlier disease states and further reshape management strategies in this evolving therapeutic space.

Improved Survival with Enzalutamide in Biochemically Recurrent Prostate Cancer. Shore ND, Luz MA, Giorgi UD, et al. N Engl J Med 2026;394:563-575.

FDA Approves Niraparib with Abiraterone Acetate plus Prednisone for BRCA2-Mutated mCSPC

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SUMMARY: The FDA on December 12, 2025, approved Niraparib and Abiraterone acetate (AKEEGA&reg;) with prednisone for adults with deleterious or suspected deleterious BRCA2-mutated (BRCA2m) metastatic Castration-Sensitive Prostate Cancer (mCSPC), as determined by an FDA-approved test.

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.

Metastatic Castration-Sensitive Prostate Cancer (mCSPC) is a heterogeneous disease. Despite therapeutic advances, outcomes vary significantly based on underlying tumor biology. Approximately 25% of patients with mCSPC harbor Homologous Recombination Repair (HRR) gene mutations, including BRCA1, BRCA2, CHEK2, CDK12, PALB2, and others. Among these, BRCA1/2 mutations account for nearly half of HRR alterations and are particularly associated with aggressive disease biology, resistance to Androgen Receptor Pathway Inhibitors (ARPIs), and shortened Progression-Free and Overall Survival. The integration of AR-pathway inhibitors such as Abiraterone Acetate plus Prednisone into first-line treatment has meaningfully improved outcomes in the general mCSPC population. However, patients with HRR mutations, especially those with BRCA1/2, derive significantly less benefit from these agents alone, highlighting a substantial unmet clinical need.

Rationale for PARP Inhibition in HRR-Altered Prostate Cancer
Cancer cells with HRR deficiencies are vulnerable to PARP (Poly ADP-Ribose Polymerase) inhibition, which blocks DNA repair pathways and induces synthetic lethality. Prior landmark trials, MAGNITUDE (Niraparib with Abiraterone Acetate plus Prednisone) and TALAPRO-2 (Talazoparib  plus Enzalutamide), demonstrated the value of combining PARP inhibitors with ARPIs in Castration-Resistant Prostate Cancer (mCRPC) with HRR mutations. However, whether such a combination could offer meaningful benefit earlier in the disease course, in the castration-sensitive setting, remained unknown, until now.

AMPLITUDE Trial Design and Methods

Study Overview
The AMPLITUDE trial (NCT04497844) is a global, Phase 3, randomized, double-blind, placebo-controlled trial designed to evaluate whether combining the PARP inhibitor Niraparib with Abiraterone Acetate plus Prednisone improves clinical outcomes in patients with mCSPC (metastatic Castration-Sensitive Prostate Cancer) and HRR gene alterations.

Patient Population

  • Total enrolled: 696 men with mCSPC and at least one HRR gene mutation (germline or somatic)
  • Mutation profile: BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, PALB2, RAD51B, RAD54L
  • BRCA1/2 prevalence: 55.6% of enrolled patients
  • Metastatic disease burden: 78% were high-volume M1disease, 87% had de novo M1disease and 16% had prior therapy with Docetaxel.
  • Prior therapies allowed:
    • 6 months or less of Androgen Deprivation Therapy (ADT)
    • 6 cycles or less of Docetaxel
    • 45 days or less of prior Abiraterone and Prednisone

Randomization and Treatment Arms

Patients were randomized 1:1 to:

  • Experimental arm: Niraparib 200 mg once daily plus Abiraterone acetate 1000 mg daily and Prednisone 5 mg daily (N=348)
  • Control arm: Placebo plus Abiraterone acetate 1000 mg along with Prednisone 5 mg daily (N=348)
    All patients continued on ADT.

Endpoints

  • Primary: Radiographic Progression-Free Survival (rPFS), assessed by investigator
  • Secondary: Time to Symptomatic Progression (TSP), Overall Survival (OS), Safety/tolerability

Key Results and Interpretation

Efficacy Outcomes

Radiographic Progression-Free Survival (Primary Endpoint)

  • Median rPFS:
    • Niraparib plus Abiraterone and Prednisone: Not reached
    • Abiraterone and Prednisone alone: 5 months (95% CI, 25.8–NR)
  • Hazard ratio: 0.63 (P=0.0001)
  • BRCA1/2 subgroup: HR =0.52 (P<0.0001)

This translates into a 37% relative risk reduction in progression or death in the overall population, and a 48% reduction in the BRCA1/2 subgroup, indicating a clear therapeutic effect in genetically defined populations.

