Although rare in high-income countries such as the US and Europe, penile cancer is 10 times more common in Africa, Asia, and Latin America. Current treatment options for advanced disease are limited, with chemotherapy rarely extending survival beyond 1 year and often causing significant toxicities.

A phase 2 HERCULES trial in Brazil found that combining pembrolizumab with platinum-based chemotherapy achieved a 39.4% objective response rate and a median overall survival of 9.6 months, surpassing historic outcomes with chemotherapy alone. Treatment-related toxicity was manageable, and no deaths were reported.

“Penile cancer is often related to hygiene issues,” said Murilo de Almeida Luz, MD, one of the authors of the study from Hospital Erasto Gaertner, Curitiba, Brazil, and faculty in urology at the Icahn School of Medicine at Mount Sinai, New York City. Speaking with Medscape’s Portuguese edition, he added, “Patients struggle to maintain personal hygiene and general health, which complicates care and treatment.”

According to him, “Although it’s not a very common neoplasm, around 1500 penile amputations are still performed each year in Brazil. There was an urgent need to bring some new hope to advanced disease, as we hadn’t had any new treatments for this condition for a long time.”

HERCULES Findings

The trial enrolled 37 patients from 11 Brazilian centers between 2020 and 2022. A total of 33 patients were included in the efficacy analysis: 24 with metastatic disease, eight with recurrent tumors, and five with locally advanced disease. The treatment comprised intravenous (IV) fluorouracil 1000 mg/m²/d on days 1-4, IV cisplatin 70 mg/m² (or carboplatin AUC 5) on day 1, and IV pembrolizumab 200 mg on day 1 every 3 weeks for six cycles, followed by 200 mg every 3 weeks for up to 34 cycles.

The median duration of response was 5.9 months, median progression-free survival was 5.4 months, and median overall survival was 9.6 months. The estimated 2-year overall survival rate was 19.4%. The most common adverse events were anemia and nausea, each occurring in 43.2% of patients. Exploratory biomarker analysis revealed higher response rates in human papillomavirus (HPV)-positive patients (55.6%) and those with a high tumor mutation burden (75%). PD-L1 expression alone did not predict the response to treatment. “The response rate of almost 40% is much higher than what we saw with chemotherapy alone,” Luz said. He added, “It is a finding that brings hope to patients who previously had very few options, and it should certainly change clinical practice. We believe this combination will become common practice in the future.”

Globally, the adoption of immunotherapy for rare tumors requires flexible regulatory pathways. Europe relies on conditional approvals, adaptive pathways, early access programs, and managed access agreements to expedite availability. Reports from the Organisation for Economic Co-operation and Development — an international body that monitors and compares economic and health policies across its 38 member countries — reported that many nations are adopting similar strategies to reduce delays in access.

In England, the Cancer Drugs Fund provides temporary coverage under managed access agreements to collect real-world data. France and Germany have broadened access to high-cost biologics through biosimilars while maintaining their comparable efficacy and safety.

“Brazil could adopt similar strategies to expand access, including biosimilars and public-private partnerships,” said Pedro Luiz Serrano Uson Junior, MD, the study’s lead author from the Center for Personalized Medicine, Einstein Hospital Israelita, Sao Paulo, Brazil. Speaking with Medscape’s Portuguese edition, he added, “This would improve cost-effectiveness and equity in access to new therapies.”

Brazilian Context

Triple chemotherapy regimens — such as paclitaxel, ifosfamide, and cisplatin or docetaxel, cisplatin, and fluorouracil — have historically shown response rates of 30%-50% but with high toxicity and treatment-related mortality.

More recently, the EPIC-A study, which assessed cemiplimab combined with chemotherapy in 29 patients, achieved a 44.8% response rate, consistent with that of the HERCULES trial.

Although Brazil is emerging as a scientific leader, it faces significant challenges in accessing pembrolizumab.

A national survey in Brazil reviewing 1288 opinions from the Center for Technical Support of the Judiciary between 2019 and 2024 on pembrolizumab found that one third of requests were denied, largely because of missing diagnostic documentation or technical errors in submissions.

“The current scenario of inequity is abysmal. Although pembrolizumab has 36 indications approved by Anvisa [Brazil’s National Health Surveillance Agency], only one is incorporated by Conitec [the National Commission for the Incorporation of Technologies into the Unified Health System], and even that does not guarantee that patients can receive the drug. Approval is not the same as access,” Uson said. He emphasized that judicial processes are often required to secure treatment and delay the provision of care.

The exploratory analysis of HERCULES showed that HPV-positive patients showed the greatest benefit, consistent with previous studies that indicated higher lymphocyte infiltration and tumor immunogenicity. A high tumor mutation burden was also associated with an improved response, confirming the findings from independent cohorts. In contrast, PD-1 ligand PD-L1 expression did not clearly predict response, highlighting the limitations of this biomarker as a standalone predictor of PD-1/PD-L1 blockade.

This study highlights the gap between scientific progress in Brazil and patient access to therapy. Luz described HERCULES as offering “hope” and the potential to shape “future common practice.” However, Uson noted persistent inequities: “Even with a favourable opinion from Conitec, patients often cannot access the drug because its cost exceeds the limits of Sistema Único de Saúde (SUS) funding.” These barriers continue to limit the real-world impact of scientific advances on patients who are most likely to benefit.

Next Steps

HERCULES was a single-arm, nonrandomized study. The global adoption of immunotherapy plus chemotherapy as the standard of care will require international randomized multicenter trials. Given the rarity of penile cancer, broad collaboration and robust funding are essential for future research.

The phase 2 HERCULES trial demonstrated Brazil’s leadership in research on neglected tumors, with persistent barriers to pembrolizumab access in routine care settings. Together, these studies highlight a gap between scientific innovation and patient access, and closing this gap is vital to delivering real benefits.

This story was translated from Medscape’s Portuguese edition.