Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club discussion. Today, we're discussing a recent publication entitled Niraparib in patients with metastatic castration resistant prostate cancer and DNA repair gene defects, the GALAHAD trial, a multicentre open-label, phase 2 study. I'm Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto and joining me is Zach Klaassen, Assistant Professor in the Division of Urology at the Medical College of Georgia.

GALAHAD was recently published in Lancet Oncology, led by Dr. Smith and his colleagues. The treatment landscape for metastatic castration resistant prostate cancer has rapidly evolved since the initial publication of TAX 327, demonstrating a survival benefit to docetaxel in this disease space. Since that time, we have seen the introduction of multiple agents targeting the androgen axis, as well as immunotherapy, checkpoint inhibitors, radio pharmaceuticals and PARP inhibitors. The sequencing of these is somewhat unclear, but what we know is that following next generation androgen signal inhibitors and Taxane based chemotherapy, despite this plethora of options, there are relatively few good treatment approaches that have proven survival benefit.

A one such approach to however targets DNA repair alterations, which are seen in approximately 12 to 23% of patients with the mCRPC when we consider both germline and somatic variants. While these are associated with poor prognosis and resistance to our androgen access targeting therapies, they do represent a novel treatment approach for PARP inhibitors. PARP inhibitors function by a synthetic lethality mechanism in which DNA damage repair is unable to be repaired by the standard part mechanisms, then as a result, we get a PARP trapping and cellular death. And this is tumor selective cell death in these recombination repaired deficient tumor cells.

And so two PARP inhibitors have already been improved in prostate cancer on the basis of data from TRITON-2, we had approval of rucaparib based on these single arm phase 2 data in men with mCRPC who'd received one or two lines of androgen access targeting agents and Taxane based chemotherapy. And notably, this was limited to the BRCA1 and BRCA2 subset. In contrast, PROfound provided data for the approval of olaparib on the basis of a double blind, phase 3 randomized control trial in men with mCRPC who had received prior androgen access targeting agents and had one of a 15 homologous for combination repair gene mutations, although the approval in the end only included 14.

Niraparib is another PARP inhibitor, which is both potent and highly selective for both PARP1 and PARP2. Currently it is FDA approved for use as maintenance therapy in patients with ovarian, fallopian tube and primary peritoneal carcinomas. And in the present study, GALAHAD seeks to assess its role both in terms of antitumor activity and safety in patients with mCRPC who have DNA repair defects and have had progression on prior androgen significant inhibitors in Taxane based chemotherapy, paralleling the study design with TRITON-2. So this is an open-label, phase II single arm study enrolling adult men with confirmed mCRPC who have pre-defined DNA repair defects, and will talk about those in coming slides, and had progression on prior treatment with androgen signaling inhibitors, such abiraterone and enzalutamide, as well as Taxane based chemotherapy on the basis of PSA progression or radiographic progression.

Patients additionally had to have adequate performance status with an ECOG performance score of 0-2. Patients were excluded if they had prior treatment with a PARP inhibitor, prior treatment with platinum-based chemotherapy while Taxane based chemotherapy was both allowed and mandated. And additionally, patients were excluded if they had a history or concurrent diagnosis of myelodysplastic syndrome or acute myeloid leukemia. Patients underwent screening based on either blood or tumor testing for DNA repair alterations using a resolution assay. The authors assessed eight genes and you see them listed here. Patients could be enrolled if deleterious germline or somatic mutations were found in any one of these eight.

Subsequently, as other studies like PROfound have done, patients were stratified into BRCA and non-BRACA cohorts. The authors further assessed three other genes known to be associated with advanced prostate cancer, including the androgen receptor CDKN2A and TP53. Patients were then considered to be DNA repair defect positive if they had known pathogenic alterations. And those with monoallelic or non-pathogenic alterations were subsequently excluded and Zach will walk us through the breakdown of patient enrollment.

Following enrollment, patients were treated with Niraparib 300 milligrams PO daily in 28 day cycles until there was evidence of disease progression, unacceptable toxicity, the development of myelodysplastic syndrome or acute myeloid leukemia. The investigator deemed that treatment was no longer appropriate or patients withdrew consent or there was death. Patients continued on ADT throughout their Niraparib treatment.

