Rucaparib in Men with Metastatic Castration-Resistant Prostate Cancer A Journal Club on the TRITON 2 Study - Christopher Wallis & Zachary Klaassen

January 17, 2021

Rucaparib was evaluated as a treatment for men with metastatic castration-resistant prostate cancer (mCRPC) associated with a BRCA gene alteration who had received prior taxane and androgen receptor–directed therapy.  In this UroToday Journal Club, Christopher Wallis and Zachary Klaassen discuss the clinical rationale which led to the exploration of PARP inhibitors in men with advanced prostate cancer, and so some of the first work in this space, specifically highlighting the TRITON2 study cohort published in Journal of Clinical Oncology Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration".  
Rucaparib has antitumor activity in patients with mCRPC and a deleterious BRCA alteration and demonstrated a manageable safety profile consistent with that reported in other solid tumor types.

Biographies:

Christopher J.D. Wallis, MD, Ph.D., Instructor in Urology, Vanderbilt University Medical Center, Nashville, Tennessee

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center


Read the Full Video Transcript

Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club. Today, we're discussing rucaparib in men with metastatic castrate-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. I'm Chris Wallis, a Fellow in urologic oncology at Vanderbilt. With me today is Zach Klaassen, Assistant Professor in the Division of Urology at the Medical College of Georgia. This is the citation from the recently published TRITON2 cohort in JCO.

By way of background, we can start with data from Dr. Nicolosi and colleagues was published in JAMA Oncology in 2019. Among 3,600 men with prostate cancer, they found germline variants in 17%, and of these, nearly 31% would be BRCA1 or 2 variants. Considering the clinical implications of these BRCA variants as well as other homologous recombination repair variants, contribute to a synthetic lethality when treated with PARP inhibitors in the homologous-recombination-deficient tumor cells here.

As such, this clinical rationale led to the exploration of PARP inhibitors in men with advanced prostate cancer, and so some of the first work in this space is presented here in this Phase II trial of 50 patients with extensively pre-treated mCRPC who received olaparib. What you can see in the two Kaplan-Meier curves is that patients who are biomarker-positive, that is with DNA repair defects, had a significantly greater response, both in terms of radiographic progression-free survival and also overall survival when treated with olaparib.

This rationale has led to a number of ongoing trials as well as recently published work, but one of these is the TRITON2 study, an international, open-label, Phase II, single-arm trial looking at rucaparib in men with metastatic castrate-resistant prostate cancer. To be eligible for inclusion, men had to be age 18 years or greater with an ECOG performance status in 0-1, adequate organ function, and mCRPC with evidence of deleterious mutations in BRCA1, 2, or other DNA defect repair genes. Notably, they had to have disease progression following one to two lines of androgen-axis-directed therapy, so that's abiraterone or enzalutamide, typically, as well as one line of taxane-based chemotherapy, and be receiving ongoing androgen deprivation.

Patients were administered rucaparib given as 600 milligrams PO twice daily, and dose reductions in increments of 100 milligrams were allowed when patients experienced high-grade or persistent grade 2 treatment-related adverse events. Treatment was continued until there was evidence of radiographic progression, unequivocal clinical progression, unacceptable toxicity, an inability to tolerate further treatment, loss to follow-up, or withdrawal of consent.

Patients were assessed with CT or MRI as well as bone scan during pre-trial screening, as well as every 8 weeks for the first 24 weeks, and then every 12 weeks thereafter. An adverse event assessment was performed from the first dose until 28 days after the last dose of treatment. The primary outcome was objective response rate as judged by an independent blinded review. Secondary outcomes included the duration of response, rate of confirmed PSA responses of at least 50%, time to PSA progression, radiographic progression-free survival, overall survival, and safety.

The outcomes were assessed in the overall population of all the evaluable patients and they designed their study according to an assumed null have an objective response rate of 20%. However, in the end, the study was powered according to regulatory requirements rather than the sample size calculation. I'll now pass it over to Dr. Klaassen to describe the results of this trial.

Zachary Klaassen: Thanks, Chris. As you can see here, this is the CONSORT diagram for the trial. This group screened almost 1,800 patients, and subsequently enrolled 209 of these patients, and subsequently, 94 of these were excluded for deleterious non-BRCA gene alteration without a deleterious BRCA alteration at screening, resulting in a population of 115 patients in this study.

This is the baseline patient characteristics for this study. The median age was 72 years. You can see that the majority of these patients were white, at 73.9%. In this heavily pretreated population, you can see that 66.1% were ECOG 1 and you can see the median baseline PSA of 61, and most of these patients, at the time of diagnosis, had a Gleason score of greater than 8. In terms of number of prior therapies for CRPC there was two. In terms of next-generation AR-directed therapy, most commonly was enzalutamide at 71.3%, and abiraterone at 64.3%. At the bottom of this section here, where my arrow is, you can see that 36.5% had greater than or equal to two AR-directed therapies. Most commonly, patients also had docetaxel in the castrate-resistant state, 93.9%, 14.8%, which had those attacks on the castrate sensitive state. And you can see here, a smattering of patients receive cabazitaxel, Sip-T, and radium-223. In terms of measurable disease, measurable visceral plus/minus nodal disease, 33.9%. So heavily pretreated, with over one-third of patients having visceral disease.