Time to Symptomatic Progression

  • HR (overall): 0.50 (P<0.0001)
  • BRCA1/2 subgroup: HR 0.44 (P=0.0001)

This is clinically meaningful, and delaying symptom onset can preserve quality of life and extend time before additional therapies are needed.

Overall Survival (Interim Analysis)

  • HR (overall): 0.79 (95% CI, 0.59–1.04; P=0.10)
  • BRCA1/2 subgroup: HR 0.75 (95% CI, 0.51–1.11; P=0.15)

In an exploratory analysis of 323 patients with BRCA2 mutations, the rPFS Hazard Ratio (HR) was 0.46 (95% CI: 0.32, 0.66) with median rPFS not estimable for Niraparib and Abiraterone acetate with prednisone compared with 26 months (95% CI: 18, 28) for placebo and Abiraterone acetate with prednisone.

In an exploratory analysis in 373 patients with non-BRCA2 mutations, the HR for rPFS was 0.88 (95% CI: 0.63, 1.24), indicating that the overall improvement was primarily attributed to the results seen in patients with BRCA2 mutations.

Although OS data are not yet mature, the trend suggests a potential survival benefit with longer follow-up.

Safety Profile
The safety of Niraparib plus Abiraterone and Prednisone was consistent with known profiles of both agents. Grade 3-4 AEs in the Niraparib plus Abiraterone and Prednisone was 75.2% versus 58.9% with Abiraterone and Prednisone alone, with the most common higher Grade 3-4 AEs  noted in the Niraparib plus Abiraterone and Prednisone group (Anemia: 29.1% vs 4.6% and Hypertension: 26.5% vs 18.4%). The discontinuation rates due to AEs in the Niraparib plus Abiraterone and Prednisone group was 11.0% vs 6.9% in the Abiraterone and Prednisone group. These AEs were manageable with appropriate monitoring. No new safety signals were identified.

Conclusion
The AMPLITUDE trial marks a milestone and provides robust evidence to support Niraparib plus Abiraterone and Prednisone as a new first-line option in mCSPC patients with BRCA1/2 or other HRR gene mutations. By demonstrating that Niraparib plus Abiraterone and Prednisone improves Progression-Free outcomes in HRR-altered mCSPC, especially those with BRCA mutations, it paves the way for a more personalized, biology-driven approach to therapy in this setting. Ongoing follow-up will determine whether this translates into improved survival, but the current data already support Niraparib plus Abiraterone and Prednisone as a new treatment benchmark for this high-risk subgroup.

Phase 3 AMPLITUDE trial: Niraparib (NIRA) and abiraterone acetate plus prednisone (AAP) for metastatic castration-sensitive prostate cancer (mCSPC) patients (pts) with alterations in homologous recombination repair (HRR) genes. Attard G, Agarwal N, Graff J, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA5006)

 

Late Breaking Abstract – ESMO 2025: Early Radioligand Intensification in mHSPC: Key Findings from the Phase III PSMAddition Trial

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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.

Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) remains a challenging disease state, even with modern intensification strategies. Androgen-Deprivation Therapy (ADT) combined with an Androgen Receptor Pathway Inhibitor (ARPI) is a widely adopted standard of care. Yet many patients continue to progress and long-term disease control remains elusive.

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. The emergence of PSMA-targeted radioligand therapy validated in metastatic Castration-Resistant Prostate Cancer (mCRPC) through the VISION and PSMAfore studies, has prompted investigation of earlier integration.

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 Phase III PSMAddition trial represents the first randomized effort to evaluate a targeted radionuclide therapy in the hormone-sensitive setting.

Study Design and Patient Population

PSMAddition enrolled 1,144 men with treatment-naïve or minimally treated (≤45 days of hormonal therapy) mHSPC. All patients had PSMA-positive metastatic disease confirmed by 68Ga-PSMA-11 PET/CT, defined as at least one lesion with uptake exceeding liver activity. Participants were randomized 1:1 to:

  • Experimental arm: 177Lu-PSMA-617 (7.4 GBq every 6 weeks for up to six cycles) + ADT + an ARPI of physician’s choice
  • Control arm: ADT + ARPI alone, with crossover to 177Lu-PSMA-617 permitted upon centrally confirmed radiographic progression

Baseline characteristics were well balanced. Half had de novo metastatic disease and more than two-thirds had high-volume disease by conventional imaging criteria. Abiraterone was the most commonly selected ARPI, followed by Apalutamide and Enzalutamide. In the experimental arm, treatment adherence was high, with 86% completing all six cycles.

