Hormone-Sensitive Prostate Cancer
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Data from a subgroup analysis of the phase 3 ARANOTE trial (NCT04736199) demonstrate that darolutamide (Nubeqa) and androgen deprivation therapy (ADT) was associated with an improvement in radiographic progression-free survival (rPFS) and other efficacy end points vs placebo plus ADT in Black patients with metastatic hormone-sensitive prostate cancer/

2025 American Urological Association Annual Meeting

In ARANOTE, patients starting on ADT were randomly assigned 2:1 to receive darolutamide 600 mg daily or placebo. The primary end point was rPFS. Time to metastatic castration-resistant prostate cancer, time to prostate-specific antigen (PSA) progression, proportion of patients reaching a PSA level lower than 0.2 ng/mL at any time, time to initiation of subsequent anticancer therapy, and safety were secondary end points.

ARANOTE included 669 patients, of whom 65 were Black. Forty-one of these patients received darolutamide and 24 received placebo. The investigators reported that the baseline characteristics were “similar between treatment arms and generally consistent with the overall ARANOTE population, except Black patients had higher median baseline PSA levels (99.6 ng/mL vs 21.3 ng/mL) and a greater proportion had high-volume mHSPC (78.5% vs 70.6%),” the investigators wrote in their poster.

“With regards to our substudy that encompassed the Black population, it's very important to understand that we had about 10% of the ARANOTE population that self-identified as Black," lead study author Quoc-Dien Trinh, MD, MBA, said. "We know that representation of minorities in clinical trials is a problem in general, but specifically in the space of metastatic prostate cancer, so these results are definitely interesting. What we found was that Black patients do relatively well from an efficacy standpoint and from a safety standpoint with ADT plus darolutamide.” Trinh is the chair of urology at the University of Pittsburgh School of Medicine and chair of urology at the University of Pittsburgh in Pennsylvania.

The investigators reported that treatment with darolutamide reduced the risk of radiological progression or death by 49% in Black men. Regarding the primary end point of rPFS, the HR for Black patients was 0.51 compared with 0.57 in the overall ARANOTE cohort.

“[Regarding] PSA suppression to less than 0.2 ng/mL, we found that nearly 60% of Black men achieved suppression with ADT plus darolutamide vs less than 20% on the ADT alone arm, so a three-fold difference,” Trinh said.

Regarding safety, the investigators reported that treatment-emergent adverse event incidence was similar between the treatment groups for Black patients and was similar to what was seen in the overall ARANOTE population. In addition, the median duration of treatment in Black patients was 22.6 months in the darolutamide group vs 17.3 months in the placebo group.

Discussing the significance of the substudy, Trinh commented, “I think this is a very important study, but also a very important type of analysis to conduct, whether it's ARANOTE or any other study, which is to look at subpopulations; in this case, Black men. We know that Black men are more likely to develop prostate cancer, but also to die from prostate cancer. So it is very reassuring to know that in this subpopulation, the outcomes and the efficacy of this drug were certainly similar, and [there was] perhaps some signal that it could be even more beneficial. That, in itself, is very interesting. The other very important thing is that we know there is a lot of real-world evidence suggesting that underserved populations are less likely to get the latest therapies, sometimes more likely to get ADT alone, and sometimes the conversations and the things we may hear pertains to the fact that perhaps intensification leads to potentially more [adverse events], and assessing the safety of this drug in this population is very important, and the findings, again, were very reassuring. So the message to clinicians and to patients is that treatment intensification with darolutamide is certainly something that should be strongly considered in light of our substudy.”

Trinh Q-D, George DJ, Shore N, et al. Efficacy and safety of darolutamide plus androgen-deprivation therapy in Black patients with metastatic hormone-sensitive prostate cancer from the phase 3 ARANOTE trial. 

 2025;213(5S):e578. doi:10.1097/01.JU.0001109908.15997.76.01

Articles

The phase 3 ARANOTE trial demonstrated that darolutamide combined with androgen deprivation therapy (ADT) significantly improved radiographic progression-free survival (rPFS) and other efficacy endpoints in Black patients with metastatic hormone-sensitive prostate cancer compared to placebo plus ADT. The study included 65 Black patients, with 41 receiving darolutamide. Results showed a 49% reduction in the risk of radiological progression or death. Nearly 60% of Black men achieved PSA suppression with darolutamide, compared to less than 20% with ADT alone. Safety profiles were consistent across treatment groups.

Darolutamide plus ADT improved rPFS in Black patients with metastatic hormone-sensitive prostate cancer treated in ARANOTE.

