Advanced penile squamous cell carcinoma (PSCC) is a lethal and rare cancer that affects 2,000 American men and 35,000 men worldwide yearly. Regional lymph node involvement level and tumor burden remain the strongest predictors of survival for patients with PSCC. Patients who present with bulky regional or pelvic PSCC metastasis are at an increased risk of disease related mortality with surgery alone and are best treated using multimodal approaches with neoadjuvant chemotherapy followed by inguinal and pelvic lymph node dissection. This approach for patients with bulky or fixed, or bilateral inguinal lymphadenopathy typically is the preferred strategy as recommended by the NCCN and the EAU guidelines.

Neoadjuvant chemotherapy allows for timely delivery of systemic chemotherapy, results in potential volume reduction for enlarged lymphadenopathies, provides prognostic information and may facilitate subsequent surgical consolidation. The trial that established the approach of neoadjuvant chemotherapy followed by surgery as the standard of care is a prospective, single-center, nonrandomized phase 2 clinical trial by Pagliaro et al. ¹ This study's objective was determining the response rate, time to progression (TTP) and overall survival (OS) of patients with bulky adenopathy who were receiving neoadjuvant chemotherapy with paclitaxel 175 mg/m ² administered through 3 hours on day 1, ifosfamide 1,200 mg/m ² on days 1 to 3, and cisplatin 25 mg/m ² on days 1 to 3 every 3 weeks (TIP) with the goal of completing a total of 4 cycles before proceeding with consolidation surgery.

The study reported that 15 patients (50.0%) had an objective response with 3 pathological complete response rate (pCRs; 10%) and 12 PRs, and 22 patients (73.3%) subsequently underwent consolidation surgery via bilateral inguinal lymph node dissections and unilateral or bilateral pelvic lymph node dissections. The estimated median TTP was only 8.1 months (95% CI 5.4–50 months) and median OS was 17.1 months (95% CI 10.3–60 months). ¹ Nevertheless, this study had major limitations that are inherent to a single-arm Bayesian trial with a small patient sample. Therefore, our group conducted a meta-analysis that included 10 studies evaluating a total of 182 patients who received preoperative chemotherapy with 66 (36.3%) and 116 (63.7%) treated with nontaxane platinum and taxane platinum regimens, respectively. The pooled results demonstrated an objective similar response rate of 53% (95% CI 42–64) and pathological complete response rate of 16%. ²

It was not possible to conduct randomized controlled trials in penile cancer to answer the basic management questions before the design of the International Penile Advanced Cancer Trial (InPACT). InPACT is a 200-patient trial that has 2 independent randomizations to answer 2 main questions, the first being the role of neoadjuvant therapy before standard surgery by randomizing to chemotherapy, chemoradiotherapy or no neoadjuvant therapy. This will answer whether there is any benefit for neoadjuvant chemotherapy or chemoradiation. The second question is on the role of prophylactic pelvic lymph node dissection following the standard surgery with therapeutic inguinal lymph node dissection in patients with high pathological risk factors after receiving chemoradiotherapy. In addition, an immense need still exists for innovative clinical trials in the neoadjuvant setting to improve on the current accepted standard of care chemotherapy regimen.

As for patients with relapsed or refractory PSCC after neoadjuvant chemotherapy, they have a dismal prognosis and have very limited benefit from second line cytotoxic systemic therapy. Every effort should be made to enroll these patients with relapsed disease in clinical trials as there is a need to explore biologically driven targeted therapies and immune therapies for patients with relapsed PSCC. Recent data from a phase II clinical showing that dacomintinib, a second-generation panHER tyrosine kinase inhibitor in 28 chemotherapy-naïve patients with locally advanced or metastatic PSCC, had clinical benefit with the ORR was 32.1%; median PFS of 4.1 months and OS of 13.7 months. The treatment was relatively well-tolerated with only 10% grade 3-4 skin rash as the major toxicity. ³

On the other hand, immunotherapy trials using single-agent immune checkpoint inhibitors have been limited by slow trial enrollment and limited single-agent clinical activity, and most of those studies are using single-agent immune checkpoint blockade in a population with all solid tumors. ⁴ Preliminary investigations into the immune milieu of PSCC have demonstrated reduced mutation burden and lack of microsatellite instability, and PSCC appears to be an immunologically cold tumor. As we have shown, a recent study in a mouse model of PSCC also confirmed an immunosuppressive tumor microenvironment and the importance of other regulators of immune activity in PSCC tumors. ⁵

The current clinical trial landscape lacks immunotherapy combinatory trials in the neoadjuvant treatment setting and platinum refractory setting for penile cancer patients. Preclinical PSCC models should continue to be optimized and used to identify the optimal therapeutic combinations to be tested in clinical trials. International efforts and initiatives like the Global Society of Rare GU Tumors and the International Rare Cancer Initiative, which are both solely dedicated to improving the care for rare genitourinary malignancies such as penile cancer through cutting edge research, education and patient advocacy, offer unique opportunities to improve the care in this often undeserved patient population.