The PROfound and TRITON2 clinical trials have demonstrated the benefit of the PARP inhibitors olaparib and rucaparib for the treatment of metastatic castration-resistant prostate cancer.
During a virtual Targeted Oncology Case-Based Roundtable event, Robert Dreicer, MD, MS, MACP, faculty chair, professor of Medicine and Urology at the University of Virginia School of Medicine, section Head, Medical Oncology, associate director for Clinical Research, and deputy director, at University of Virginia Cancer Center, and the codirector, Paul Mellon Urologic Cancer Institute discussed treatment options for a patients with metastatic castration-resistant prostate cancer.
Targeted OncologyTM: How often do you test for BRCA germline and somatic mutations? Have you seen any patients with both germline and somatic BRCA1 or BRCA2 mutations?
DREICER: Most of us don’t see both of these. Honestly, if you’ve got a germline BRCA mutation, it doesn’t really matter whether you have a somatic BRCA [mutation]. You could argue that from a clinical perspective, it’s not going to change anything.
What are the National Comprehensive Cancer Network (NCCN) recommendations for germline testing and genetic counseling in prostate cancer?
The NCCN recommendations for genetic counseling and germline [testing center on] personal history and disease history.1 Increasingly, germline testing is recommended [in several scenarios], including a couple with well-known high-risk features. Germline testing should consist of panels [for Lynch syndrome and homologous recombination repair (HRR) genes].
The concept of pretest genetic counseling is nice [but not always realistic]. If I have a young man with a BRCA-positive [tumor], I’ll send that patient to genetics, but most of the time, it’s not reimbursed by insurance. If I have findings that worry me, I will endeavor to get them to genetic counseling, but all of us have very busy practices, and the concept of sending all of these patients to genetic counseling before we [test]—it’s [not feasible].
What somatic mutation tests are suggested by the NCCN for prostate cancer?
Certain recommendations for somatic tumor testing are [based on whether the cancer is] metastatic and castration resistant.1 [Testing in] earlier disease is more of a [consideration than a] recommendation. Over the next couple of years, we’ll have better information about this, and it will be easier to sort out. I also think that costs will change.
Can you describe the study design of the PROfound trial?
Results from the PROfound study [NCT02987543] led to the regulatory approval of olaparib [Lynparza]. Olaparib and rucaparib [Rubraca] are the new PARP inhibitors. In this trial, patients with [metastatic] castration-resistant prostate cancer [mCRPC] received prior abiraterone acetate [Zytiga] or enzalutamide [Xtandi].2,3
[The study design] was a little bit confusing. There were 2 cohorts. Cohort A included patients [with tumors harboring] BRCA1, BRCA2, or ATM mutations. Cohort B represented patients with 12 other HRR abnormalities, like CHEK1, CHEK2, and PALB2. The randomization of both cohorts was 2:1 to standard-dose olaparib versus [physician’s] choice, which was typically the alternative androgen receptor [AR] drug. The primary end point was radiographic progression-free survival [rPFS], and there were several standard secondary end points.
About 30% of all comers had [tumors with] an HRR mutation, but there are many HRR mutations [as a whole].2 The challenge is, except for olaparib and rucaparib, we [don’t] have great drugs for anything other than BRCA, maybe ATM [mutations.]
What were the key efficacy results from PROfound?
In patients with BRCA or ATM mutations, there was a significant rPFS benefit, more than double [with olaparib (7.4 months vs 3.6 months with control; P < .001)].2 The hazard ratio was 0.34—a very significant difference.
[In] the overall study population, [which] combined cohort A and cohort B, there was a rPFS benefit [with olaparib of 5.8 months] compared with control [3.5 months; P < .001]. The hazard ratio was 0.49. This was driven almost entirely by cohort A.
[A subgroup analysis demonstrated that results were] broadly in favor of olaparib, irrespective of prior taxane use where there was measurable disease, or where the disease [had metastasized]. There were differences based on gene alterations. For almost all of the HRR mutations other than BRCA, [olaparib did not offer a clear benefit].
For cohort A, overall survival [OS] favored olaparib, with about a 31% reduction [in death] which was a statistical and clinically meaningful difference [P = .02 vs control].4
In the overall population, for OS, there was a [33%] reduction in death with olaparib versus physician-chosen control therapy.
The objective response rate in cohort A was pretty impressive [with olaparib (33%) compared with control (2%)].3
What was the safety profile for patients receiving olaparib in the PROfound trial?
