A Phase II Study of Rucaparib Monotherapy in Nonmetastatic, Hormone-Sensitive Prostate Cancer Demonstrating “BRCAness” Genotype (ROAR)

Abstract 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. Conclusion 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).


Lessons Learned
• Rucaparib demonstrated acceptable toxicity and efficacy signal in biomarker selected patients with prostate cancer with biochemical recurrence.• No treatment-related severe adverse events were seen with rucaparib monotherapy in men with systemic treatment naïve high-risk non-metastatic castration sensitive prostate cancer.

Discussion
2][3] This has prompted additional studies incorporating PARPi earlier in the disease course (ie, in a castration-sensitive setting).For instance, TALAPRO-3 is a phase III clinical trial of enzalutamide plus talazoparib in patients with DDR gene mutated metastatic castrationsensitive prostate cancer (mCSPC). 4Currently, treatment for patients with biochemical recurrence (nonmetastatic castrationsensitive prostate cancer) is not specifically tailored differently for patients with BRCAness versus those without BRCAness.Standard of care includes treating all patients with androgen deprivation therapy (ADT) or combined with enzalutamide.Hence, there is an unmet need to tailor prostate cancer therapy based on BRCAness.ADT contributes to the quality of life decrements in patients with prostate cancer. 5][8][9][10] In contrast, PARPi has less impact on quality of life than hormone therapy and is generally a very well-tolerated intervention. 11 conducted this study with the aim to intervene early with PARPi in patients with BCR non-metastatic CSPC with BRCAness-related alterations to both achieve disease control while concurrently avoiding the toxicity of ADT treatment.All patients were treated with rucaparib monotherapy, and none were treated with ADT.The primary endpoint was to assess the PSA progression-free survival (PSA-PFS).
This trial demonstrated a signal of activity in biomarkerselected patients with rucaparib monotherapy while maintaining a good safety profile.The best responders were patients with BRCA 1/2 and RAD 51 mutations as measured by prolonged PSA-PFS.No robust clinical activity was seen in patients with only ATM mutations.PSA 50% response rates were observed in those patients with durable PSA responses.The study was prematurely terminated after the enrollment of seven patients when PSMA-PET/CT imaging was approved by the Food and Drug Administration for patients with elevated serum PSA levels following definitive treatment, which changed the standard of care for these patients.Currently, adjuvant/salvage radiation therapy, palliative ADT, or surveillance remains the standard of care in patients with PSA recurrence following definitive treatment for localized prostate cancer.These hypothesis-generating data suggest that rucaparib may be an alternative option in this selected group of patients with high-risk biochemically recurrent CSPC, with specific BRCAness genotypes who prefer to delay ADT.
Author disclosures and references available online.

Secondary endpoints
To assess the safety of rucaparib in patients with biochemically recurrent non-metastatic castrationsensitive prostate cancer.To assess the proportion of patients with a 50% reduction in PSA levels (PSA50) compared to the baseline value at the time of study nrolment.To assess the proportion of patients with an undetectable PSA after initiation of PARPi therapy at 6 and 12 months.To evaluate overall survival.

Patients
This was a phase II study in high-risk BCR non-metastatic CSPC setting with BRCAness genotype to investigate the efficacy of rucaparib monotherapy.High-risk biochemically recurrence was defined as PSA doubling time of <9 months.Target was to enroll 15 evaluable patients with BRCAness.Detailed inclusion and exclusion criteria can be found in Fig. 1.

