(UroToday.com) The 2024 American Society of Clinical Oncology (ASCO) Annual Meeting held in Chicago, IL was host to a prostate, testicular, and penile cancers trials in progress poster session. Dr. Rana McKay presented NePtune, a phase II trial of neoadjuvant PARP inhibition followed by radical prostatectomy in patients with unfavorable intermediate- or high-risk prostate cancer with BRCA1/2 gene alterations.
Patients with high-risk, localized 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.1 Patients with germline BRCA1/2 mutations have higher rates of aggressive disease, distant metastases, and worse survival, compared to non-carriers.
Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor that improves overall survival in metastatic castration resistant prostate cancer (mCRPC) patients with BRCA1/2 germline and somatic alterations.2 Additionally, olaparib has demonstrated improved invasive disease-free survival as adjuvant therapy in patients with germline BRCA1/2 HER-2 negative breast cancer.
Neoadjuvant therapy has been demonstrated to improve survival in multiple solid organ tumors, and pathologic response in other solid tumors has been associated with improved long-term outcomes, including prostate cancer whereby improved pathologic responses have been correlated with superior biochemical progression-free survival outcomes. Novel, multimodal treatment strategies for patients with high-risk localized prostate cancer with germline or somatic BRCA1/2 alterations may improve outcomes for these patients.
NePtune is an investigator-initiated, phase II, multi-center, open-label, single-arm trial.
A total of 32 subjects with localized prostate cancer with germline or somatic BRCA1/2 alterations found on standard of care chemiluminescence immunoassay (CLIA)-based testing will be enrolled. Eligible patients will receive treatment with an LHRH analogue plus olaparib for six months followed by radical prostatectomy. Post-radical prostatectomy treatments are at the discretion of the treating physician.
The key inclusion criteria are as follows:
- Histological or cytological evidence of prostate adenocarcinoma
- Patient must have either Gleason score ≥ 4+3=7, PSA >20 ng/mL or T3 disease [by digital rectal exam or multi-parametric MRI (mpMRI)] and lymph node <20 mm on CT/MRI.
- Patients must have M0 disease on CT/MRI and bone scan.
- 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.
The key exclusion criteria are as follows:
- Small cell or neuroendocrine component.
- Prior local treatment for prostate cancer.
- Prior LHRH analogue (though patients may have initiated therapy no more than 4 weeks prior to enrollment.
The primary study endpoint is the proportion of pathologic complete response (pCR) or minimal residual disease (MRD; i.e., tumor ≤5 mm), as determined by central pathology review. The key secondary endpoints include:
- PSA response
- Surgical staging at radical prostatectomy
- Positive margin rate
- Time to testosterone recovery
- Safety.
Exploratory Endpoints will 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 target sample size is 32 patients. The sample size was estimated based a Binomial Exact test to assess the null hypothesis of the pCR/MRD rate ≤10% with a one-sided 5% significance level.
If the observed rate from this study is ≥32.5%, then this study will have 90% power to conclude that the pCR/MRD rate is above 10% and a total of 30 patients will be enrolled. The investigators can reject the null hypothesis if there are ≥7 responses.
Presented by: Rana McKay, MD, Associate Professor, Department of Medicine, University of California, San Diego, CA
Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, May 31 – Tues, June 4, 2024.
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