Physicians Discuss When to Use a PARP Inhibitor in mCRPC

Alicia K. Morgans, MD, MPH (Moderator)

Associate Professor of Medicine

Feinberg School of Medicine

Northwestern University

Chicago, IL

DISCUSSION QUESTIONS

• 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? ​
• What if a patient had a non-BRCA pathogenic HRR (homologous recombination repair) mutation? ​
• Do you ever consider something other than a PARP inhibitor for non-BRCA pathogenic HRD (homologous recombination deficient) mutations? ​
• If yes, for which mutations? What treatment do you consider? ​​

ALICIA K. MORGANS, MD, MPH: Where do you sequence your PARP inhibitors for eligible patients with mCRPC? What are you thinking about as being optimal?

PHILIP BROOKS, MD: 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].

MORGANS: 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 BRCA2 alteration? When would you sequence in a PARP inhibitor, if at all?

BARBARA BJORNSON, MD: With progression after the prior agent.

MORGANS: So you’d use it early on in mCRPC?

BJORNSON: Definitely.

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

ANKUR MEHTA, MD: I had 1 patient more recently who was BRCA 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.

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

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

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

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

MORGANS: 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.

MEHTA: 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.

MORGANS: 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?

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

MORGANS: That makes sense because you’ve just used it as a second line. If this patient had an ATM mutation, or maybe a CDK12 mutation, would you do something different?

MARK SHPARBER, MD: I would probably use it as a third line in a patient with an ATM [mutation]. I did use it for ATM 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] ATM.

MORGANS: 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. PPP2R2A [did not have] a good response; there may be evidence of AR-targeted agents being better.¹ But ATM was pretty much right down the middle.² 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 CHEK2 alteration, would your decision making be different? Would you use something else rather than a PARP inhibitor early on?

OWEN PICKUS, DO: Certainly if they have an HRR mutation or a BRCA 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.

SHEILA DONNELLY, MD: The [PROfound] trial [NCT02987543] randomly assigned patients to a different AR blocker [versus olaparib].³ 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?

MORGANS: 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.^4-6 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.

_References:

_{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. Oncogenesis. 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. N Engl J Med. 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. N Engl J Med. 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. Ann Oncol. 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. Eur J Cancer. 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. Ann Oncol. 2013;24(7):1802-1807. doi:10.1093/annonc/mdt138}