Trial Design and Treatment
This is a single-arm, single-center, open-label, phase II trial to assess the efficacy of rucaparib in high-risk non-metastatic CSPC with "BRCAness" genotype.Treatment with rucaparib was given on cycle 1 day 1 and continued at 600 mg per oral twice daily.No patients were allowed to be on ADT therapy either by surgical castration or with GnRH agonist or antagonist or on androgen synthesis blocker or androgen receptor antagonists during the study period.Duration of administration: Patients were allowed to remain on study treatment until unacceptable toxicity, PSA progressive disease (unless they meet the criteria for continued treatment post-progression), or patient withdrawal.
Dose modifications and safety assessments: adjustment of rucaparib dosage was permissible for adverse event (AE) management, and study specific protocol guidelines for dose modifications were followed.Delays in dosage administration were sanctioned for both therapeutic agents to effectively address adverse events (AEs).AEs and laboratory abnormalities were systematically categorized and evaluated based on the grading system delineated in the National Cancer Institute (NCI) CTCAE v5.0.Dose-limiting toxicity (DLT) was characterized by any adverse event of severity grade ≥3 manifesting The Oncologist, 2024, Vol. 29, No. 5 e717 within the initial 3 weeks of treatment, and its association with either of the experimental compounds was to be determined by the principal investigator.Interruption of rucaparib treatment was permissible under the following circumstances, prompting consideration or implementation of a dosage reduction: (1) hematologic toxicity of grade 3 or 4 and (2) non-hematologic toxicity of grade 3 or 4.
Patients received treatment until the point of disease progression, which was defined as the emergence of new metastatic instances on conventional imaging or a confirmed rise in prostate-specific antigen (PSA) levels.Alternatively, treatment was halted in the presence of unacceptable toxicity or upon meeting other stipulated withdrawal criteria outlined in the study protocol.Discontinuation of treatment was mandated for adverse events (AEs) categorized as grade 4, except for isolated laboratory values that deviated from the norm and were determined to be unrelated to the administered treatment.Such deviations lacked clinical correlation and were resolved within a span of 7 days under medical supervision.
Furthermore, patients were allowed to continue receiving treatment beyond the point of disease progression if the treating investigator perceived potential clinical benefit.The scope of safety assessments encompassed the meticulous documentation of AEs, comprehensive physical examinations, and a battery of clinical laboratory tests including hematology analyses, hepatic panels, and serum chemistries.Additionally, concurrent medication usage was duly recorded for each patient.Within this context, a serious adverse event (SAE) was precisely defined as any unfavorable incident leading to fatal consequences, a lifethreatening situation, necessitating inpatient hospitalization, extending an ongoing hospital stay, resulting in enduring or significant impairment, contributing to a congenital anomaly or birth defect, or otherwise deemed medically imperative.

Outcomes
For the outcome assessment, patients must have received at least one full cycle of rucaparib and have PSA assessed after that cycle to be evaluable for efficacy.PSA levels were monitored monthly PSA progression-free survival (PSA-PFS) was defined as the time from study enrollment until the time of PSA progression as defined by PCWG3 criteria or death. 12atients who started another anti-cancer treatment prior to PSA progression or who completed one year of follow-up without PSA progression had their data censored at that time point.The primary objective of this phase II study was to assess PSA progression-free survival (PSA-PFS) upon receipt of rucaparib monotherapy in BCR non-metastatic CSPC setting with BRCAness genotype.The secondary objective was to assess the safety of rucaparib, proportion of patients with a 50% reduction in PSA levels from baseline, proportion of patients with an undetectable PSA after initiation of PARPi therapy at 6 and 12 months, and to evaluate overall survival (OS).

Primary Objectives
Patient demographics and baseline characteristics were described using frequencies and percentages (%) for categorical variables and medians and interquartile ranges for continuous variables.The total sample size was planned to enroll 15 patients.The null hypothesis was that the median PSA-PFS would be 3 months.With an alternative hypothesis that the median PSA-PFS would be 12 months, a sample size of 15 provides 90% power at one-sided alpha = 0.05.

Secondary Objectives
Descriptive analysis methods were used to analyze tabulated safety characteristics.Kaplan-Meier methods and associated confidence intervals were used to analyze PSA, PFS, and OS.The proportion of subjects who achieve PSA50 are reported along with a 95% confidence interval.The proportion of subjects with an undetectable PSA after initiation of PARP therapy at 6 and 12 months are assessed using Kaplan-Meier methods and associated confidence intervals.The proportion of subjects who exhibited an objective response was reported along with an exact binomial confidence interval.1).Molecular testing results are as follows: ATM (n = 3), BRCA2 (n = 2), BRCA1 (n = 1), BRIP1 (n = 1), RAD51 (n = 1).One patient had both ATM and RAD51 mutations.All these mutations are germline except for the BRIP 1 which was somatic.

Outcome Notes
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, 0-85.11months) (Figure 2).At the time of data censoring, there was no PSA progression in 3 patients (2 patients had BRCA2, and 1 had ATM/RAD 51).Two patients achieved the PSA 50% (BRCA 2, and ATM/ RAD 51), with both patients achieving an undetectable PSA level during the treatment period (Table 2 and Figure 3).The rate of PSA change over time during follow-up has been described in Figure 4. Evaluation method Monitoring and recording all adverse events and serious adverse events using the CTCAE version 5.0 Safety assessment Dose-limiting toxicity: 0/7 Severe adverse events: 0/7 All grade adverse events: 7/7 Grade ≥ 3 adverse events: 2/7 (28.57%)

