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Department of Medicine (Oncology)
University of Washington
Division of Clinical Research
Fred Hutch Cancer Center
Heather H. Cheng, MD, PhD, has disclosed that she has received consulting fees from AstraZeneca and funds for research support from Astellas, Clovis, Color Genomics, Janssen, Medivation, Phosplatin, and Sanofi.
In association with the 2022 ASCO Genitourinary Cancers Symposium, experts presented a live program titled “PARP Combination Therapies: A New Horizon in Prostate Cancer Care.” Here, Heather H. Cheng, MD, PhD, addresses topics that were raised by the audience during the question and answer session of this program.
Treatment After Progression on PARP Inhibitor Monotherapy
Both olaparib and rucaparib are approved for use in certain patients with metastatic castration-resistant prostate cancer (mCRPC). Olaparib is indicated for use in patients with homologous recombination repair (HRR) mutations who progressed on prior enzalutamide or abiraterone. Rucaparib is indicated for patients who have a BRCA mutation and previously have been treated with an androgen receptor (AR) inhibitor and taxane-based chemotherapy.
Patients With mCRPC and a BRCA2 Mutation
For patients with mCRPC associated with a BRCA2 mutation, it’s fantastic that we have olaparib and rucaparib as treatment options. Some patients respond very well to these agents, for example, with symptomatic improvement, dropping prostate-specific antigen (PSA) levels, and visible improvement on their scans. Ideally, we hope that patients have multiple years of response before the treatment is no longer effective. However, patients eventually develop resistance to PARP inhibitors, as indicated by changes in those same parameters—perhaps the patient begins to feel bad due to symptoms from their cancer, they have new lesions on scans, and their PSA is going up. This leads to the frequent question about how to treat a patient with mCRPC and a BRCA2 mutation who progresses after achieving response to PARP inhibitor monotherapy.
For a patient who develops PARP inhibitor resistance, I would discourage continuation of PARP inhibitor monotherapy. There is strong emerging evidence that one of the major resistance mechanisms to PARP inhibition is restoration of BRCA function, sometimes observed as a result of reversion of the inactivating mutations in a way that re-establishes a functional BRCA2 gene in the resistant cancer cells. Those cells would no longer be expected to be sensitive to PARP inhibitors. My next step in that situation would depend on what therapy the patient had prior to the PARP inhibitor, but I might consider AR‑targeted therapy if it has been several years since they have last been treated with one, or chemotherapy if they have not already received docetaxel. Cabazitaxel can be used if docetaxel was given recently and/or had limited benefit. We also know that platinum‑based therapy can be a very effective approach for patients whose cancers have BRCA2 alterations, for example, and sometimes can be effective after a PARP inhibitor, so incorporating carboplatin may also be worth considering. Radium-223 and the newly FDA-approved lutetium Lu 177 vipivotide tetraxetan may also be considered.
Some patients show a suboptimal response to PARP inhibition. Their PSA may initially drop, but within a few months, it begins to rise with evidence of radiographic or symptomatic progression. For these patients, I also would be concerned about the effectiveness of ongoing PARP inhibitor use and the approaches I just described can also be considered in this context.
Patients With mCRPC and Other HRR Mutations
Less is known about resistance to PARP inhibitor therapy in patients who have other HRR mutations. Patients with mutations in PALB2 are eligible to receive olaparib, and there has been at least one report where resistance was associated with reversion of PALB2—this supports the idea that PALB2 inactivating mutations are associated with response to PARP inhibitor therapy. In general, the concept of resistance due to reversion mutations may be true for other HRR genes as well, although more research is needed, of course. But generally, for patients whose prostate cancer has progressed on a PARP inhibitor after a prior response, I would probably change treatment strategies. Until there is data to suggest otherwise or if it is in the context of a clinical trial, I would generally not consider changing to a different PARP inhibitor.
PARP Inhibitor Combination Therapy
Now, we have new randomized, double-blind, placebo-controlled phase III trials exploring the use of PARP inhibition in combination with an AR inhibitor as initial treatment for mCRPC.
Phase III Data From MAGNITUDE and PROpel
At ASCO Genitourinary Cancers Symposium, we saw new data from the MAGNITUDE trial of niraparib in combination with abiraterone and prednisone, and from the PROpel trial of olaparib with abiraterone and prednisone. The PROpel data showed significant improvement in radiographic progression-free survival (PFS) in patients who received olaparib compared with patients who received placebo, with an HR of 0.65. This radiographic PFS benefit was reported regardless of HRR mutation status, which was assessed retrospectively using tissue biopsies or blood samples obtained at baseline. Interestingly, the MAGNITUDE trial reported similar findings in patients with HRR mutations, but different outcomes in patients without HRR mutations, which were identified by prescreening of tissue biopsies or blood samples before randomization. The cohort of patients without HRR mutations met a prespecified futility endpoint and was stopped early due to a lack of benefit, but patients with HRR mutations—especially those with BRCA1 or BRCA2 mutations—were shown to have a survival benefit with niraparib in combination with abiraterone and prednisone compared with placebo in combination with abiraterone and prednisone. Based on these trials, it appears that the addition of a PARP inhibitor to an AR‑targeted agent does seem to have benefit, at least in patients with HRR mutations. The discrepancy in outcomes between MAGNITUDE and PROpel among patients without HRR mutations is intriguing and merits further follow up to understand the basis for the differences observed in the two studies.