This table looks at the rate of response to rucaparib of treatment. On the left here is the investigator-evaluable population, on the right is the independent radiology review population. In terms of confirmed objective response, 50.8% had an ORR in the investigator-valuable population, in the radiology review, 43.5%; 6.2% complete response, compared to 11.3% complete response in the radiology review population. Partial response, 44.6% and 32.3%. Stable disease, 38.5% and 45.2%. In terms of the confirmed PSA response rate, 54.8% of patients had a confirmed PSA response.

This is one of the supplementary tables that looks at the confirmed objective response rate by BRCA1 or BRCA2 in the independent radiology review evaluable population. You can see here that the majority of these patients were BRCA2 at 53, compared to only 9 patients with BRCA1, and that confirmed objective response in the BRCA2 patients was 45.3%, compared to 33.3% in the BRCA1 population. Similar complete response rates, just over 11%, and 34% partial response in BRCA2 compared to a 22.2% in BRCA1.

This is the waterfall plot looking at the best change from baseline in sum of target lesions in the evaluable population. You can see here that the majority had a decrease in some of their target lesion, with only a handful of patients having an increase in the size of their lesion. Another waterfall plot looking at the best change from baseline in PSA. Once again, the majority of these patients having a decrease in their PSA for baseline, with a handful of patients having an increase, and about seven patients having a very high increase in their PSA from baseline.

This slide here is the subgroup analysis for objective response rate and PSA response. On the left side panel here is objective response in the independent-radiology-review-evaluable population. On the right is the PSA response rate in the overall efficacy population. If you go down here to the bottom, you can see that the objective response rate, the hash mark is just above 40%. You can see that, generally, for all of these subgroups, whether it be BRCA1 or BRCA2, germline or somatic, number lines of therapy, measurable disease, hepatic metastasis, and age, that there was a good signal for response in all of these subgroups.

If we go over here to the right with the PSA response rate, you can see on the bottom here for PSA response rate, the hash mark is just above 50%. Similar to objective response, a very consistent signal across most of these subgroups with the one exception being the BRCA1 patients having a less robust response, perhaps because of the smaller sample size of nine patients.

This is the radiographic progression-free survival Kaplan-Meier curve. You can see here that there's a median 9.0 months with a 95% confidence interval of 8.3 to 13.5 months. This is the time to PSA progression in the efficacy population Kaplan-Meier curve, with a median time to PSA progression of 6.5 months with a 95% confidence interval of 5.9 to 7.8 months.

In terms of the most commonly reported treatment adverse related events, in terms of grade 3, the most common was anemia at 25.2%, followed by fatigue at 8.7%. In terms of any grade treatment-related adverse event, most commonly fatigue at 61.7%, nausea at 52.2%, and anemia at 43.5%.

Several discussion points from the TRITON2 study that we think are important. This study showed that for men with metastatic CRPC with disease progression after AR-directed therapy and taxane-based chemo, response to previously approved therapies has been historically poor with confirmed objective response rates of only 8% to 15%, and PSA response rates have only 8% to 39%. TRITON2 illustrates the importance of genomic screening to identify men who may benefit from a PARP inhibitor, and certainly the guidelines, particularly the NCCN, have been strong advocates of genomic screening in any high-risk patient with prostate cancer.

However, this study highlights that this is a relatively infrequent subset of the mCRPC population. In this study, it is important to point out that they had to screen almost 1,800 patients to identify 200 with DDR mutations and only 115 with BRCA mutations. So while it is important to screen these patients, you can see that 1,800 patients had to be screened to find only 115 with BRCA mutations.

In conclusion, results from the TRITON2 study showed that rucaparib has meaningful anti-tumor activity and a manageable safety profile in patients with metastatic CRPC, and this is specifically for deleterious germline or somatic BRCA alterations. These results are consistent with other PARP inhibitor trials, most notably, published earlier year, was the PROfound study that looked at BRCA alterations with the radiographic progression-free survival for olaparib versus enzalutamide or abiraterone, of a median 9.8 versus 3 months, and a hazard ratio of 0.22. This data for rucaparib is consistent with outcomes as seen in other solid tumor types and does support the use of rucaparib in this population, specifically for roles with BRCA alterations. This was reflected by the FDA accelerated approval in May of 2020, which was rucaparib being approved for men with deleterious BRCA mutations associated with metastatic CRPC previously treated with androgen-receptor-directed therapy and taxane-based chemotherapy.

Thank you very much. We hope you enjoyed this UroToday Journal Club discussing the TRITON2 study.

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