This report reflects the second interim analysis for radiographic Progression-Free Survival (rPFS; data maturity 74%) and the first interim analysis for Overall Survival (OS; data maturity 47%) after a median follow-up of 23.6 months.

Efficacy Outcomes

Radiographic Progression-Free Survival: Primary Endpoint Achieved

The addition of 177Lu-PSMA-617 significantly prolonged rPFS compared with ADT + ARPI alone (HR 0.72; P=0.002). Median rPFS has not been reached in either arm. Importantly, benefit was observed across all predefined subgroups, including high- vs low-volume disease, de novo vs recurrent mHSPC, as well as varying ARPI backbones. These findings confirmed that PSMA-targeted radioligand therapy can improve disease control even in the presence of potent systemic hormonal intensification.

Early Overall Survival Trends

Although OS data are immature, there is a favorable trend for early 177Lu-PSMA-617 (HR 0.84). As nearly 60% of progressing control-arm patients crossed over to 177Lu-PSMA-617, subsequent analyses may be confounded, potentially attenuating the ability to detect an OS difference with further follow-up.

Secondary Efficacy Measures

Across all Secondary endpoints, outcomes favored the 177Lu-PSMA-617 arm:

  • ORR: 85% vs 81%
    • Complete responses: 57% vs 42%
  • PSA endpoints:
    • PSA <0.2 ng/mL rates at multiple prespecified time points were higher in the experimental arm
    • PSA progression significantly delayed (HR 0.42)
  • Time to mCRPC: HR 0.70
  • Investigator-assessed PFS: HR 0.64
  • Time to symptomatic skeletal events: Comparable between arms, but favored 177Lu-PSMA-617 numerically

Collectively, these findings indicate deeper and more durable disease responses with early radioligand therapy.

Safety and Tolerability

Overall toxicity was higher with the addition of 177Lu-PSMA-617 but consistent with the known safety profile of radioligand therapy. Common all-grade adverse events (experimental arm) included dry mouth (46%), fatigue (35%), nausea (34%), Hot flashes (29%) and anemia (27%). Grade ≥3 cytopenias occurred more often with 177Lu-PSMA-617 (14% vs 5%), though most were low grade and manageable. Importantly, no treatment-related deaths were reported. Despite higher toxicity rates, Quality-of-Life measures including FACT-P and EQ-5D were not adversely impacted, and time to worsening pain was similar between arms.

Clinical Implications

PSMAddition provides the first Phase III evidence supporting integration of PSMA-targeted radioligand therapy into initial systemic treatment for PSMA-positive mHSPC. While rPFS and multiple disease-control endpoints clearly favor the triplet approach, questions remain regarding long-term survival benefit, patient selection, and optimal treatment duration. Additional biomarker-driven analyses and longer follow-up will be critical in defining how broadly early LuPSMA-617 should be adopted in routine practice.

Phase 3 trial of [177Lu]Lu-PSMA-617 combined with ADT + ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition). Tagawa ST, Sartor O, Piulats JM, et al. Presented at: European Society for Medical Oncology (ESMO) Congress. October 17-21, 2025. Berlin, Germany. Abstract LBA6

ERSPC Final Analysis: Long-Term PSA Screening Reduces Prostate Cancer Deaths

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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. Prostate cancer remains one of the most pressing global cancer burdens, with mortality rates projected to double by 2040 as populations age and life expectancy increases.

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 question of how and in whom to implement early detection strategies, continues to challenge clinicians and public health systems. The European Randomized Study of Screening for Prostate Cancer (ERSPC), initiated in 1993, represents the most comprehensive effort to evaluate whether population-based Prostate-Specific Antigen (PSA) screening reduces prostate cancer mortality. Now, with more than two decades of follow-up completed for over 160,000 men, the ERSPC provides its final unified analysis, offering critical insights into both the enduring benefits and ongoing challenges of PSA-based screening.

