A phase II clinical trial published in The Oncologist on March 7, 2024 evaluated the use of rucaparib monotherapy in patients with nonmetastatic, hormone-sensitive prostate cancer demonstrating "BRCAness" genotypes. The single-arm, single-center, open-label study, known as ROAR, was conducted at the Huntsman Cancer Institute at the University of Utah and funded by Clovis Oncology.
The primary purpose of the study was to assess the efficacy and safety of rucaparib, a PARP inhibitor, in delaying disease progression and postponing the need for androgen deprivation therapy (ADT) in men with high-risk biochemically recurrent prostate cancer harboring DNA damage repair gene mutations. The trial aimed to enroll 15 patients, but was prematurely terminated after accruing 7 participants due to changes in the standard of care, particularly the introduction of advanced imaging techniques like PSMA-PET scans.
To be eligible for the study, patients had to have histologically proven adenocarcinoma of the prostate with a "BRCAness" genotype, defined as pathogenic or likely pathogenic alterations in genes such as BRCA1, BRCA2, ATM, CHEK2, PALB2, and RAD51. Inclusion criteria specified nonmetastatic disease on conventional imaging, prior definitive local therapy, testosterone levels >50 ng/dL, and PSA doubling time ≤10 months. Key exclusion criteria included metastatic disease, recent cardiovascular events, and prior treatment with PARP inhibitors or platinum-based chemotherapy.
The study enrolled 7 male patients with a median age of 69 years (range 59-75). All patients had undergone prostatectomy and adjuvant/salvage radiation therapy, with 4 having received prior ADT concurrent with radiation. The specific mutations identified were: ATM (n=3), BRCA2 (n=2), BRCA1 (n=1), BRIP1 (n=1), and RAD51 (n=1), with one patient harboring both ATM and RAD51 mutations.
Patients received rucaparib 600 mg orally twice daily in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was PSA progression-free survival (PSA-PFS), with secondary endpoints including safety, proportion of patients achieving ≥50% PSA reduction (PSA50), and undetectable PSA levels.
Results showed a median PSA-PFS of 35.37 months (95% CI, 0-85.11 months) after a median follow-up of 18 months. Two patients (29%) achieved PSA50 response, both of whom also reached undetectable PSA levels during treatment. These responding patients had BRCA2 and ATM/RAD51 mutations. At the time of data cutoff, 3 patients (43%) had not experienced PSA progression, including two with BRCA2 mutations and one with ATM/RAD51 mutations.
The safety profile of rucaparib was generally consistent with previous studies. All patients experienced at least one adverse event, with fatigue (71%) and dysgeusia (57%) being the most common. Two patients (29%) developed grade 3 adverse events (anemia and acneiform rash). Importantly, no dose-limiting toxicities or severe adverse events were reported, and no patients required treatment interruptions.
The study has several notable limitations. The small sample size of only 7 patients limits the generalizability of the results and precludes definitive conclusions. The premature termination of the trial further restricts the analysis of long-term outcomes and duration of response. Additionally, the study examined a narrow spectrum of "BRCAness" mutations, leaving the potential efficacy in patients with other DNA damage repair gene alterations unexplored.
Despite these limitations, the authors conclude that rucaparib demonstrated an acceptable toxicity profile and a promising efficacy signal as an ADT-sparing approach in this select patient population. The study suggests that PARP inhibitor monotherapy may be a viable strategy to delay disease progression and postpone the need for ADT in men with nonmetastatic, hormone-sensitive prostate cancer harboring specific DNA repair defects.
The potential clinical impact of these findings is significant, particularly given the long-term side effects associated with ADT. If validated in larger studies, this approach could offer a new treatment option for patients with biochemically recurrent prostate cancer and "BRCAness" genotypes, potentially improving quality of life by delaying the onset of ADT-related symptoms. The results align with other recent studies demonstrating the efficacy of PARP inhibitors in prostate cancer, particularly in patients with BRCA mutations.
However, the authors emphasize that the rapidly evolving landscape of prostate cancer treatment, including the introduction of advanced imaging techniques and novel therapies, complicates the interpretation of these results in the context of current clinical practice. They suggest that future research should focus on larger, randomized controlled trials to confirm both the safety and efficacy of PARP inhibitor monotherapy in this patient subset.
The study also highlights the importance of personalized medicine in prostate cancer treatment. The differential responses observed among patients with various mutations underscore the need for tailored therapeutic approaches based on individual genetic profiles. This aligns with the broader trend towards precision oncology, where treatment decisions are increasingly guided by molecular characteristics of the tumor.
In conclusion, while the ROAR study provides intriguing preliminary data on the potential of rucaparib monotherapy in nonmetastatic, hormone-sensitive prostate cancer with "BRCAness" genotypes, its small sample size and premature termination necessitate cautious interpretation. The findings warrant further investigation in larger, well-designed clinical trials to definitively establish the role of PARP inhibitors in this setting and to identify the subset of patients most likely to benefit from this approach. As the field of prostate cancer treatment continues to evolve rapidly, studies like ROAR contribute valuable insights that may ultimately lead to more personalized and effective therapeutic strategies for patients with specific genetic alterations.
References
Sahu KK, Li H, Mathew Thomas V, et al. A Phase II Study of Rucaparib Monotherapy in Nonmetastatic, Hormone-Sensitive Prostate Cancer Demonstrating "BRCAness" Genotype (ROAR). Oncologist. 2024;29(5):450-e725. doi:10.1093/oncolo/oyae030