Completion Study terminated prior to completion
Investigator's assessment Active but results overtaken by other developments Prostate cancer stands as one of the most prevalent malignancies among men.In 2023, there will be an estimated 288 300 new cases resulting in 34 700 fatalities in the United States. 13hile early-stage prostate cancer can often be treated with local therapy, such as surgery or radiation therapy, advanced or metastatic prostate cancer requires systemic therapy. 14atients with germline alterations typically have more advanced disease and shorter overall survival. 15The risk of disease progression to metastatic disease is significant in patients with this genotype of prostate cancer.The percentage The Oncologist, 2024, Vol. 29, No. 5 e719 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). 16Recent advancements have showcased significant clinical efficacy in managing metastatic prostate cancer by targeting the PARP pathway.
Our trial evaluated the efficacy and safety of rucaparib monotherapy for patients diagnosed with high-risk, nmCSPC, and exhibiting the BRCAness genotype.For this study, eligible mutations included were alterations in one or more of the following genes: BARD1, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA, NBN, PALB2, RAD51C, RAD51D, or RAD51, RAD51B from soft tissue based genomic testing or liquid biopsy-based genomic or genetic testing.Also, pathogenic, or likely pathogenic alterations were accepted.The study enrolled a cohort of 7 patients with the primary objective of PSA progression-free survival (PSA-PFS).Secondary endpoints included were safety assessment defined per CTCAE (version 5.0), the proportion of patients experiencing a 50% decrease in PSA (PSA50), and the attainment of an undetectable PSA at any time after starting rucaparib.
We hypothesized that PARPi monotherapy in patients with nmCSPC will yield acceptable disease control, as reflected by PSA response.Notably, 3 patients demonstrated sustained PSA response, including 2 individuals with BRCA2 mutations and 1 harboring ATM/RAD 51 mutations.Remarkably, no severe adverse events (SAEs) were observed.The adverse event profile of rucaparib remained consistent with the previous studies and no new safety signals were identified. 17The rate of treatment-related adverse events (TRAEs) of moderate grade was acceptable, with no instances of grade 4-5 TRAEs reported.The promising outcomes observed in patients with BRCA2 and RAD 51 mutations suggest the potential benefits of rucaparib in this subgroup of patients.
Another study that also investigated PARPi (Olaparib) monotherapy in the setting of BCR prostate cancer (s/p prostatectomy) was reported recently by Marshall et al. 18 This phase 2 trial investigated olaparib therapy in men with high-risk BCR prostate cancer post-prostatectomy.The trial enrolled 51 patients irrespective of their DDR mutation status.The tissue-based sequencing identified 27/51 patients with DDR mutations, predominantly involving BRCA2, CHEK2, and ATM genes.The overall PSA50 response rate was 24%, with a substantial 44% response rate in the DDR [+] group and no responses in the DDR [−] group.Notably, all patients with BRCA2 mutations (n = 11) achieved a PSA50 response.Furthermore, the DDR [+] group exhibited a longer median PSA progression-free survival (22 months) compared to the DDR [−] group (13 months).The study concluded that olaparib is a safe and effective treatment for men with BCR prostate cancer and DDR mutations, specifically highlighting its efficacy in patients with BRCA2 mutations, thereby encouraging further research into this treatment option.The total number of patients included in both studies is low.However, the results in the biomarker-selected groups are entirely consistent suggesting that PARPi is effective as monotherapy.
With the evolution of new advanced treatments for metastatic prostate cancer, patient survival rates have witnessed significant improvement.Median overall survival (OS) has extended from a minimum of 5 years for those diagnosed with metastatic disease to over 8 years for individuals progressing to metastatic status following definitive local interventions. 19,20The long-term repercussions of sustained ADT are progressively becoming evident and of clinical significance in the context of enhanced disease control, and prolonged survival.ADT escalates the susceptibility to cardiovascular disease, osteoporosis, and metabolic syndrome. 21Identifying therapeutic strategies that can effectively control prostate cancer and delay ADT use can further improve the care of patients with prostate cancer by both directly controlling metastatic disease progression, while simultaneously circumventing the health complications entailed by prolonged ADT.Our study represents a pioneering effort to uncover ADTsparing options for patients afflicted with high-risk BCR prostate cancer.
Our findings correlate with larger prospective trials of PARP inhibitors conducted in prostate cancer in metastatic setting.Notably, the PROfound study, a phase III randomized trial, demonstrates the remarkable efficacy of olaparib.The median radiographic progression-free survival (rPFS) was 7.4 months compared to 3.6 months with and without PARPi, respectively. 2Similar outcomes were observed in the TRITON study in patients specifically harboring BRCA1/2 mutations. 1ore recently, the TALAPRO-2 trial further reaffirms the efficacy of PARPi treatment (talazoparib plus enzalutamide) in these patients.The median rPFS was not reached with talazoparib and enzalutamide combination as compared to 21.9 months for placebo plus enzalutamide.In patients, whose tumors had BRCA gene alterations, integration of talazoparib with enzalutamide yielded a notable 77% lower risk of radiographic progression or death when compared with those in the placebo group. 22These investigations underscore the clinical benefit of PARP inhibitors in selected patients with DNA damage repair gene mutations.
Inclusion of ADT remains the care standard for patients with advanced or metastatic prostate cancer.However, its implementation comes with an array of adverse effects including fatigue, diminished libido, cardiovascular events, and osteoporosis. 23The outcomes from the ROAR study suggest that PARPi therapy might serve as a novel approach for patients to postpone ADT initiation while concurrently providing durable disease control.This might enhance patients' quality of life and delay the onset of ADT-linked adverse effects.
The variability in response observed among patients could be attributed to specific gene mutations.In our study, the best responses were observed in patients with BRCA1/2 and RAD51 mutations.In contrast, patients with exclusively ATM mutations did not exhibit robust clinical activity.This finding was consistent with existing literature, particularly emphasizing the discordant response rates associated with distinct mutations. 22Patients harboring BRCA1/2 mutations tend to exhibit more frequent and enduring responses to therapy, setting them apart from those with other mutations.It underscores the significance of understanding the genetic makeup of an individual's tumor when predicting therapeutic outcomes.
It is important to acknowledge the limitations inherent in our study, including the very limited sample size and absence of a comparative arm making it impossible to draw any definitive conclusions.Furthermore, the study's premature termination further limits the analysis of duration of response, which is important for patients early in the disease course given the favorable long-term prognosis.Further studies with larger sample sizes and randomized controlled designs are imperative to corroborate both the safety and efficacy of rucaparib monotherapy within this patient subset.Additionally, it is e720 The Oncologist, 2024, Vol. 29, No. 5 noteworthy that the study solely examined a confined spectrum of BRCAness gene alterations, leaving the response to other DDR gene mutations unknown.
The potential next steps from this manuscript involve several key areas.First, with the advent of newer diagnostic technologies like PSMA PET/CT, future studies can more accurately identify and stratify patients with nonmetastatic castration-sensitive prostate cancer (nmCSPC).This advanced imaging technology could aid in better selecting patients who might benefit most from PARP inhibitor therapy, particularly those with "BRCAness" genotypes.Second, given the small cohort in our current study, larger-scale trials are needed to robustly investigate the differential responses to PARP inhibitors in patients with monoallelic versus biallelic BRCA 1/2 mutations.Such differentiation could provide deeper insights into the biological mechanisms driving treatment efficacy.Finally, the recent approval of enzalutamide in this setting opens new possibilities for combining PARPi with NHTs.This combination could potentially enhance therapeutic efficacy, targeting different pathways involved in prostate cancer progression.