Patients underwent clinical assessment weekly for one month, biweekly for one month, and then monthly thereafter. During treatment, imaging was performed every eight weeks for the first 24, and then every 12 weeks thereafter. During follow up, patients received imaging every 12 weeks until radiographic progression. I should have noted during treatment, patients had CTC testing each cycle and PSA testing every four weeks. During follow up there was imaging every 12 weeks, and then toxicity assessment was performed both during treatment and during follow up using the CTCAE version four.

The primary endpoint of a GALAHAD was investigator assessed and objective response rate was defined as a confirmed partial or complete response, according to RECIST version 1.1 criteria, using the sum of the target tumor lesions without bone progression, according to the Prostate Cancer Working Group 3 definition, among the cohort of patients who had BRCA mutations and measurable disease. So this is in a subset population, just as Profound had done.

We then have a number of secondary endpoints, including the objective response rate. Patients with non-BRACA mutations who had measurable disease, CTC response rates, overall survival, radiographic progression-free survival, time to PSA progression, time to symptomatic skeletal events, duration of objective response and safety. And further, there is additional exploratory endpoints, including a composite response rate comprising the objective response, CTC conversion, or PSA 50 response, as well as CTC conversion and PSA 50 response individually.

In terms of the study design, the authors used Simon's two-stage design and in the non-BRACA cohort, a futility analysis was planned at 14 patients where ongoing accrual required at least three or more responses in the first 14 patients, and at that point, you could proceed to stage II, enrolling a total of 45 patients in this patient population. Among the 45, we would reject the null hypothesis, if 10 or more responses were observed. Among the BRCA subset who comprised the primary objective, a null hypothesis of an objective response rate of 15% was tested, compared to an alternate of 32%. And if accrual of 75 BRCA patients and 45 non-BRACA patients was achieved, this would provide 90% power for the lower limit of the 95% confidence interval to exclude this null hypothesis of 15%.

The authors performed their efficacy analysis and among the patients who had final biomarker eligibility and measurable disease. Patients who terminated treatment before their first assessment of efficacy were deemed non-responders, whereas those who had no imaging available were considered non evaluable and censored. The authors calculated response rates using exact two-sided 95% confidence intervals and used the Kaplan Meier technique to assess time to event outcomes. They further performed a number of post hoc analyses, including subgroup analyses by baseline characteristics, evaluation of stable disease and biomarker analyses in non-DNA repair alterations, including the androgen receptor in TP53. Safety and compliance were assessed as is typically done among all patients who received at least one dose of treatment. At this point in time, I'll hand it over to Zach to walk us through the results of GALAHAD, including this initial patient screening.

Zachary Klaassen: Thanks Chris for that great introduction for the walk through the methods. This is the trial profile figure for GALAHAD. As you can see here on the right, there was 4,292 patients that were prescreened, and subsequently 385 patients that were screened with DRDs. Ultimately there was 223 patients that were allocated to cohorts per the biomarker assay, including 142 patients to the BRCA cohort and 81 patients to the non-BRCA cohort. Looking at this table one, this is the baseline characteristics, it's a long table, so I split it into two panels. We'll focus on column two and column four, which is the bracket cohort in column two and the non-bracket cohort in column four. You can see that the age was roughly late sixties to early seventies. The majority of patients in this trial nearly three quarters were Caucasian. With regards to the PSA at baseline, was 141.5 in the bracket cohort and 161.7.

In the non-bracket cohort with regards to the BRCA1/2 breakdown, the majority of these patients were BRCA2 at 89%. And in the non-BRCA cohort, the most common alteration was 46% followed by FANCA at 22%. Even in this pretreated cohort, the majority of patients in both arms were ECOG zero or one. With regards to extent of disease progression and study entry, the overwhelming majority had bone metastasis, 89% in BRCA cohort and 98% in the non-BRCA cohort, including visceral metastases in 23% of patients in the BRCA cohort and 25% in the non-BRCA cohort.

