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PARPi Plus ARSI in mCRPC
My Thoughts on the Use of PARP Inhibitor Plus AR-Signaling Inhibitor Combinations for Our Patients With mCRPC

Released: September 27, 2023

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Key Takeaways
  • The recent approval of 3 different combinations of a PARP inhibitor plus an androgen receptor–signaling inhibitor for frontline metastatic castration-resistant prostate cancer offers additional therapeutic options for selected patients.
  • Healthcare professionals need to be aware of the varying approved indications for these combinations and for single-agent PARP inhibitors.
  • Among factors to consider when selecting therapy is the presence of HRR mutations, including BRCA1/2 mutations and any previous therapy that the patient has received for prostate cancer.

In this commentary, I will address some of the factors to think about when considering using one of the recently approved combinations of a PARP inhibitor plus an androgen receptor–signaling inhibitor (ARSI) in metastatic castration-resistant prostate cancer (mCRPC).

Germline and Somatic Tumor Testing for HRR Gene Mutations

Single-agent PARP inhibitors and the new combinations with an ARSI have varying indications based on the type of homologous recombination repair (HRR) mutation present. We generally perform germline testing for BRCA1/2 and other HRR mutations at diagnosis of metastatic or advanced disease. BRCA1/2 mutations are both prognostic and predictive in that the presence of these mutations potentially can guide therapy selection. Germline testing also can inform cascade testing for family members and inform screening for other malignancies for an individual patient.

Somatic tumor profiling on biopsy tissue is generally preferred, but circulating tumor DNA can be tested. My preference is to perform somatic testing up front when patients are diagnosed with metastatic disease, and that helps me understand how I might sequence their therapies later should they develop castration-resistant disease. I perform somatic testing throughout the course of therapy as a patient’s disease evolves, as exposure to different treatments or the development of new sites of metastases or organ-based metastases may cause mutations to evolve or new mutations to develop.

Factors to Consider When Selecting Therapy for Patients With HRR Gene Mutations

Of importance, the indications for the PARP/ARSI combinations and monotherapy PARP inhibitors are quite different. The indication for olaparib plus abiraterone is for patients with deleterious or suspected deleterious BRCA-mutated mCRPC, whereas the indication for single-agent olaparib is for patients with deleterious or suspected deleterious HRR gene–mutated mCRPC who have progressed following prior treatment with enzalutamide or abiraterone. Like olaparib plus abiraterone, niraparib plus abiraterone is indicated for patients with deleterious or suspected deleterious BRCA-mutated mCRPC. The combination of talazoparib plus enzalutamide has a broader indication for patients with HRR gene–mutated mCRPC. Rucaparib is indicated for patients with a deleterious BRCA mutation (germline and/or somatic)–associated mCRPC who have received androgen receptor–directed therapy and a taxane-based chemotherapy.

When selecting patients for PARP/ARSI combination therapy, the major thing that I consider is which therapies the patient has previously received. Within the 3 studies that looked at an ARSI plus a PARP inhibitor, there were few patients enrolled who had received treatment beyond androgen deprivation therapy (ADT) alone. In the PROpel study of olaparib plus abiraterone, no patients had received an ARSI, and in the TALAPRO-2 study of talazoparib plus enzalutamide, 6% had received an ARSI. In the MAGNITUDE study of niraparib plus abiraterone, 4% had received an ARSI in the metastatic hormone-sensitive prostate cancer (mHSPC) or nonmetastatic CRPC setting. However, 25% received abiraterone for mCRPC for ≤4 months prior to enrolling on trial. There were 20% to 25% of patients who had received docetaxel enrolled on these trials. Thus, the number of patients who previously had received an ARSI or docetaxel was low, but in modern clinical practice the majority of patients with mHSPC now receive escalated therapy with, at a minimum, the addition of an ARSI to ADT and sometimes triplet therapy with the addition of docetaxel and an ARSI to ADT.

Type of HRR Mutation
Another thing I consider is the type of DNA alteration present. Individuals with a BRCA1/2 mutation seem to respond the best to PARP inhibitors, followed by patients with PALB2 mutations. I think the degree of benefit appears to be less in individuals with other HRR mutations, but I would not say the benefit is zero, so there is still a signal of efficacy with the dual therapy. I think the choice of therapy depends on balancing goals of the patient, assessing the toxicity associated with treatment, and understanding that there is not a strong overall survival signal in those specific subgroups. The data are limited just because the number of patients enrolled on the 3 trials with the rarer HRR alterations was really low.

Single-Agent PARP Inhibitor vs Combination Therapy
If a patient previously had been exposed to an ARSI, the data for dual therapy are actually quite limited. Approximately 50 patients on the TALAPRO trial and even fewer on the MAGNITUDE trial had received an ARSI, and there are no data for olaparib plus abiraterone in that context. If a patient has been receiving an ARSI for a long time, they have a BRCA1/2 alteration (tumor or germline), and then they develop progressive CRPC, there are not strong data on the use of the combination in these patients. This is a scenario where using either single-agent olaparib or rucaparib might be a better choice than a combination.

Comorbidities and Adverse Events With Combination Therapy
The combinations carry a risk of increased cardiovascular toxicity and an increased risk of embolism, although the rates are quite low. Anemia and fatigue are common. With enzalutamide, the most important thing to consider is the potential for drug–drug interactions, so for the combination of enzalutamide plus talazoparib, an accurate evaluation of other medications the patient is receiving is key. We also consider patient factors, including performance status and comorbidities such as prior history of venous thromboembolism, in addition to other medications. These are all things that factor into the selection of therapy.

Conclusion
It has really been exciting to see the advent of new combination strategies for frontline mCRPC. I think we have moved the needle for our patients who for some reason did not receive an ARSI in the mHSPC setting and have a BRCA1/2 alteration. I think the data are quite strong for using the combination of an ARSI with a PARP inhibitor up front for frontline mCRPC in that situation. Where the combinations fit for patients who already have received an ARSI is one of several areas that we need to learn more about and understand as the data evolve. The next series of trials is looking at the application of PARP inhibition in combination with ARSIs in the mHSPC setting, and several trials are underway—such as TALAPRO-3 (NCT04821622) and AMPLITUDE (NCT04497844)—that will help provide some answers on PARP/ARSI combinations in mHSPC.

Your Thoughts?
How are you using PARP/ARSI combinations in your clinical practice? Answer the polling question and join the conversation by posting a comment.

In addition, in collaboration with Alicia Morgans, MD, MPH; Tanya B. Dorff, MD; Michael Schweizer, MD; David VanderWeele, MD, PhD; and myself, Clinical Care Options developed an online treatment decision support tool to provide expert recommendations on prostate cancer treatment including the use of PARP inhibitors. When you are considering treatment options for your patients in clinical practice, enter their specific characteristics into the tool to see what we recommend and let us know what you think.

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