(UroToday.com) The 2024 GU ASCO annual meeting included a prostate cancer session featuring trials in progress and a presentation by Dr. Rana McKay discussing the trial design of NePtune, a phase 2 study of neoadjuvant PARP inhibition followed by radical prostatectomy in patients with unfavorable intermediate-risk or high-risk prostate cancer with BRCA1/2 gene alterations. Patients with localized high-risk prostate cancer have an increased risk of relapse following radical prostatectomy. Approximately 6% of patients with high-risk disease harbor germline alterations in the DNA repair pathway, of which BRCA1/2 alterations are the most common. Furthermore, patients with germline BRCA1/2 mutations have higher rates of aggressive disease, distant metastases, and worse survival compared to non-carriers.
Olaparib is a PARP inhibitor which demonstrates improved overall survival in patients with metastatic castration resistant prostate cancer with BRCA1/2 germline and somatic alterations. Additionally, olaparib has demonstrated improved invasive disease-free survival as adjuvant therapy in patients with germline BRCA1/2 HER-2 negative breast cancer. Pathologic response after neoadjuvant chemotherapy in other solid tumors has been associated with improved long-term outcomes, including pathologic response correlating with biochemical progression free survival in prostate cancer. Novel, multimodal treatment strategies for patients with high-risk localized prostate cancer with germline or somatic BRCA1/2 may improve outcomes for these patients.
Dr. McKay and colleagues designed a multicenter phase 2 single arm study evaluating neoadjuvant olaparib in combination with a LHRH agonist for 6 months followed by radical prostatectomy. The NePtune trial design is as follows:
Eligible patients include those with a Gleason score ≥ 4+3 = 7, PSA >20 ng/mL or T3 disease (by DRE or prostate MRI) and lymph node <20 mm. Patients with intraductal carcinoma are eligible independent of Gleason score, PSA, or T stage. Patients must have a germline or somatic BRCA1/2 pathogenic or likely pathogenic alterations identified on standard of care molecular profiling. Eligible patients receive olaparib 300 mg twice daily and a LHRH agonist for 6 months followed by radical prostatectomy. The primary endpoint of NePtune is the rate of a pathologic complete response or minimum residual disease (tumor ≤5 mm) as determined by central pathology review.
Secondary endpoints include:
- PSA response
- Surgical staging at radical prostatectomy
- Positive margin rate
- Time to testosterone recovery
- Safety
Exploratory endpoints include:
- Quality of life assessment
- Proportion of downstaging on mpMRI
- Correlation of mpMRI with pathologic response
- Tissue based molecular predictors of response and resistance
The sample size for this trial was estimated based a Binomial Exact test to assess the null hypothesis of the pathologic complete response/minimum residual disease rate ≤10% with one-sided 5% significance level. If the observed rate from this study is ≥32.5%, to have 90% power to conclude that the pathologic complete response/minimum residual disease rate is above 10%, a total of 30 patients will be enrolled. The null hypothesis can be rejected if there are at least 7 responses.
This trial is enrolling patients through the Hoosier Cancer Research Network. The study is currently enrolling patients at the University of California San Diego, University of Pennsylvania, Johns Hopkins Hospital, and Memorial Sloan Kettering Cancer Center.
Clinical trial information: NCT05498272.
Presented by: Rana R. McKay, MD, University of California San Diego, San Diego, CA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, January 25th – January 27th, 2024
Related Content: SUO 2023: NePtune - A Phase 2 Study of Neoadjuvant PARP Inhibition followed by Radical Prostatectomy in Patients with Unfavorable Intermediate-Risk or High-Risk Prostate Cancer with BRCA1/2 Gene Alterations