背景:在患有局限性或转移性前列腺癌的男性患者中,种系和体细胞的BreastCancer基因(BRCA)突变都是预后不良的标志物。例如,与没有类似突变的男性相比,这些突变的男性通常更早被诊断为前列腺癌,并更早发生转移性疾病。具有种系改变的患者通常具有更晚期的疾病和更短的总生存期(CastroE,吴丙,奥尔莫斯D,etal.种系BRCA突变与淋巴结受累的高风险相关,远处转移,前列腺癌的生存结果较差。JClinOncol。2013;31(14):1748-1757。doi:10.1200/JCO.2012.43.1882)。在具有这种基因型的前列腺癌患者中,疾病进展为转移性疾病的风险是显著的。无转移性疾病的患者比例为90%,72%,50%,分别,与97%相比,94%,完整DNA修复的患者在3年、5年和10年时为84%(P<0.001)(CastroE,吴丙,LeongamornlertD,etal.BRCA突变对局部前列腺癌根治性治疗后转移性复发和病因特异性生存率的影响.乌罗尔。2015;68(2):186–193。doi:10.1016/j.eururo.2014.10.022)。DNA损伤修复非BRCA突变包括ATM等基因的改变,CHEK2、PALB2和RAD51。虽然不像BRCA突变那么常见,它们已成为前列腺癌的重要预后标志物.这些BRCAness突变与侵袭性疾病的高风险和较差的生存结果相关。鉴于雄激素剥夺疗法(ADT)在相对年轻的前列腺癌男性中的身体和心理副作用使人衰弱,延迟这些男性的ADT可能是一个有吸引力的策略。鉴于聚二磷酸腺苷-核糖聚合酶(PARP)抑制剂在去势抵抗性前列腺癌中的有效性,在非转移性去势敏感(nmCSPC)的情况下,PARP抑制剂单一疗法具有延迟转移和延迟ADT相关症状发作的潜力。
方法:这是一个单臂,单中心,开放标签,II期试验,以评估rucaparib在高风险生化复发(BCR)nmHSPC患者中的疗效,定义为PSA倍增时间<9个月,显示“BRCAness”基因型(BRCA1/2和其他同源重组修复突变)。总共有15名患者打算入组,预期入组时间为12个月。患者每天两次口服600mgrucaparib,并允许患者继续进行研究治疗,直到前列腺癌工作组3定义的PSA进展,研究治疗后随访2年。我们预计总共需要2-3年才能完成临床试验。主要终点是评估PSA无进展生存期(PSA-PFS)。研究的次要终点是安全性,PSA50%反应(PSA50)的患者比例,和无法检测到的PSA。4周的治疗持续时间包括一个周期。
结果:该研究于2019年6月开始注册,并于2022年6月因引入下一代扫描而改变护理治疗标准而提前终止7名患者。例如,前列腺特异性膜抗原正电子发射断层扫描(PSMA-PET)。7名患者被纳入研究,具有以下致病性改变: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。完成了20个周期的中位数(范围4-42),PSA-PFS中位数为35.37个月(95%CI,0-85.11个月).总的来说,2例患者达到PSA50;两者都达到了无法检测的最低点PSA。≥3级不良事件(AE)为贫血和皮疹(各1例)。没有观察到剂量限制性毒性或严重的AE。
结论:Rucaparib在生化复发性非转移性前列腺癌患者中表现出可接受的毒性和疗效信号,作为一种保留ADT的方法。由于快速变化的护理标准,目前很难理解这种疾病背景下全身治疗的最佳价值。此外,相对较少的BRCAness患者出现非转移性激素敏感型前列腺癌(ClinicalTrials.govIdentifier:NCT03533946).
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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).