The median treatment duration for patients receiving olaparib was 7.6 months, and [physician’s choice] was less than 4 months.4 There was nothing particularly surprising in terms of toxicities [with olaparib]. Approximately 20% of patients stopped [taking olaparib] because of AEs [adverse events], and almost a quarter of patients needed dose reductions. [About] 52% of patients had grade 3 or higher AEs.
Olaparib is a drug that requires some experience and expertise in a population that’s been moderately treated. PARP inhibitors [are associated with cytopenias and] gastrointestinal toxicities. PARP inhibitors used in both ovarian and pancreatic cancer display similar toxicities. I don’t think [AEs are] distinct in this disease. It’s just the somewhat older population.
What are your thoughts on the FDA approval of olaparib and its efficacy in different HRR alterations?
Olaparib was approved by the FDA based on results from the PROfound study cohorts A and B.5 About the same time, there were 3 very well-written editorials by thought leaders in prostate cancer genomics in the Journal of Clinical Oncology and Lancet Oncology. All 3 of those editorials basically said, [given] the data in cohort A, there’s no question these agents are active in BRCA [tumors], but they’re really less impressive in the other [HRR] mutations. The 3 editorialists said [they] are a little worried that just because there’s an [agent with an] FDA approval for a CHEK2 mutation, the likelihood that a patient is going to benefit from olaparib, as opposed to doing something else such as another conventional therapy, may not necessarily be optimal for the patient.
What was the study design in TRITON2?
Rucaparib was approved on the basis of data from the TRITON2 study [NCT02952534], which was an [open-label], phase 2 study in mCRPC [associated with alterations] in HRR genes.6 There is a similar randomized ongoing trial, and we’ll be reporting [results] in the near term. The difference was that TRITON2 required prior AR therapy and 1 taxane regimen. The trial used the standard dose of rucaparib [600 mg twice daily], and the end points were objective response rate and biochemical and radiographic progression.
Investigators needed to screen 1800 patients to get 200 for the trial.7 It’s a challenge to [enroll this number of] patients.
What were the main efficacy findings in TRITON2?
[The radiographic response in] BRCA1/2-mutant disease was pretty impressive.7 A small [percentage of patients achieved a] complete response [CR], about 30% to 40% of patients had a partial response [PR], and a good proportion had stable disease. So unequivocally, rucaparib is an active drug in BRCA1/2-mutated disease in patients who’ve received chemotherapy and an AR drug.
There is very limited activity in other HRR mutations—no CRs in [ATM, CDK12, or CHEK2 alterations], 2 PRs in ATM, and 1 PR [in CHEK2].8 In non–BRCA-[mutated disease], this isn’t a particularly active compound.
Can you describe the safety of rucaparib in TRITON2?
As a PARP inhibitor, rucaparib had the same kind of PARP toxicities that you would expect.7 I don’t think there were any surprises.
How do the FDA approvals of olaparib and rucaparib compare?
Rucaparib was approved in BRCA1- and BRCA2-mutated mCRPC as opposed to the other 12 HRR mutations.9 It was approved in patients post-AR [therapy and] post docetaxel. The approvals of olaparib and rucaparib are different.6,9 The clinical settings in which the approvals were granted are different.
Have you increased your next-generation sequencing testing as a consequence of the PARP approvals?
For 90% of the patients, you’re going to get [testing] for the specific purpose of looking for BRCA [mutations]. You’re not going to find it in maybe 95% of them. But you still do it because you have a therapy to offer.
How often does circulating tumor DNA (ctDNA) testing give a false negative result?
There is increasing evidence from studies that were not directly randomized, but comparative studies looking at tissue and ctDNA showed that in most prostate cancer [cases], we are not missing very much.
There is the concern that as you push these tests earlier and earlier in the disease, when [the patient is] not shedding as much DNA, you may be missing things. The issue is not that it’s a perfect test, but [is] it likely to be representative of what you might see in tissue?
Right now, it’s clearly not entirely defined. However, in prostate cancer, there is no future for tissue-based assays. We’re not going to do bone biopsies in most of our patients. We’re going to use ctDNA assays at some point. I suspect that the technology will get better and better and our confidence in the information will go up.
Have you ever seen a response in a patient who does not have MSI (microsatellite instability)-high disease but does have tumor mutational burden (TMB)-high disease?
Off study, a patient is not going to get immunotherapy if they don’t have MSI[-high] status. I am fortunate to have a number of investigational options of very novel immunotherapy combinations. Patients are responding outside of MSI status. [However], TMB in prostate cancer is even less useful than in many other diseases in which immunotherapy is a standard.
