Updates in prostate cancer

1- Darolutamide (Nubeqa®, Bayer Healthcare Pharmaceuticals Inc.)

Darolutamide is a recently FDA-approved treatment for metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy (ADT), based on the ARANOTE phase 3 trial showing significantly improved radiographic progression-free survival versus ADT alone. [1]

2- Lutetium-177-vipivotide tetraxetan (Pluvicto®, Novartis)

A PSMA-targeted radioligand therapy initially approved for metastatic castration-resistant prostate cancer (mCRPC) is now approved for earlier use after one androgen receptor pathway inhibitor (ARPI), showing significant reductions in the risk of progression or death in the phase III PSMAfore study.[2]

3- Precision Therapy for BRCA2 Mutations: AKEEGA®, Johnson & Johnson (niraparib + abiraterone acetate)

4- Pylarify® (piflufolastat F 18), Lantheus, second PSMA-targeted PET imaging drug

The U.S. Food and Drug Administration has approved Pylarify, a prostate-specific membrane antigen (PSMA)–targeted positron emission tomography (PET) imaging agent for men with prostate cancer. It is indicated for patients with suspected metastatic disease who are eligible for definitive therapy and for those with biochemical recurrence based on rising prostate-specific antigen levels. Pylarify improves the detection of PSMA-positive lesions that may not be visible with conventional imaging, supporting more accurate staging, earlier detection of recurrence, and better treatment planning in prostate cancer care.

Emerging Evidence and Clinical Trials

1- Expansion of Radioligand Therapy in Earlier Disease Settings

In the phase 3 PSMAfore trial (NCT04689828), lutetium-177 vipivotide tetraxetan (177Lu-PSMA-617) demonstrated significant clinical benefit in patients with prostate-specific membrane antigen (PSMA)–positive metastatic castration-resistant prostate cancer (mCRPC) who had not received prior taxane chemotherapy and whose disease had progressed after one previous androgen receptor pathway inhibitor (ARPI). A total of 468 eligible patients were randomly assigned to receive lutetium-177 vipivotide tetraxetan (7.4 Gbq intravenously every 6 weeks for six cycles) or a change in ARPI to abiraterone or enzalutamide; crossover to 177Lu-PSMA-617 was permitted after centrally confirmed radiographic progression. In the primary analysis, median radiographic progression-free survival (rPFS) was 9.30 months with 177Lu-PSMA-617 compared with 5.55 months with ARPI change (hazard ratio [HR] 0.41; p<0.0001). At the third data cutoff, with a median follow-up of approximately 24 months, rPFS remained significantly prolonged at 11.60 months versus 5.59 months (HR 0.49). More than half of patients in the control group crossed over to receive 177Lu-PSMA-617 after progression.

Importantly, patient-reported outcomes also favored 177Lu-PSMA-617. Median time to worsening in the Functional Assessment of Cancer Therapy–Prostate (FACT-P) total score was 7.46 months compared with 4.27 months in the ARPI change group (HR 0.61). Median time to worsening in the European Quality of Life Five-Dimension Five-Level (EQ-5D-5L) utility score was 6.28 months versus 3.88 months (HR 0.67), and median time to worsening in pain intensity as assessed by the Brief Pain Inventory–Short Form (BPI-SF) was 5.03 months versus 3.65 months (HR 0.72). In addition, time to first symptomatic skeletal event (SSE) was significantly delayed, with the median not reached in the 177Lu-PSMA-617 group compared with 17.97 months in the ARPI change group (HR 0.41).

The safety profile was favorable and manageable. Grade 3 to 5 treatment-emergent adverse events occurred in 36% of patients treated with 177Lu-PSMA-617, compared with 48% in the ARPI change group; grade 5 events were uncommon in both arms, and none were considered treatment-related in the radioligand therapy group. Overall, these findings support lutetium-177 vipivotide tetraxetan (177Lu-PSMA-617) as an effective and well-tolerated alternative to sequential ARPI therapy in taxane-naïve patients with PSMA-positive mCRPC, providing prolonged radiographic progression-free survival, meaningful preservation of health-related quality of life, and a delay in skeletal complications. [4, 5]

2- Addition of short-course androgen deprivation therapy (ADT) to stereotactic body radiotherapy (SBRT) in metachronous oligorecurrent hormone-sensitive prostate cancer.

The RADIOSA trial (NCT02680587) is a randomized, open-label phase II study conducted at the European Institute of Oncology that evaluates whether the addition of short-course androgen deprivation therapy (ADT) to stereotactic body radiotherapy (SBRT) improves outcomes in men with metachronous oligorecurrent hormone-sensitive prostate cancer. The trial enrolled 105 patients (102 evaluable) with histologically confirmed prostate adenocarcinoma, biochemical recurrence after radical local treatment, and up to three metastatic lesions detected on advanced imaging. Participants were randomized 1:1 to receive either SBRT alone or SBRT plus 6 months of ADT. With a median follow-up of 31 months, the combination arm demonstrated a significant improvement in median clinical progression-free survival (32.2 months vs 15.1 months; HR 0.43, p=0.001), representing a 57% reduction in the risk of clinical progression. Treatment was well tolerated, with minimal grade ≥3 toxicities and no treatment-related deaths. These findings position RADIOSA as the first randomized phase II trial in this setting to show a clinically meaningful benefit from combining metastasis-directed SBRT with short-course ADT, reinforcing the role of tailored treatment intensification while highlighting the importance of careful patient selection, as selected low-risk patients may still derive benefit from SBRT alone [6].

