Recommendations for the use of PARP inhibitors in prostate cancer

A. Oliver Sartor, MD, discusses treatment options for the use of PARP inhibitors in patients with prostate cancer.

In a recent OncViewâ„¢ discussion, A. Oliver Sartor, MDCE and Bernadine Laborde, Professor of Medicine and Cancer Research Professor at Tulane University School of Medicine, as well as Medical Director of Tulane Cancer Center in New Orleans, Louisiana, shared their clinical experiences and their prospects for the use of PARP inhibitors to treat certain patients with prostate cancer.

To start off the discussion, Sartor talked about the basic testing strategies he uses to match patients with the best systemic therapy. “In terms of molecular testing for metastatic disease, I have always [want] do germ line tests. I might also like to get some additional genetics, [such as] somatic genetics within the tumor, ”he said. “I also cover family history when I [begin] analysis of a patient.

Testing for somatic and germline aberrations is important in the treatment of these patients, especially now that targeted therapies become available in this space. “Discoveries like a BRCA mutation, [such as] BRCA2, which can often be taken from primary prostate tissue, [are] important to be able to identify due to [their] therapeutic implications.

Test and overcome obstacles

Sartor said tests for HRR genes such as BRCA1 / 2 and others like AT M, CHEK2, and PALB2 in metastatic castration-resistant prostate cancer (CRPC) can help clinicians identify patients who may be candidates for treatment with the PARP inhibitors olaparib (Lynparza) or rucaparib (Rubraca).

“In a non-genomic way, you can look at immunohistochemistry for things like MSH2 and MSH6– where, for the classic mismatch repair genes, you will obtain a loss of protein coloration. You can also collect it genomically. It’s good to do both, ”said Sartor, adding that testing for microsatellite instability and tumor mutational load can also be useful in determining which patients may receive pembrolizumab (Keytruda) in subsequent treatment lines.

Sartor noted, however, that various obstacles can hinder patient testing, such as reimbursement issues and the inability to obtain adequate samples. “It’s not uncommon for us to have a patient who was seen and diagnosed in a community urology clinic 7 years ago and then presents to me with metastatic disease. If we’re trying to get any archival tissue, then we have to look for this community hospital sample from 7 years ago. It could be a big problem, ”he said.

Treatment selection and monitoring for metastatic CRPC

Sartor said the selection of treatment for patients begins with a basic assessment of the patient’s age and comorbidities. “The 49-year-old marathoner [will be treated] differently from a 99-year-old patient. We have to look at the basic settings. Some people come in with basic thrombocytopenia, and some of the chemotherapy can be particularly problematic, ”he noted.

Doctors should also consider the possibility of treating their patients in a clinical trial. “There is a great evolution going on,” Sartor said. “If you don’t have a specific clinical trial, then [being] Knowing about a nearby center that might be able to offer a good clinical trial is also something to think about.

Next, he advised looking at genomic alterations and previous treatments administered in the non-metastatic setting to further help determine which agents are available to treat patients in subsequent treatment settings.

“You have to look at a variety of parameters, including the cost of what you have to do, affordability, patient insurance and ability to pay. There are a lot of factors included in the decision making, ”Sartor said.

For follow-up, Sartor said he often emphasizes the need for communication between himself and his patients. “I explain it to patients this way: I need to know how you are feeling,” he said.

Other important aspects for monitoring disease progression include laboratory studies, such as complete blood count, complete metabolic panel, liver function and prostate specific antigen (PSA) levels as well as imagery.

“By looking at these factors taken together, we are monitoring the patient’s disease and the toxicities of the therapy. Then we put it together in the context of good patient care and see the patient on a relatively frequent basis, especially when we introduce new therapies, ”Sartor said.

Role of PARP inhibitors in prostate cancer

Although many are familiar with PARP inhibitor therapy in the context of treating ovarian cancer, 2 of these agents have indications for treating people with metastatic CRPC, Sartor said.

In May 2020, the FDA granted full approval to olaparib for the treatment of adult patients with deleterious or suspected deleterious germline disease or a somatic HRR gene mutation who have progression of disease after enzalutamide (Xtandi) or abiraterone (Zytiga).1

Regarding HHR gene mutations, Sartor says data is unclear on genes outside BRCA1 and BRCA2 indicate the best response, but the indication of olaparib allows the treatment of these patients.

“You have a series of other genes, including PALB2, this may be indications for treatment, ”said Sartor (FIGURE).2 “It doesn’t have to be somatic. It turns out that the germ line BRCA1 and BRCA2 may also apply.