I would like to see more data before deciding whether to offer a PARP inhibitor combination upfront to patients without an HRR mutation or to those who are unselected. For patients whose cancers are associated with BRCA2 mutations, I think both studies clearly demonstrate that a PARP inhibitor combination is an effective option and worth considering. If we can address additional practical considerations associated with these combination therapies, such as the affordability of not one but two potentially expensive drugs, I think this paradigm has clinical benefit. But I do think we need to review the details further. The PROpel trial did not stratify patients by HRR status, and we need to understand with better granularity the types of mutations and the way they were assigned as HRR mutant vs nonmutant in both cohorts. Their use of circulating tumor DNA to assess HRR mutation status is an exciting prospect, but we also need a clearer understanding of whether the use of different methods and timing of sampling may have affected how people were assigned to HRR mutant or nonmutant cohorts. These warrant a closer look as we consider both trials and other important studies that we anticipate reading out soon.
Other Ongoing Trials of PARP Inhibitor Combination Therapy
Two other ongoing phase III studies may offer some additional insight. The phase III TALAPRO‑2 study (NCT03395197) is evaluating talazoparib plus enzalutamide vs placebo plus enzalutamide as first-line therapy in mCRPC. This study is designed to look at DNA damage repair (DDR) status, with planned analysis of DDR-mutant and DDR-unselected populations. The CASPAR study (NCT04455750) is investigating enzalutamide with or without rucaparib. HRR mutation is not required for enrollment, but a secondary analysis will evaluate outcomes by HRR mutation status. Although these trials are using different agents, they should give us more information about AR‑targeting with PARP inhibitor combinations in patients without HRR mutations.
Dosing in PARP Inhibitor Combination Therapy
One hypothesis about why the MAGNITUDE trial didn’t show a PFS benefit in patients without an HRR mutation is that the trial used a 200 mg dose of niraparib, lower than the 300 mg dose used for monotherapy. Any combination therapy must be tolerable for the patient and reducing the dosing of one or more of the agents when used in a combination is not uncommon in my clinical practice. So although it is possible that the dosing could have affected efficacy in this trial, I think that the 200 mg dose is reasonable when considering tolerability and patient quality of life. I am personally more interested in further understanding the details of biomarker detection and assignment of patient HRR status than in the dosing.
Moving PARP Inhibitor Combination Therapy Into Earlier Settings
Following the general pattern in oncology to first define efficacy and benefit of drugs in later stages of disease and then moving them into earlier stages of disease, there is interest in evaluating PARP inhibitor therapy in earlier settings of prostate cancer. Early results from trials such as MAGNITUDE and PROpel support the biological rationale for combination therapy with a PARP inhibitor and AR-targeted agent in mCRPC. Now we can ask, can we leverage this therapy earlier—in the metastatic hormone‑sensitive setting or even at biochemical recurrence? If the biological rationale is there, why not?
There are a few exciting trials underway looking at the same PARP inhibitor combination therapies that we discussed above in earlier stages of disease. For example, the AMPLITUDE phase III trial (NCT04497844) is testing the same combination as MAGNITUDE, niraparib and abiraterone plus prednisone, but in metastatic hormone‑sensitive prostate cancer. The TALAPRO-3 phase III trial (NCT04821622), like TALAPRO-2, is investigating talazoparib and enzalutamide also in the metastatic hormone‑sensitive prostate cancer setting. There are also ongoing phase II trials, such as the ZZ-First study (NCT04332744) of talazoparib plus enzalutamide and a study of olaparib plus abiraterone and prednisone (NCT05167175) in hormone-sensitive disease. If these trials show benefit of PARP inhibition, perhaps we can consider moving PARP inhibition into the neoadjuvant setting. If we can identify the patients most likely to benefit from PARP inhibition, can we use it prior to surgery with a curative intent? I think that’s probably the most exciting part of seeing that these agents are efficacious and well tolerated. Right now, we can use them to help people in the later stages of disease, but in the future, we can explore the role of using them early enough that patients need not progress to needing them in the advanced stages of disease.
What questions do you have about PARP inhibitor therapy for prostate cancer? Do you currently use PARP inhibitors or consider clinical trials of PARP inhibitor combination therapy for your patients with newly diagnosed metastatic prostate cancer? Answer the polling question and join the conversation by posting a comment in the discussion section.