3- Addition of metastasis-directed therapy (MDT) to androgen deprivation therapy (ADT) in oligometastatic prostate cancer.

The EXTEND trial (NCT03599765) is a multicenter, randomized phase II study evaluating whether the addition of metastasis-directed therapy (MDT) to androgen deprivation therapy (ADT) improves outcomes in patients with oligometastatic prostate cancer. A total of 174 patients were randomized (1:1) to receive ADT alone or MDT plus ADT across two independently powered cohorts: intermittent ADT and continuous ADT.

The primary endpoint was progression-free survival (PFS), with secondary endpoints including radiologic PFS (rPFS) and castration resistance–free survival (CRFS). In the continuous ADT cohort (n=87), median PFS was 47 months with MDT + ADT versus 22 months with ADT alone. In the combined analysis of both cohorts, median PFS was 36 months versus 17 months, respectively (HR 0.45; p<0.001). Radiologic PFS and CRFS were also significantly improved with combination therapy. Translational analyses demonstrated that durable responses were associated with systemic immune activation, including upregulation of Th1-polarizing cytokines and CD8+ T-cell proliferation, with pronounced T-cell receptor expansion and contraction patterns. The greatest PFS benefit was observed in patients demonstrating systemic T-cell receptor dynamics. These results provide randomized evidence that MDT combined with ADT significantly prolongs disease survival compared with ADT alone in oligometastatic prostate cancer, supporting progression to phase III validation and future investigation of T-cell–directed immunotherapeutic strategies.[7]

4- Aggressive margin-reduction (AMR) with MRI guidance reduces 2-year acute toxic effects in localized prostate cancer

The MIRAGE trial is a phase III randomized clinical trial evaluating magnetic resonance imaging (MRI)–guided versus computed tomography (CT)–guided stereotactic body radiotherapy (SBRT) for localized prostate cancer. A prespecified secondary analysis assessed whether MRI-guided aggressive margin reduction (AMR) translates into sustained reductions in physician-scored and patient-reported toxicities at 2 years. The primary toxicity endpoint was cumulative incidence of grade ≥2 genitourinary (GU) and gastrointestinal (GI) adverse events per Common Terminology Criteria for Adverse Events v4.03. At 2-year follow-up, MRI-guided SBRT was associated with significantly lower cumulative rates of late grade ≥2 toxicity compared with CT guidance: 27% versus 51% for GU toxicity (p=0.004) and 1.4% versus 9.5% for GI toxicity (p=0.025). Patient-reported outcomes demonstrated significantly lower odds of clinically meaningful deterioration in bowel function, as measured by the Expanded Prostate Cancer Index Composite-26 (OR 0.444; p=0.035), and in sexual function, as measured by the Sexual Health Inventory for Men (OR 0.366; p=0.03). No significant differences were observed in other quality-of-life domains. These results provide phase III evidence that MRI-guided SBRT with aggressive margin reduction offers durable reductions in treatment-related toxicity over 2 years, supporting MRI guidance as a strategy to optimize the therapeutic ratio in prostate SBRT. [8]

New outcomes of therapeutics

1- Musculoskeletal and connective tissue disorders were the most common serious adverse events in Abiraterone acetate in mCRPC

A recent individual patient data meta-analysis of 14 randomized phase 2 and 3 trials (4,296 patients) provides an updated look at the safety of Abiraterone acetate in metastatic castration-resistant prostate cancer (mCRPC). Nearly all patients experienced at least one adverse event, but serious adverse events (grade 3–5) were less frequent with abiraterone (64.1%) compared with standard of care (71.8%), and overall odds of adverse events were lower in the abiraterone group. The most common toxicities included musculoskeletal disorders, anemia, back pain, hypertension, fatigue, hypokalemia, and bone pain. Notably, older patients had a 22% lower risk of serious musculoskeletal events, suggesting no excess age-related safety signal. While these findings support the favorable safety of abiraterone in clinical trial populations, further more prospective data are needed—particularly regarding fractures and neuromuscular toxicities—to better define risks in broader patient populations. [9]

2- PSA Response and Survival Outcomes with Enzalutamide in mHSPC

The phase 3 ARCHES trial (NCT02677896) evaluated the prognostic impact of PSA levels in 1,150 men with metastatic hormone-sensitive prostate cancer (mHSPC) treated with Enzalutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT. Across PSA subgroups at enrollment (0.2–4 ng/mL and >4 ng/mL), enzalutamide plus ADT significantly improved radiographic progression-free survival (rPFS), with hazard ratios of 0.32 and 0.44, respectively. Most notably, patients achieving undetectable PSA (<0.2 ng/mL) during treatment experienced an 86% reduction in risk of radiographic progression (HR 0.14; P < .001) and a 76% reduction in risk of death (HR 0.24; P < .001). These findings reinforce the benefit of enzalutamide plus ADT regardless of baseline PSA and highlight undetectable PSA as a strong prognostic marker, while underscoring the need for further research on treatment intensification strategies for patients who do not achieve deep PSA responses [10].

Updates in prostate cancer