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PARPi Combinations in Prostate Cancer
My Thoughts on Expanding the Role of PARP Inhibitors in Prostate Cancer With Combination Therapy

Released: January 25, 2021

Expiration: January 24, 2022

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Men with metastatic castration-resistant prostate cancer (mCRPC) whose cancer has become resistant to endocrine therapy or taxanes have no available treatments that can improve their outcomes or curative therapies. More advances in treatment for this population are urgently needed.

Approximately 20% to 30% of all advanced prostate cancers have defects in DNA repair pathways, and some of these defects affect genes that are known to sensitize tumors to PARP inhibitors. Alterations in BRCA2 are the most common genomic DNA repair alteration in prostate cancer, occurring in approximately 10% of patients. It is important to note that significant proportions of these cancers have germline alterations that mandate cascade testing of family members. PARP inhibitors have demonstrated antitumor activity for prostate cancer with DNA repair defects. BRCA‑altered prostate cancers are the molecular subset that derive the most benefit from PARP inhibitors, although we have evidence for benefit in prostate cancers with other types of DNA repair defects.

PARP inhibitors have been approved as single-agent therapy in both Europe and the United States to treat mCRPC. In Europe, olaparib is approved based on the phase III PROfound trial as monotherapy for the treatment of adult patients with mCRPC cancer and BRCA1/2-mutations (germline and/or somatic) who have progressed following previous therapy that included a new hormonal agent. In the United States, olaparib and rucaparib are approved with different indications. Olaparib approval in the United States is for patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene–mutated mCRPC who have progressed following prior treatment with enzalutamide or abiraterone. The indication includes mutations in 14 HRR genes. Accelerated approval of rucaparib in the United States is for patients with deleterious BRCA mutation (germline and/or somatic)–associated mCRPC who have been treated with androgen receptor (AR)–directed therapy and a taxane-based therapy. Approval is based on a nonrandomized phase II trial focused on the BRCA-mutated patient population (TRITON2). There are other promising PARP inhibitors showing similar antitumor activity in prostate cancer, specifically talazoparib and niraparib. In addition, numerous combination strategies using PARP inhibitors are being evaluated in clinical trials, many in unselected patient populations with the potential to expand the utility of PARP inhibitors in prostate cancer.

PARP Inhibitors Plus Androgen Receptor Targeted Therapies
When combining therapies, one must keep in mind toxicity profiles. The main toxicity of PARP inhibitors is anemia and, to a lesser extent, neutropenia and thrombocytopenia. This means that PARP inhibitors can be safely combined with drugs that do not affect the hematologic indices, and that includes endocrine agents like enzalutamide and abiraterone as well as immunotherapy.

Evidence for this approach comes from a double‑blind, randomized, placebo‑controlled, phase II trial of olaparib and abiraterone/prednisone vs abiraterone/prednisone alone in patients with mCRPC after docetaxel and with no previous second-generation hormone therapy (N = 142). The primary endpoint of radiographic PFS, based on Response Evaluation Criteria in Solid Tumors and Prostate Cancer Clinical Trials Working Group 2 criteria was 13.8 months with olaparib plus abiraterone and 8.2 months for placebo and abiraterone. This trial was not powered for OS and no difference in OS was observed between the arms. There was no molecular genomic selection built into this trial, which, I would argue, would have been key for seeing a survival difference. Of note, data from this trial suggested a significant increase in myocardial infarctions with the combination arm, 4 vs 0 for the control arm, which do need to be further evaluated.

What is the basis for combining PARP inhibitors with these AR pathway–targeting drugs such as abiraterone and enzalutamide? One argument is that PARP inhibition has been shown to have some impact on AR signaling, affecting the transcriptional changes induced by the AR, which may increase the benefit imparted by abiraterone. In my opinion, the data would indicate that the impact of PARP inhibitors in tumors that do not have a DNA repair defect does not result in tumor kill, but more a cytostatic effect. Another hypothesis that may support the pursuit of these combinations is that PARP inhibition may affect subclones that cause resistance to abiraterone and enzalutamide. We have incontrovertible evidence from multiple cancers that combination therapy may be superior to single‑agent treatment. Perhaps by combining AR pathway–targeting agents with PARP inhibition, the combination may be superior to the single agent in eradicating subclones that are resistant to these next-generation hormonal agents like abiraterone and enzalutamide.

There are numerous phase III trials of similar design exploring combinations of PARP inhibition plus AR pathway directed therapy as first-line therapy in mCRPC. The TALAPRO2 (NCT03395197) and CASPAR (NCT04455750) trials combine enzalutamide with either talazoparib or rucaparib, respectively. Two other trials, PROpel (NCT03732820) and MAGNITUDE (NCT03748641), pair olaparib or niraparib with abiraterone/prednisone, respectively. I think it is very important for the community to understand that these trials are not enrolling selected populations except for MAGNITUDE, which does have a cohort of patients with HRR mutations. However, each trial is performing biomarker analyses so that they will be able to analyze subgroups of patients with DNA repair defective tumors. The primary endpoint for these trials is radiographic PFS, with CASPAR having a coprimary endpoint of OS. In my opinion, there would be merit for these trials to pursue patient selection, particularly selection for patients whose tumors already have a DNA repair defect in a subclone or a major truncal clone. I think that improvement in OS, which is a key secondary endpoint, and what we would all like to see, may be affected by the lack of selection in these trials.

Additional PARP Inhibitor Combination Strategies
I should note that we also have evidence that a small number of prostate cancers, approximately 3% to 5%, have mismatch repair defects and these tumors, as well as the CDK12 biallelic–altered prostate cancers, can have quite profound, spectacular responses to immunotherapy. PARP inhibition merits combination studies with immunotherapy, based on the fact that there is evidence, particularly for other cancers such as ovarian cancer and breast cancer, that PARP inhibition can result in cytosolic DNA release and STING pathway activation, and this may sensitize these tumors to immunotherapy. There is significant biologic rationale for combining immunotherapy targeting PD-1/PD-L1 with PARP inhibition, and there are phase III trials of anti–PD-1/PD-L1–targeting drugs with PARP inhibition ongoing.

There is also value in combining the taxanes with PARP inhibition. If one thinks about ovarian cancer that has a very high frequency of BRCA alterations, we have data where platinum and taxanes are superior to taxanes alone. We would argue, as many others have done too, that either PARP inhibitors or platinum merits combining with taxanes such as docetaxel or cabazitaxel, particularly for the tumors with either truncal, clonal, or subclonal alterations affecting DNA repair genes that sensitize to PARP or platinum. I strongly endorse the pursuit of taxane‑based combinations with PARP inhibition, which is obviously the other major systemic treatment option that is approved today for advanced prostate cancer.

I hope, in the not-too-distant future, that we may have prostate-specific membrane antigen (PSMA) radioimmunonuclide therapies emerging as a therapeutic strategy. I would also envision that PARP inhibition may have merit in combination with those PSMA‑targeting drugs that cause double‑strand DNA breaks, since PSMA can enhance the induction of that DNA damage and double‑strand break generation and therefore tumor cell kill.

Your Thoughts?
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