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Spotlight

This roundtable series assesses treatment after first-line progression for patients with deleterious germline or somatic homologous recombination repair-mutated metastatic castration-resistant prostate cancer, as discussed by key opinion leaders and participants at virtual live events.

Options Post First-Line Progression in mCRPC With HRR Mutations

Targeted Oncology: What is the significance of the phase 3 PROpel trial (NCT03732820) of olaparib (Lynparza) plus abiraterone acetate (Zytiga) for metastatic castration-resistant prostate cancer (mCRPC)?

This [combination] is moving from later-stage mCRPC up into the first line of mCRPC. The PROpel study included patients who had potentially had docetaxel [Taxotere] in the metastatic hormone-sensitive setting, no prior treatment with abiraterone, and no exposure for most of the patients to any of the other novel intensive hormonal agents. Patients were essentially those with first-line mCRPC, and they were randomly assigned to treatment with abiraterone, which is a standard of care in first-line mCRPC, with or without olaparib. This was an all-comers patient population.

After enrollment, before data analysis, they did assess patients for their germline and somatic alterations to try to understand that, but that was not known at the time of randomization. The primary end point here was radiographic progression-free survival [rPFS] in the overall all-comer population, with overall survival (OS) being the key secondary end point, and then of course they did look at patients by the HRR [homologous recombination repair] alteration status.

The baseline characteristics showed that just under 30% of patients had an HRR alteration.

 The teams used tissue to try to understand the HRR status and then also did circulating tumor DNA test as a backup, but for about 2% of patients they couldn’t. This was a pretty [fit] group, with the majority of patients having an ECOG performances status of 0 and most of these patients were not symptomatic. Only about 20% of patients had exposure to docetaxel in the hormone-sensitive setting.

For investigator-assessed rPFS, the combination of olaparib and abiraterone had a 34% reduction in the risk of progression or death than abiraterone alone. Abiraterone is the standard of care in this setting. This is an incredibly effective first-line treatment for mCRPC in a population that did not get prior AR exposure. To benefit on top of that is interesting to me and it’s also interesting that this is an all-comers population, so it includes people with HRR mutations and without. The HR was 0.66 [95% CI, 0.54-0.81; 

What are the most recent updates to these results?

We saw at the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium [ASCO GU] that this was updated and it continues to show this benefit with an HR that holds at 0.66.

Those patients who did have the HRR mutations have a significantly improved rPFS. Even those patients who were negative for HRR had a significant improvement in rPFS. [This is] just an interesting piece of the data here, a subgroup analysis not powered for this. Patients with 

 mutation have a way bigger benefit than patients who had an HRR mutation but were not 

OS was a temporally driven end point, so the investigators said that at these time points we’re going to get these analyses, and the final OS analysis by time [were presented at ASCO GU]. But it didn’t have enough events to…meet the power needed to answer this question.

The HR for OS in the all-comers population is trending in the right direction, but the 

 value is not statistically significant because they did so many looks at the data [HR, 0.81; 95% CI, 0.67-1.00; 

 = .0544]. You would need to have a lot more zeros in there to reach statistical significance. They are going to do another analysis.

But if we look at the median OS between these 2 arms, 42 months for the all-comers population in the combination versus 34 months for the abiraterone alone, [it is a] highly effective first-line treatment for mCRPC. That’s a big numerical difference, [though] not quite statistically significant.

Which types of patients benefited most? Did those without HRR mutations benefit?

In the non-HRR patients, in the abiraterone/olaparib group, there’s about a 3.5 month improvement, [which is] not statistically significant in OS. There’s a possibility that these are equivalent, but it’s numerically separating and that’s difficult to understand why that’s happening in a group that should not have any benefit at all from PARP inhibitors as far as we know. It’s interesting that there is at least this rPFS that’s statistically significant even in the non-HRR mutation [population]. The all-comers data is being pulled by the 

 and the HRR. But, when we look only at the non-HRR, there’s still a statistically significant improvement in rPFS and it’s difficult to sort.

What stood out in regard to safety and tolerability of the combination on this trial?

The adverse events suggest that there are not any new safety signals.

Cytopenias still are an issue with PARP inhibitors, [as well as] fatigue and some gastrointestinal [toxicities]. They also noted incidental pulmonary embolisms were numerically greater in patients getting the combination. If this becomes a combination that we use in the clinic, we are going to have to be careful and note when our patients have lower extremity swelling or shortness of breath. We have to look for deep vein thrombosis and pulmonary embolism. It was a numerical difference, did not seem statistically significant, but it is something for all of us clinicians to keep an eye on.

1. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al; PROpel Investigators. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. 

2. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. Final overall survival (OS) in PROpel: abiraterone (abi) and olaparib (ola) versus abiraterone and placebo (pbo) as first-line (1L) therapy for metastatic castration-resistant prostate cancer (mCRPC). 

. 2023;41(suppl_6):LBA16. doi:10.1200/JCO.2023.41.6_suppl.LBA16

During a Targeted Oncology™ Case-Based Roundtable™ event, Alicia K. Morgans, MD, MPH, discussed results of the phase 3 PROpel trial of patients with metastatic castration-resistant prostate cancer. This is the second of 2 articles based on this event.

