Darolutamide Maintenance in Patients With Metastatic Castration-Resistant Prostate Cancer With Nonprogressive Disease After Taxane Treatment (SAKK 08/16).

PURPOSE: To assess the efficacy and safety of darolutamide maintenance after successful taxane chemotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Swiss Group for Clinical Cancer Research (SAKK) 08/16 is a randomized phase II study. Patients with mCRPC who received prior androgen-receptor pathway inhibitors (ARPIs) and subsequently had nonprogressive disease on a taxane were randomly assigned to darolutamide 600 mg twice a day or placebo twice a day. The primary end point was radiographic progression-free survival (rPFS) at 12 weeks. Secondary end points were rPFS, event-free survival, overall survival (OS), prostate-specific antigen (PSA) 50% response rate, and adverse events. RESULTS: Overall, 92 patients were recruited by 26 centers. Prior taxane was docetaxel in 93% and cabazitaxel in 7%. Prior ARPI was abiraterone in 60%, enzalutamide in 31%, and both in 9%. rPFS at 12 weeks was significantly improved with darolutamide (64.7% v 52.2%; P = .127). Median rPFS on darolutamide was 5.5 versus 4.5 months on placebo (hazard ratio [HR], 0.54 [95% CI, 0.32 to 0.91]; P = .017), and median event-free survival was 5.4 versus 2.9 months (HR, 0.46 [95% CI, 0.29 to 0.73]; P = .001). PSA 50% response rate was improved (22% v 4%; P = .014). Median OS for darolutamide was 24 versus 21.3 months for placebo (HR, 0.62 [95% CI, 0.3 to 1.26]; P = .181). Treatment-related adverse events were similar in both arms. CONCLUSION: SAKK 08/16 met its primary end point, showing that switch maintenance with darolutamide after prior taxane chemotherapy and at least one ARPI resulted in a statistically significant but clinically modest rPFS prolongation with good tolerability. The median OS with darolutamide maintenance appears promising. Should these findings be confirmed in a larger trial, maintenance treatment could be a novel strategy in managing patients with mCRPC, especially those who responded well to prior ARPI.

A Phase 1/2 Single-arm Clinical Trial of Recombinant Bacillus Calmette-Guérin (BCG) VPM1002BC Immunotherapy in Non-muscle-invasive Bladder Cancer Recurrence After Conventional BCG Therapy: SAKK 06/14.

BACKGROUND: VPM1002BC is a genetically modified Mycobacterium bovis bacillus Calmette-Guérin (BCG) strain with potentially improved immunogenicity and attenuation. OBJECTIVE: To report on the efficacy, safety, tolerability and quality of life of intravesical VPM1002BC for the treatment of non-muscle-invasive bladder cancer (NMIBC) recurrence after conventional BCG therapy. DESIGN, SETTING, AND PARTICIPANTS: We designed a phase 1/2 single-arm trial (NCT02371447). Patients with recurrent NMIBC after BCG induction ± BCG maintenance therapy and intermediate to high risk for cancer progression were eligible. INTERVENTION: Patients were scheduled for standard treatment of six weekly instillations with VPM1002BC followed by maintenance for 1 yr. Treatment was stopped in cases of recurrence. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was defined as the recurrence-free rate (RFR) in the bladder 60 wk after trial registration. The sample size was calculated based on the assumption that ≥30% of the patients would be without recurrence at 60 wk after registration. RESULTS AND LIMITATIONS: After exclusion of two ineligible patients, 40 patients remained in the full analysis set. All treated tumours were of high grade and 27 patients (67.5%) presented with carcinoma in situ. The recurrence-free rate in the bladder at 60 wk after trial registration was 49.3% (95% confidence interval [CI] 32.1-64.4%) and remained at 47.4% (95% CI 30.4-62.6%] at 2 yr and 43.7% (95% CI 26.9-59.4%) at 3 yr after trial registration. At the same time, progression to muscle-invasive disease had occurred in three patients and metastatic disease in four patients. Treatment-related grade 1, 2, and 3 adverse events (AEs) were observed in 14.3%, 54.8%, and 4.8% of the patients, respectively. No grade ≥4 AEs occurred. Two of the 42 patients did not tolerate five or more instillations during induction. Limitations include the single-arm trial design and the low number of patients for subgroup analysis. CONCLUSIONS: At 1 yr after treatment start, almost half of the patients remained recurrence-free after therapy with VPM100BC. The primary endpoint of the study was met and the therapy is safe and well tolerated. PATIENT SUMMARY: We conducted a trial of VPM100BC, a genetically modified bacillus Calmette-Guérin (BCG) strain for treatment of bladder cancer not invading the bladder muscle. At 1 year after the start of treatment, almost half of the patients with a recurrence after previous conventional BCG were free from non-muscle-invasive bladder cancer (NMIBC). The results are encouraging and VPM1002BC merits further evaluation in randomised studies for patients with NMIBC.

An open-label, noncomparative phase II trial to evaluate the efficacy and safety of docetaxel in combination with gefitinib in patients with hormone-refractory metastatic prostate cancer.

BACKGROUND: Prostate cancer is the most common type of cancer in men, however, therapeutic options are limited. 50-90% of hormone-refractory prostate cancer cells show an overexpression of epidermal growth factor receptor (EGFR), which may contribute to uncontrolled proliferation and resistance to chemotherapy. In vitro, gefitinib, an orally administered tyrosine kinase inhibitor, has shown a significant increase in antitumor activity when combined with chemotherapy. PATIENTS AND METHODS: In this phase II study, the safety and efficacy of gefitinib in combination with docetaxel, a chemotherapeutic agent commonly used for prostate cancer, was investigated in patients with hormone-refractory prostate cancer (HRPC). 37 patients with HRPC were treated continuously with gefitinib 250 mg once daily and docetaxel 35 mg/m2 i.v. for up to 6 cycles. PSA response, defined as a =50% decrease in serum PSA compared with trial entry, was the primary efficacy parameter. PSA levels were measured at prescribed intervals. RESULTS: The response rate and duration of response were consistent with those seen with docetaxel monotherapy. The combination of docetaxel and gefitinib was reasonably well tolerated in this study. CONCLUSION: Future studies should investigate whether patients with specific tumor characteristics, e.g. EGFR protein overexpression, respond better to gefitinib than patients without, leading to a more customized therapy option.

Gefitinib ('Iressa', ZD1839) is active against brain metastases in a 77 year old patient.

This report highlights the case of a symptomatic 77-year-old non-smoking female patient who was diagnosed with advanced non-small-cell lung cancer (NSCLC), metastatic to the liver and contralateral lung. After tumor progression in the liver and lung following polychemotherapy, multiple diffuse brain and cerebellar metastases were apparent. Oral treatment with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa') 250 mg/day resulted in progressive and durable symptom relief, and improvements in quality of life and performance status. Reductions in the size of the primary pulmonary tumor and brain, cerebellar, and liver metastases were observed. Furthermore, gefitinib was well tolerated with an absence of adverse events. These results provide evidence that oral gefitinib is active in patients with advanced NSCLC and central nervous system metastases.