Sahu Kamal Kant, Li Haoran, Mathew Thomas Vinay, Benson Mallory, Boucher Ken, Gupta Sumati, Kohli Manish, Swami Umang, Agarwal Neeraj, Maughan Benjamin L
Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Division of Medical Oncology, Department of Internal Medicine, University of Kansas Cancer Center, Westwood, KS, USA.
Oncologist. 2024 May 3;29(5):450-e725. doi: 10.1093/oncolo/oyae030.
Both germline and somatic BReast CAncer gene (BRCA) mutations are poor prognostic markers in men with localized or metastatic prostate cancer. For instance, men with these mutations often are diagnosed with prostate cancer earlier and develop metastatic disease earlier compared with those who do not harbor similar mutations. Patients with germline alterations typically have more advanced disease and shorter overall survival (Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882). The risk of disease progression to metastatic disease is significant in patients with this genotype of prostate cancer. The percentage of patients free from metastatic disease was 90%, 72%, and 50%, respectively, compared with 97%, 94%, and 84% at 3, 5, and 10 years for patients with intact DNA repair (P < .001) (Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68(2):186-193. doi: 10.1016/j.eururo.2014.10.022). DNA damage repair non-BRCA mutations include alterations in genes such as ATM, CHEK2, PALB2, and RAD51. While less common than BRCA mutations, they have emerged as significant prognostic markers in prostate cancer. These BRCAness mutations are associated with a higher risk of aggressive disease and poorer survival outcomes. Given the debilitating physical and psychological side effects of androgen deprivation therapy (ADT) in relatively younger men with prostate cancer, delaying ADT in these men may be an attractive strategy. Given the proven efficacy of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors in the castration-resistant prostate cancersetting, PARP inhibitor monotherapy in a nonmetastatic castration-sensitive (nmCSPC) setting has the potential to delay metastasis and delay the onset of ADT related symptoms.
This is a single-arm, single-center, open-label, phase II trial to assess the efficacy of rucaparib in patients with high-risk biochemically recurrent (BCR) nmHSPC, which was defined as PSA doubling time of <9 months, demonstrating a "BRCAness" genotype (BRCA1/2 and other homologous recombination repair mutations). A total of 15 patients were intended to be enrolled, with an expected enrollment duration of 12 months. Patients were given rucaparib 600 mg orally twice daily and were allowed to remain on study treatment until PSA progression defined by Prostate Cancer Working Group 3, with 2 years of follow-up after study treatment. We anticipated a total of 2-3 years until completion of the clinical trial. The primary endpoint was to assess the PSA progression-free survival (PSA-PFS). The secondary endpoints of the study were safety, the proportion of patients with a PSA 50% response (PSA 50), and an undetectable PSA. A 4-week treatment duration comprised one cycle.
The study started enrolling in June 2019 and was prematurely terminated in June 2022 after the accrual of 7 patients because of changing standard of care treatments with the introduction of next-generation scans, eg, prostate-specific membrane antigen positron emission tomography (PSMA-PET). Seven patients were enrolled in the study with the following pathogenic alterations: ATM (n = 3), BRCA2 (n = 2), BRCA1 (n = 1), BRIP1 (n = 1), and RAD51 (n = 1). The median duration of follow-up was 18 months. A median of 20 cycles (range 4-42) was completed, median PSA-PFS was 35.37 months (95% CI, 0-85.11 months). In total, 2 patients achieved PSA50; both also achieved nadir PSA as undetectable. Grade ≥ 3 adverse events (AEs) were anemia and rash (in 1 patient each). No dose-limiting toxicities or severe AEs were seen.
Rucaparib demonstrated acceptable toxicity and efficacy signal as an ADT-sparing approach in patients with biochemically recurrent nonmetastatic prostate cancer. It is currently challenging to understand the optimal value of systemic therapy in this disease setting due to the rapidly changing standard of care. Additionally, there are relatively few patients with BRCAness who present with nonmetastatic hormone-sensitive prostate cancer (ClinicalTrials.gov Identifier: NCT03533946).