Conclusion
In view of the profound physiological and psychological side effects of ADT in men with BRCAness prostate cancer, delaying ADT may be an attractive therapeutic strategy.Despite the small sample size, these results are consistent with other published studies of PARPi in prostate cancer.The use of PARPi monotherapy presents an opportunity for exploration in future clinical trials.The ROAR study adds to the growing body of evidence supporting the use of PARP inhibitors in patients with prostate cancer and BRCAness.
The baseline demographics and clinical characteristics are summarized above.The median age of patients in our cohort was 69 years (59-75 years).The median time from the initial diagnosis of local disease to rucaparib treatment was 45.23 months (30.03-249.93 months).The median PSA at initial diagnosis, and at the time of study enrollment was 9.43 ng/ mL (2.3-53.77ng/mL), and 0.9 ng/ml (0.07-9.2 ng/mL), respectively.Regarding the previous treatment, all patients underwent prostatectomy and adjuvant/salvage radiation.Prior androgen deprivation therapy exposure was noted in 4 patients given concurrently with radiation (Table

Table 2 .
Treatment duration with rucaparib, and PSA responses.

Table 3 .
Adverse events per Common Terminology Criteria for Adverse Events (CTCAE) 5.0.

Table 1 .
Demographics, disease characteristics, and treatment details before enrollment in the study.