Olaparib/Abiraterone Shows rPFS Benefit in mCRPC Regardless of HRR Status

Where do you sequence PARP inhibitors for eligible patients with mCRPC (metastatic castration-resistant prostate cancer)? What do you consider optimal? ​

What is your approach for patients who progress on a PARP inhibitors? ​

 pathogenic HRR (homologous recombination repair) mutation? ​

Do you ever consider something other than a PARP inhibitor for non-

 pathogenic HRD (homologous recombination deficient) mutations? ​

If yes, for which mutations? What treatment do you consider? ​​

 Where do you sequence your PARP inhibitors for eligible patients with mCRPC? What are you thinking about as being optimal?

 I would think after the initial treatment, whether it’s a new patient and if they’re going to get doublet or triplet treatment. It would probably be as a second line when there is progression [that I would use a PARP inhibitor].

 That’s a completely fair answer. There’s no right answer here. Dr Bjornson, what do you think about this patient population when they have a germline or a somatic 

 alteration? When would you sequence in a PARP inhibitor, if at all?

 Does anybody feel like they would wait and use a PARP inhibitor in a later line of therapy after something else?

 positive, and I went through the initial lines of AR [androgen receptor] targeting, then chemotherapy. He progressed through the chemotherapy without having any response…. So I put him on olaparib [Lynparza] and he had a very good response, but the problem was it was not [durable]…. He was like a different person, but over 4 or 5 months it progressed. Just from that experience alone, I would say I would discuss [using it] earlier on.

 It sounds like this patient got treatment later, had a response that was pretty transformative. However, it was short-lived.

 Yes, it was a deep response but short-lived.

 What is your approach when a patient progress on a PARP inhibitor?

 [My patient] unfortunately decided not to pursue anything else. He had significant comorbidities.

 It sounds like he had had a lot of disease burden…to begin with, and we were happy for the time that he got, but it sounds like he was borderline in terms of performance status even when he got to the next line.

 Yes, and he decided to go on hospice. But had he decided to get treated, I don’t know what I would have offered him. We had run through everything else before.

 That sounds like that was the right decision for that patient. Dr Cheung, have you treated any patients with PARP inhibitors, and have you had to make a decision about treating them with something when they had disease progression?

 I use it…as the second line. If they progress on it, chemotherapy would be my first choice as a third line.

 That makes sense because you’ve just used it as a second line. If this patient had an 

 mutation, would you do something different?

 I would probably use it as a third line in a patient with an 

 after a prolonged battle with the insurance company, but they finally gave in. I didn’t get a great response. I don’t know [if this was] because I used it as third or fourth line [in a patient with] 

 That is an interesting experience because that’s what the data suggested that when we look at some of these other alterations, some of them seem to have a strong response. 

 [did not have] a good response; there may be evidence of AR-targeted agents being better.

 A lot of patients didn’t seem to necessarily have a response, so it's interesting to hear that. Dr Pickus, if you had a patient with a 

 alteration, would your decision making be different? Would you use something else rather than a PARP inhibitor early on?

 Certainly if they have an HRR mutation or a 

 mutation, I would consider using a PARP inhibitor. Other than that, I’d probably look to other options, depending on what they’ve already gotten. If they haven’t had chemotherapy or docetaxel, I’d use a taxane. If they did, then I might consider cabazitaxel [Jevtana] with carboplatin.

 The [PROfound] trial [NCT02987543] randomly assigned patients to a different AR blocker [versus olaparib].

 We know they don’t work very well in sequence. Is that fair? Shouldn’t they have been randomly assigned to cabazitaxel versus a PARP inhibitor?

 Thank you for bringing that up. First of all, I would say that there’s a lot of back-to-back AR-targeting agents still happening, particularly in urology practices. There’s geographic difference. I would say here in New England, physicians [understand]…the similar resistance mechanisms and they’re not sequencing [AR targeting agents]. But in other parts of the country and certainly around the world, they still are, which is unfortunate.

But this trial was designed before we had…overwhelming data that showed that the back-to-back—or even sequential with something else in between—use of these AR-targeted agents is ineffective.

 It’s almost treating somebody with a placebo and I think that’s why you’re asking the question. But I would say that when the study was designed, we didn’t have strong evidence. This study is a few years old now, and, in fact, I use the control arm as another piece of evidence to tell physicians to stop sequencing AR-targeted agents.

1. Zhao Z, Kurimchak A, Nikonova AS, et al. PPP2R2A prostate cancer haploinsufficiency is associated with worse prognosis and a high vulnerability to B55α/PP2A reconstitution that triggers centrosome destabilization. 

. 2019;8(12):72. doi:10.1038/s41389-019-0180-9

2. Hussain M, Mateo J, Fizazi K, et al. Survival with Olaparib in metastatic castration-resistant prostate cancer. 

 2020;383(24):2345-2357. doi:10.1056/NEJMoa2022485

3. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. 

 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440

4. Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL, Chi KN. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. 

. 2013;24(7):1802-1807. doi:10.1093/annonc/mdt138

5. Bianchini D, Lorente D, Rodriguez-Vida A, et al. Antitumour activity of enzalutamide (MDV3100) in patients with metastatic castration-resistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone. 

. 2014;50(1):78-84. doi:10.1016/j.ejca.2013.08.020

6. Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL, Chi KN. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. 

During a Targeted Oncology™ Case-Based Roundtable™ event, Alicia K. Morgans, MD, MPH, and participants discussed situations when they would use a PARP inhibitor to treat patients with metastatic castration-resistant prostate cancer in the second or third line. 

This is the first of 2 articles based on this event.