Subgroup Data From ARANOTE Highlight rPFS Benefit of Darolutamide Plus ADT in Black Patients With mHSPC

Treatment with pembrolizumab (Keytruda) plus platinum-based therapy elicited safe and efficacious outcomes in patients with penile squamous cell carcinoma (PSCC), according to data from the single-arm phase 2 HERCULES trial (NCT04224740) presented at the 

Fernando Cotait Maluf, MD, of Hospital Beneficência Portuguesa de São Paulo and Hospital Israelita Albert Einstein, São Paulo, Brazil, presented the data at the meeting in Chicago, Illinois. In his presentation, Maluf noted that PSCC has up to a 10 times higher incidence in low-income countries in Africa, Asia, and Latin America.

 He added that advanced PSCC is a disease for which no improvements have been made of late, and prognosis is poor, with an overall survival (OS) of approximately 6 to 7 months.

“Platinum-based chemotherapy has been considered the standard of care…Immune checkpoint inhibitors have been associated with efficacy in different tumor types, including HPV16-positive tumors, such as cervical and head and neck squamous cell carcinoma,”

Maluf and his coauthors hypothesized that the addition of pembrolizumab to platinum-based chemotherapy for first-line treatment of advanced penile cancer would be safe and associated with improved outcomes for patients.

Eligible patients were required to have an ECOG Performance Status of 0-1, have metastatic (de novo or recurrent) disease, locally advanced disease (TanyN3M0 or T4NanyM0) that is not amenable to curative-intent therapy, loco-regional recurrence that is not amenable to curative-intent therapy, and no prior exposure to chemotherapy for advanced disease; however, prior neoadjuvant chemotherapy was allowed if disease progressed after 12 months.

Patients received cisplatin 70 mg/m2 or carboplatin AUC 5 D1 plus 5-FU 1000 mg/m

/day D1-D4 plus pembrolizumab 200 mg IV Q3W for 6 cycles. This was followed by maintenance pembrolizumab 200 mg IV Q3W for up to 34 cycles. The primary outcome was confirmed overall response rate (ORR) (RECIST 1.1) per investigator assessment. Secondary end points included confirmed ORR by central review, progression-free survival (PFS), OS, safety, and translational research analysis.

A total of 37 patients were included in the study, of whom 5 (13.5%) had locally advanced disease and 8 (21.6%) had loco-regional recurrence. Thirty-three patients were eligible for efficacy analysis. Confirmed ORR by investigator was 39.4% (95% CI, 22.9%-57.9%). Of these, 1 was a complete response (3.0%) and 12 (36.4%) were partial responses. Confirmed ORR by central review was 42.4% (95% CI, 25.5%-60.8%). Clinical benefit rate by investigator over 24 weeks was 45.5% (95% CI, 28.1%-63.7%).

Maluf reported that tumor shrinkage of any magnitude was seen in 75.8% of patients. After a median follow-up of 24 months, median duration of response was 5.9 months (95% CI, 4.4-9.0), and median time to response was 1.4 months (95% CI, 1.3-1.8). Median PFS was 5.4 months (95% CI, 2.7-7.2), and median OS was 9.6 months (95% CI, 6.4-13.2).

“Our biomarker exploratory analysis showed a potential correlation between response with TMB as well as HPV16 status,” Maluf reported.

Regarding treatment-related adverse events (AEs), Maluf reported 19 AEs (51.4%) of grade 3 or higher, and noted that only 6 patients (16.2%) experienced neutropenia. Two (5.4%) immune-related AEs of grade 3 or higher were observed.

“The HERCULES trial is the first trial to demonstrate the efficacy of immune checkpoint inhibitors in [patients with] advanced penile cancer with [a] manageable safety profile. We are proud to say that pembrolizumab plus platinum-based therapy is a new treatment option for [patients with] advanced penile cancer,” Maluf said in his concluding remarks.

1. Maluf FC, Trindade K, Almeida Preto DD, et al. A phase II trial of pembrolizumab plus platinum-based chemotherapy as first-line systemic therapy in advanced penile cancer: HERCULES (LACOG 0218) trial. Presented at: 2024 American Society of Clinical Oncology Annual Meeting. May 31-June 4, 2024. Chicago, Illinois. Abstract 5009. https://meetings.asco.org/abstracts-presentations/234520

2. Coelho RWP, Pinho JD, Moreno JS, et al. Penile cancer in Maranhão, Northeast Brazil: the highest incidence globally? 

 2018;18(1):50. doi:10.1186/s12894-018-0365-0

3. Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. 

 2019;394(10212):1915-1928. doi:10.1016/S0140-6736(19)32591-7

4. Colombo N, Dubot C, Lorusso D, et al. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. 

 2021;385(20):1856-1867. doi:10.1056/NEJMoa2112435

Pembrolizumab and platinum-based therapy elicited safe and efficacious outcomes in penile squamous cell carcinoma.

Benjiman Saylor

Articles

Subgroup Data From ARANOTE Highlight rPFS Benefit of Darolutamide Plus ADT in Black Patients With mHSPC

Pembrolizumab With Platinum-Based Therapy is Safe and Efficacious in PSCC