Study Overview and Screening Approach

The ERSPC spanned eight European countries and included a predefined core cohort of men aged 55–69 years at randomization. Participants were assigned to organized repeated PSA screening or to usual care without screening invitations. Screening protocols varied modestly by country, but all centers relied on standardized PSA assays and risk-based biopsy thresholds. Most participants received screening every four years, although the interval ranged from two to seven years. The Primary outcome was prostate cancer mortality.

  • Population: 162,236 men (55–69 yrs)
    • Screening group: 72,888
    • Control group: 89,348
  • Screening Protocol: Repeated PSA, 2–8 invitations, biopsies for elevated PSA
  • Follow-Up: Median 23 years
  • Outcomes:
    • Relative reduction in prostate cancer death: 13%
    • Absolute risk reduction: 0.22%

Key Points for Clinical Practice:

Three decades after its inception, the ERSPC provides unequivocal evidence that PSA-based screening reduces prostate cancer mortality. However, it also highlights that how screening is implemented may matter, as much as whether it is implemented at all.

  • PSA-based screening reduces prostate cancer mortality by ~13% over 23 years; absolute benefit continues to rise with long-term follow-up.
  • Overdiagnosis and overtreatment remain central harms. Risk-adapted strategies (MRI, biomarkers, active surveillance) mitigate these risks.
  • Screening should ideally start at age 50 for maximal benefit and continue based on life expectancy rather than age alone.
  • Modern guidelines support selective biopsy only in patients with high-risk features and conservative management/active surveillance for low-risk disease, to optimize the harm–benefit ratio.
  • Individualized decision-making and cessation of screening is essential, particularly for older men or those with competing health risks.

Such strategies aim to preserve the mortality benefit demonstrated in ERSPC while minimizing harms associated with overdiagnosis and overtreatment.

Conclusion

The final unified analysis of the ERSPC confirms that PSA screening offers a sustained reduction in prostate cancer mortality that becomes more pronounced over long-term follow-up. While screening continues to carry risks, particularly through detection of indolent disease, its harm–benefit balance has improved with time and can be further optimized through modern, risk-adapted approaches. As prostate cancer incidence continues to rise worldwide, these data provide essential guidance for developing screening policies that maximize benefit, reduce harm, and ensure evidence-based care for patients at risk.

European Study of Prostate Cancer Screening-23-Year Follow-up. Roobol MJ, de Vos II, Månsson M, et al for the ERSPC Investigators. N Engl J Med 2025;393:1669-1680.

Late Breaking Abstract – ASCO 2025: AMPLITUDE Trial: Defining a New Treatment Paradigm in HRR-Altered mCSPC

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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.

Metastatic Castration-Sensitive Prostate Cancer (mCSPC) is a heterogeneous disease. Despite therapeutic advances, outcomes vary significantly based on underlying tumor biology. Approximately 25% of patients with mCSPC harbor Homologous Recombination Repair (HRR) gene mutations, including BRCA1, BRCA2, CHEK2, CDK12, PALB2, and others. Among these, BRCA1/2 mutations account for nearly half of HRR alterations and are particularly associated with aggressive disease biology, resistance to Androgen Receptor Pathway Inhibitors (ARPIs), and shortened Progression-Free and Overall Survival. The integration of AR-pathway inhibitors such as Abiraterone Acetate plus Prednisone into first-line treatment has meaningfully improved outcomes in the general mCSPC population. However, patients with HRR mutations, especially those with BRCA1/2, derive significantly less benefit from these agents alone, highlighting a substantial unmet clinical need.

Rationale for PARP Inhibition in HRR-Altered Prostate Cancer
Cancer cells with HRR deficiencies are vulnerable to PARP (Poly ADP-Ribose Polymerase) inhibition, which blocks DNA repair pathways and induces synthetic lethality. Prior landmark trials, MAGNITUDE (Niraparib with Abiraterone Acetate plus Prednisone) and TALAPRO-2 (Talazoparib  plus Enzalutamide), demonstrated the value of combining PARP inhibitors with ARPIs in Castration-Resistant Prostate Cancer (mCRPC) with HRR mutations. However, whether such a combination could offer meaningful benefit earlier in the disease course, in the castration-sensitive setting, remained unknown, until now.