In urothelial cancer, TMB is not very helpful, and MSI is not useful. TMB is a parameter. Prostate cancer is not particularly responsive to immunotherapy as we currently administer it, [and we need] to figure out who’s going to respond.
I have never treated a patient with pembrolizumab [Keytruda] based solely on TMB. In patients with MSI-high disease, which is about 2% of prostate cancer, there is a response. We have little information on TMB, so it wouldn’t be something that I would offer unless I have expended standard options. I certainly wouldn’t use that drug and expect a wonderful response.
Considering the results from PROfound and TRITON2, would you ever give chemotherapy prior to doing a FoundationOne CDx analysis?
No. Our standard practice is [to get testing for patients who] have locally advanced, hormone-sensitive or castration- [resistant] metastatic disease if this is the first time seeing them. All of my patients with mCRPC get genetic testing and almost all of them [get] ctDNA. So I’m going to know the mutations before I make decisions. I’ve given a fair amount of PARP inhibitors. They have a lot of toxicities, [especially in] a patient with metastatic prostate cancer who’s had 3 lines of therapy. Their hemoglobin [hovers] around 10, and you rapidly make it 7.5 [with a PARP inhibitor]. They are really hard drugs to give, and I want to do so early.
If a patient has BRCA2-[mutated disease] and they’ve received hormone-sensitive metastatic therapy, and then maybe abiraterone or enzalutamide, and they progress, I’m going to then give [a PARP inhibitor] to them. It’s an active drug, and it’s better tolerated. This is not an end-of-the-line drug. There are about 12 trials that are going to be reporting [results] over the next 2 years that ask the question, “Can you create BRCA mutations?”
Can you cause synthetic lethality by combining abiraterone or enzalutamide with a PARP inhibitor in non- HRR mutations? There’s some compelling evidence that you might be able to do that, in which case, how we think about this is going to change a lot. Data will start [coming out] over the next 12 months that could revolutionize what we do with PARP inhibitors. But without these data, I’m going to use PARP inhibitors as early as possible in patients who are most likely to benefit.
What is the role of carboplatin when a PARP is not feasible?
Probably platinum therapy, and I have certainly used carboplatin-based chemotherapy in patients prior to [the availability] of PARP inhibitors when I saw [it worked in] HRR mutations and got responses. I will tell you anecdotally in maybe 5 patients who I have given platinum and then had availability to give them a PARP inhibitor, 0 out of 5 responded.
I used carboplatin-based therapy in patients as I could not get a PARP inhibitor when [they were] still investigational, and I saw responses. They’re not durable, but PARP inhibitors [responses] aren’t, for the most part. I think that’s a very important question.
1. NCCN. Clinical Guidelines in Oncology. Prostate cancer, version 2.2021. Accessed March 22, 2021. https://bit.ly/3f56V9i
2. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091-2102. doi:10.1056/ NEJMoa1911440
3. Hussain M, Mateo J, Fizazi K, et al. PROfound: Phase 3 study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations. Presented at: European Society of Medical Oncology 2019 Congress; September 27-October 1, 2019; Barcelona, Spain. Abstract 5059. April 9, 2021. https://bit.ly/3r6xw8o
4. Hussain M, Mateo J, Fizazi K, et al; PROfound trial investigators. Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. 2020;383(24):2345-2357. doi:10.1056/NEJMoa2022485
5. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. News release. FDA. May 19, 2020. Accessed April 9, 2021. https://bit.ly/3jIugw6
6. Abida W, Bryce AH, Vogelzang NJ, et al. Preliminary results from TRITON2: a phase 2 study of rucaparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination repair (HRR) gene alterations. Presented at: European Society of Medical Oncology 2018 Congress; October 19-23, 2018; Munich, Germany. Abstract 3619. April 9, 2021. https://bit.ly/3f9Misy
7. Abida W, Patnaik A, Campbell D, et al; TRITON2 investigators. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol. 2020;38(32):3763-3772. doi:10.1200/JCO.20.01035
8. Abida W, Campbell D, Patnaik A, et al. Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration-resistant prostate cancer: analysis from the phase II TRITON2 study. Clin Cancer Res. 2020;26(11):2487-2496. doi:10.1158/1078-0432.CCR-20-0394
9. FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer. News release. FDA. May 15, 2020. Accessed April 9, 2021. https://bit.ly/3qgIh7v