Measurable disease at the time of enrollment was 54% in the BRCA cohort and 58% in the non-BRCA cohort. And in terms of previous therapies for prostate cancer, most commonly was three lines of therapy at 38% in the BRCA cohort, as well as 38% in the non-BRCA cohort. Moving to the right to complete this baseline characteristics table, with regards to previous androgen signaling inhibitor therapies, most commonly was one line at 68% in the BRCA cohort and one line in the non-BRCA cohort at 56%. Previous Taxane therapy, 70% of patients in the BRCA cohort had one previous Taxane based chemotherapy, whereas it was nearly a 50/50 split between one or two lines of prior Taxane chemotherapy in the non-BRCA cohort.

This is the objective response rate over a median follow up of 10 months in IQR 6.6 to 13.3 months. This is the measurable BRCA cohort here. You can see objective response rate of 34.2% with a complete response rate of 3% and a partial response rate of 32%. As would be likely expected, the non-BRCA cohort did not do as well with an objective response rate of 10.6%, no complete responses and 11% of patients having a partial response.

This is the plethora of secondary and exploratory efficacy endpoints. In the BRCA cohort here in the second column, the immeasurable BRCA cohort, a third column in the non-BRCA cohort in the far column to the right. In terms of CTC response, 24% in the BRCA cohort, 8% in the non-BRCA cohort. Overall survival was 13 months in the BRCA cohort compared to 9.6 months in the non-BRCA cohort. In terms of time to radiographic progression, eight months in the BRCA cohort and 3.78 months in the non-BRCA cohort. Time to symptomatic skeletal related event was 13.8 months in the BRCA cohort and 10.3 months in the non-BRCA cohort. And finally, the duration of objective response, 6.3 months in the BRCA cohort and 5.2 months in the non-BRCA cohort.

With regards to the Capital Meier curves, this is radiographic progression free survival. BRCA is listed in blue and the non-BRCA is listed in red. The median RPFS in the BRCA cohort was 8.0 months, 95% confidence interval of 5.55 to 8.38. And then in the non-BRCA cohort, was 3.7 months with a 95% confidence interval of 1.97 to 5.49. This is overall survival median, overall survival in the BRCA cohort was 13.01 months and in the non-BRCA cohort was 9.63 months.

This is the treatment emergent adverse events for the GALAHAD study. In terms of common grade three adverse events, most commonly was anemia at 32%. Also, common was thrombocytopenia at 8% and fatigue at 7%. Of note, in terms of grade 4 adverse events, thrombocytopenia was the most common at 8% and there was several grade 5 adverse events attributed to anemia and general physical health deterioration.

So several discussion points from the GALAHAD trial. The results from this study, which was an open-label, phase 2 study, established the anti-tumor activity of Niraparib in patients with metastatic CRPC and DRDs, who have progressed on ASIs and Taxanes. The activity of Niraparib with an objective response rate, as we mentioned of 34.2% in the measurable BRCA cohort is notable given the heavily pre-treated end-stage patient population who have few therapeutic options. With regards to contextualization of GALAHAD, we compared these results to the other PARP inhibitor trials as listed here.

So PROfound, which looked at olaparib versus ASI. There was an improvement with regards to olaparib for radiographic progression free survival with a hazard ratio of 0.34, for overall survival, with a hazard ratio of 0.69. Objective response rate at 33% versus 2%, and this is specific to cohort A which included BRCA1, 2 or ATM alteration patients. Other phase 2 trials, as well, is the TRITON-2 trial looking at rucaparib, objective response rate of 47.5% with a median time to PSA progression of 6.5 months, as well as the phase 2 TALAPRO-1 trial looking at talazoparib with an objective response of 29.8% after median follow up of 16.4 months.

So in conclusion, these results suggest that niraparib has promising clinical activity with a manageable safety profile, when administered as a monotherapy for treatment refractory metastatic CRPC with BRCA alterations or select non-BRCA alterations. These findings underscore the need for and importance of molecular testing to inform management, along with continued research to establish treatment paradigms with appropriately targeted therapies for men with prostate cancer. And finally, efforts to investigate and better understand predictive markers and signatures at both response and resistance to treatment with PARP inhibitors, such as niraparib are needed to guide therapy selection and optimize treatment outcomes. We thank you very much for attending this URO Today Journal Club discussion in which we discussed the recently published GALAHAD Trial in Lancet Oncology.