AMPLITUDE Trial Design and Methods

Study Overview
The AMPLITUDE trial (NCT04497844) is a global, Phase 3, randomized, double-blind, placebo-controlled trial designed to evaluate whether combining the PARP inhibitor Niraparib with Abiraterone Acetate plus Prednisone improves clinical outcomes in patients with mCSPC (metastatic Castration-Sensitive Prostate Cancer) and HRR gene alterations.

Patient Population

  • Total enrolled: 696 men with mCSPC and at least one HRR gene mutation (germline or somatic)
  • Mutation profile: BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, PALB2, RAD51B, RAD54L
  • BRCA1/2 prevalence: 55.6% of enrolled patients
  • Metastatic disease burden: 78% were high-volume M1disease, 87% had de novo M1disease and 16% had prior therapy with Docetaxel.
  • Prior therapies allowed:
    • 6 months or less of Androgen Deprivation Therapy (ADT)
    • 6 cycles or less of Docetaxel
    • 45 days or less of prior Abiraterone and Prednisone

Randomization and Treatment Arms

Patients were randomized 1:1 to:

  • Experimental arm: Niraparib 200 mg once daily plus Abiraterone acetate 1000 mg daily and Prednisone 5 mg daily (N=348)
  • Control arm: Placebo plus Abiraterone acetate 1000 mg along with Prednisone 5 mg daily (N=348)
    All patients continued on ADT.

Endpoints

  • Primary: Radiographic Progression-Free Survival (rPFS), assessed by investigator
  • Secondary: Time to Symptomatic Progression (TSP), Overall Survival (OS), Safety/tolerability

Key Results and Interpretation

Efficacy Outcomes

Radiographic Progression-Free Survival (Primary Endpoint)

  • Median rPFS:
    • Niraparib plus Abiraterone and Prednisone: Not reached
    • Abiraterone and Prednisone alone: 5 months (95% CI, 25.8–NR)
  • Hazard ratio: 0.63 (P=0.0001)
  • BRCA1/2 subgroup: HR =0.52 (P<0.0001)

This translates into a 37% relative risk reduction in progression or death in the overall population, and a 48% reduction in the BRCA1/2 subgroup, indicating a clear therapeutic effect in genetically defined populations.

Time to Symptomatic Progression

  • HR (overall): 0.50 (P<0.0001)
  • BRCA1/2 subgroup: HR 0.44 (P=0.0001)

This is clinically meaningful, and delaying symptom onset can preserve quality of life and extend time before additional therapies are needed.

Overall Survival (Interim Analysis)

  • HR (overall): 0.79 (95% CI, 0.59–1.04; P=0.10)
  • BRCA1/2 subgroup: HR 0.75 (95% CI, 0.51–1.11; P=0.15)

Although OS data are not yet mature, the trend suggests a potential survival benefit with longer follow-up.

Safety Profile
The safety of Niraparib plus Abiraterone and Prednisone was consistent with known profiles of both agents. Grade 3-4 AEs in the Niraparib plus Abiraterone and Prednisone was 75.2% versus 58.9% with Abiraterone and Prednisone alone, with the most common higher Grade 3-4 AEs  noted in the Niraparib plus Abiraterone and Prednisone group (Anemia: 29.1% vs 4.6% and Hypertension: 26.5% vs 18.4%). The discontinuation rates due to AEs in the Niraparib plus Abiraterone and Prednisone group was 11.0% vs 6.9% in the Abiraterone and Prednisone group. These AEs were manageable with appropriate monitoring. No new safety signals were identified.

Conclusion
The AMPLITUDE trial marks a milestone and provides robust evidence to support Niraparib plus Abiraterone and Prednisone as a new first-line option in mCSPC patients with BRCA1/2 or other HRR gene mutations. By demonstrating that Niraparib plus Abiraterone and Prednisone improves Progression-Free outcomes in HRR-altered mCSPC, especially those with BRCA mutations, it paves the way for a more personalized, biology-driven approach to therapy in this setting. Ongoing follow-up will determine whether this translates into improved survival, but the current data already support Niraparib plus Abiraterone and Prednisone as a new treatment benchmark for this high-risk subgroup.

Phase 3 AMPLITUDE trial: Niraparib (NIRA) and abiraterone acetate plus prednisone (AAP) for metastatic castration-sensitive prostate cancer (mCSPC) patients (pts) with alterations in homologous recombination repair (HRR) genes. Attard G, Agarwal N, Graff J, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA5006)