种系和体细胞乳腺癌基因（BRCA）突变在局限性或转移性前列腺癌男性患者中均为不良预后标志物。例如，与未携带类似突变的患者相比，携带这些突变的男性通常更早被诊断出前列腺癌，且更早发生转移性疾病。种系改变的患者通常疾病进展更严重，总生存期更短（Castro E, Goh C, Olmos D等。种系BRCA突变与前列腺癌淋巴结受累、远处转移及不良生存结局的高风险相关。《临床肿瘤学杂志》。2013年；31(14):1748 - 1757。doi:10.1200/JCO.2012.43.1882）。这种基因型的前列腺癌患者疾病进展为转移性疾病的风险很大。与DNA修复完整的患者在3年、5年和10年时分别为97%、94%和84%相比，该基因型患者无转移性疾病的比例分别为90%、72%和50%（P < .001）（Castro E, Goh C, Leongamornlert D等。BRCA突变对局限性前列腺癌根治治疗后转移复发及特异性生存的影响。《欧洲泌尿外科杂志》。2015年；68(2):186 - 193。doi: 10.1016/j.eururo.2014.10.022）。DNA损伤修复非BRCA突变包括ATM、CHEK2、PALB2和RAD51等基因的改变。虽然比BRCA突变少见，但它们已成为前列腺癌重要的预后标志物。这些BRCA样突变与侵袭性疾病的高风险和较差的生存结局相关。鉴于雄激素剥夺治疗（ADT）在相对年轻的前列腺癌男性患者中会产生使人衰弱的身体和心理副作用，在这些男性中延迟ADT可能是一种有吸引力的策略。鉴于聚腺苷二磷酸核糖聚合酶（PARP）抑制剂在去势抵抗性前列腺癌中的已证实疗效，在非转移性去势敏感性（nmCSPC）环境中使用PARP抑制剂单药治疗有可能延迟转移并延迟ADT相关症状的出现。
这是一项单臂、单中心、开放标签的II期试验，旨在评估rucaparib在高危生化复发（BCR）nmHSPC患者中的疗效，这些患者被定义为前列腺特异性抗原（PSA）倍增时间<9个月，表现出“BRCA样”基因型（BRCA1/2及其他同源重组修复突变）。共计划招募15名患者，预计招募持续时间为12个月。患者口服rucaparib 600 mg，每日两次，允许继续接受研究治疗直至前列腺癌工作组3定义的PSA进展，研究治疗后随访2年。我们预计完成临床试验总共需要2 - 3年。主要终点是评估PSA无进展生存期（PSA - PFS）。该研究的次要终点是安全性、PSA降低50%（PSA 50）的患者比例以及不可检测的PSA。4周的治疗期为一个周期。
该研究于2019年6月开始招募，在招募了7名患者后，由于引入了下一代扫描（如前列腺特异性膜抗原正电子发射断层扫描（PSMA - PET））导致护理标准改变，于2022年6月提前终止。7名患者入组该研究，具有以下致病改变：ATM（n = 3）、BRCA2（n = 2）、BRCA1（n = 1）、BRIP1（n = 1）和RAD51（n = 1）。中位随访时间为18个月。中位完成20个周期（范围4 - 42），中位PSA - PFS为35.37个月（95% CI，0 - 85.11个月）。总共有2名患者达到PSA50；两人的PSA最低点也均不可检测。≥3级不良事件（AE）为贫血和皮疹（各1例）。未观察到剂量限制性毒性或严重AE。
作为一种避免ADT的方法，rucaparib在生化复发的非转移性前列腺癌患者中显示出可接受的毒性和疗效信号。由于护理标准迅速变化，目前在这种疾病环境中理解全身治疗的最佳价值具有挑战性。此外，表现为非转移性激素敏感性前列腺癌的BRCA样患者相对较少（ClinicalTrials.gov标识符：NCT03533946）。