The data for this approval comes from the PROfound study (NCT02987543),
a phase 3 trial of olaparib or physician’s choice of enzalutamide or abiraterone in men with metastatic CRPC who have experienced disease progression while receiving a new hormonal agent. Patients were evaluated in 2 cohorts with either 1 alteration of BRCA1 / 2 Where AT M (cohort A) or one of the 12 other pre-specified HHR gene mutations (cohort B).

On initial reading, olaparib demonstrated statistically significant increases in radiographic progression-free survival compared to the control group in Cohort A (RR: 0.34; 95% CI: 0.25-0.47; P P = 0.02) and a numerical benefit in cohort B (HR, 0.96; 95% CI: 0.63-1.49) were noted for overall survival (OS) with the PARP inhibitor. In the overall trial population, olaparib resulted in a median OS of 17.3 months versus 14.0 months with control treatment (RR: 0.79; 95% CI: 0.61-1.03), with 66% of the control group switching to receive olaparib at progression.4

“The overall survival data [were] strong enough despite the crossover, ”Sartor said. “Ultimately, the FDA saw fit to include all homologous recombinant repair genes in the FDA approval.”

Another agent, rucaparib, became available for accelerated approval the same month for patients with germline and / or somatic deleterious diseases. BRCA disease associated with a mutation that had previously received treatment with androgen receptor directed therapy and taxane chemotherapy.5 Maintaining this indication will depend on confirmation from a randomized trial.

The data to support this decision comes from the phase 2 trial TRITON2 (NCT02952534), in which rucaparib was examined in men with metastatic CRPC with alterations in BRCA1 Where BRCA2 who progressed after 1 or 2 previous lines of new generation antiandrogen therapy and 1 previous taxane-based chemotherapy. The objective response rate by independent radiological examination was 43.5% (95% CI, 31.0% to 56.7%) and according to the investigator’s assessment was 50.8% (95% CI %, 38.1% to 63.4%), the responses being similar regardless of germline or somatic mutations. The confirmed PSA response was 54.8% (95% CI, 45.2% to 64.1%).6

With rucaparib, Sartor said it was possible to reduce the treatment dose in patients who respond well. “If you get a good response in a patient, then you can create an even lower dosage and potentially have good activity. I have a patient right now on 300 mg once a day, and he’s having a great response. He was suffering from severe anemia when he entered it, and he had a PALB2 [mutation] Rather than a BRCA [mutation]. He just cannot tolerate the 300 mg twice daily dose; we had to cut it down for the anemia, ”Sartor said.

Anemia is one of the most common side effects seen with this agent, along with fatigue and gastrointestinal effects, but “anemia is present in virtually all patients with metastatic CRPC, so not everyone will not be affected to the same degree, ”noted Sartor. .

Sequencing of therapies

From the start, Sartor said he plans to use hormones to treat his patients first. “I’m trying to get the new hormones [into treatment] first, because we have an accumulation of data whose earlier use translates into better benefits in terms of survival, ”he said. “In fact, we have a lot of new data that demonstrates in the castration-sensitive space [that] if you deal with these new hormones you have an incredible effect on overall survival.

After that, treatment options are scarce, with clinicians relying on genomics and precision medicine to select the next therapy.

To conclude, Sartor said physicians should be aware of several factors when treating their patients, including the use of a new initial hormone therapy, the appropriate use of taxanes, the possibility of clinical trials, and the use. biomarkers. “There are [many] things you need to be open to — a [being] the idea of ​​precision medicine, ”he said.

The references

1. The FDA approves olaparib for metastatic, castration-resistant prostate cancer mutated with the HRR gene. FDA. Updated May 20, 2020. Accessed November 5, 2021.

2. NCCN. Clinical practice guidelines in oncology. Prostate cancer, version 1.2022. Accessed November 5, 2021.

3. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N English J Med. 2020; 382 (22): 2091-2102. doi: 10.1056 / NEJMoa1911440

4. Hussain M, Mateo J, Fizazi K, et al. Survival with olaparib in metastatic castration-resistant prostate cancer. N English J Med. 2020; 383 (24): 2345-2357. doi: 10.1056 / NEJMoa2022485

5. FDA grants fast-track approval to rucaparib for

Metastatic castration-resistant prostate cancer with BRCA.FDA mutation. Updated May 15, 2020. Accessed November 5, 2021.

6. Abida W, Patnaik A, Campbell D, et al; TRITON2 investigators. Rucaparib in men with metastatic castration-resistant prostate cancer with BRCA1 Where BRCA2 alteration of genes. J Clin Oncol. 2020; 38 (32): 3763-3772. doi: 10.1200 / JCO.20.01035

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