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Beyond AR-targeted therapy, there are numerous other combination approaches focused on PARPi being explored in prostate cancer. How are we thinking about development of other PARPi combinations in prostate cancer? One option is to target downstream effects of DNA repair defects by combining PARPi with immunotherapy. Another option involves damaging the DNA and then impeding DNA repair in malignant cells, resulting in synthetic lethality. These are both exciting and interesting possible avenues forward that I will discuss next.
Single-agent immune checkpoint inhibitors have not shown much efficacy in prostate cancer beyond tumors that are microsatellite instability high, and PARPi are currently limited to select populations of patients. Combination approaches are needed to improve the efficacy of immunotherapy and broaden the patient population where PARP inhibition is effective in prostate cancer. As with all combinations, the goal is to improve efficacy, hopefully in a synergistic or at least additive manner, while minimizing additional toxicities.
There is ample evidence demonstrating that many cancer cells have a DNA repair defect of some variety, suggesting that they are reasonable targets for immunotherapy.31 PARP inhibition may make tumor cells more immunogenic by altering interferons and other cytokines that may enable the recruitment of T-cells whereas immune checkpoint blockade disrupts the negative regulation of such recruited T-cells.
KEYNOTE‑365 is a multicohort phase I study examining pembrolizumab in different combination regimens including pembrolizumab plus olaparib in cohort A.32-34 Patients with mCRPC and progressive disease who had previously received docetaxel were enrolled (N = 84). Patients received pembrolizumab 200 mg every 3 weeks and olaparib at either 400-mg capsule daily or 300-mg tablet twice daily. Treatment continued until disease progression or a maximum of 35 cycles (2 years). The primary endpoints were safety, PSA response, and ORR by BICR (RECIST 1.1). Secondary endpoints were disease control rate, rPFS, and OS. It is important to note there was no patient selection for DNA repair alterations or PD-L1 expression.
Treatment with pembrolizumab plus olaparib produced modest improvements in PFS and response rates among all patients. The median rPFS was 4.3 months, with a 12-month rPFS rate of 23.3%.
The combination of pembrolizumab plus olaparib is relatively safe, although there were some toxicities associated with PARPi or checkpoint inhibition, such as nausea and anemia. Two deaths were treatment related, one of which was due to an unknown cause and the other due to myocardial infarction. Another death from pneumonia was deemed not treatment related.
The ongoing phase III KEYLYNK‑010 trial randomizes patients with mCRPC 2 to 1 to receive olaparib plus pembrolizumab or either enzalutamide or abiraterone/prednisone (estimated N = 780).35 Enrolled patients must have progressed on androgen deprivation therapy and have received either abiraterone or enzalutamide; previous docetaxel is also allowed. Again, no molecular selection in this trial. The primary endpoints are OS and rPFS, with secondary endpoints including ORR, duration of response, time to PSA progression, and safety.
The ongoing phase II CheckMate 9KD trial is evaluating nivolumab plus either rucaparib, docetaxel, or enzalutamide in unselected patients (estimated N = 330).36 Primary endpoints are ORR and PSA response rate, and secondary endpoints include rPFS, OS, time to response, duration of response, and safety.
A phase Ib study of nivolumab plus rucaparib was recently terminated due to lack of efficacy in analysis of data from 7 patients.37,38
Another small phase I/II study evaluated olaparib and durvalumab in patients with mCRPC (N = 17).39,40 There was a difference in outcome early on from patients with DDR mutations, which probably accounts for the response observed in the waterfall plot on the upper left.
There are multiple ongoing trials evaluating the combination of PARPi with immunotherapies in patients with mCRPC. Most of these trials have a strong rationale behind them and could lead to novel approaches, although we would also have to determine which patients will benefit from these approaches. I would encourage you identify patients who might be eligible for these trials and to discuss clinical trial enrollment with them.
Chemotherapy allows us to manipulate the biology of the cancer toward a therapeutic benefit from PARPi by causing replication errors. The underlying basis for PARPi efficacy is synthetic lethality due to an inability to repair DNA. In cells with deficient DNA repair, mutations accumulate over time and can result in lethality. Thus combining DNA damaging agents with PARPi to impair DNA repair is a logical strategy.
Platinum is a DNA‑damaging chemotherapy that creates chelation and cross‑linking of single and double‑stranded DNA.41 These changes inhibit DNA synthesis and transcription, ultimately triggering cell death.
Patients with DDR mutations who get platinum‑based therapy can benefit, as shown in these retrospective data.42 Some patients with BRCA2 alterations have very deep responses to platinum. Before PARPi were available, we would treat patients with DDR alterations with agents like carboplatin to damage the DNA.
Data on the impact of DDR mutations on OS with platinum‑based therapy suggest that patients with DNA repair alterations may live longer when treated with platinum. These data were not prospective or randomized, but I have also observed this in my own practice. One challenge with platinum is that long-term treatment is difficult, but it can certainly lead to improvements in short‑term outcome.
Based on these data, should we combine PARPi with platinum in prostate cancer? Although this has been studied in several trials, it is challenging because there are no definitive data. The open-label, single-arm phase II PLATI‑PARP study will evaluate the combination of docetaxel and carboplatin followed by rucaparib in patients with mCRPC who have HRD (planned N = 20).43 The primary endpoint will be PFS. The strategy used in this study builds on a treatment strategy in ovarian cancer where patients are given platinum chemotherapy and put on PARPi as maintenance.
Although radium is not a chemotherapy, it damages DNA similar to carboplatin or platinum. The phase Ib dose-finding NiraRad study evaluating the optimal phase II dose of niraparib plus radium-223 found that 3 patients (10%) had a ≥50% decline in PSA at 12 weeks.44,45 In addition, 13 patients (43%) had a ≥30% decline in alkaline phosphatase. This will continue to be explored in the expansion phase II study.
Other ongoing studies are evaluating the combination of radionuclide therapies with olaparib.
Antiangiogenic agents are also being evaluated in combination with PARPi. The idea is to induce stress on the tumor through hypoxia generated by the antiangiogenic agent. In a hypoxic environment, HRR genes are downregulated.46,47 This ongoing, randomized phase II trial is evaluating olaparib plus cediranib vs olaparib alone (planned N = 400).48,49 Patients with progressive mCRPC and ≥1 previous therapy are eligible to enroll. Cediranib will be given at a dose of 30 mg once daily and olaparib 200 mg twice daily (in the combination group) or 300 mg (in the control group). Therapy will continue until radiographic progression, toxicity, or study withdrawal. Crossover from the olaparib arm to the combination arm is allowed. The primary endpoint is rPFS by PCWG3 criteria and secondary endpoints include rPFS by somatic and germline HRR status, OS, ORR, and safety.
Preliminary data from 87 patients demonstrate a possible signal for cediranib plus olaparib in rPFS. In the combination group, median PFS was 8.47 months vs 3.97 months with olaparib alone.
Additional analysis revealed that HRR‑deficient patients may have an enhanced benefit from combination therapy, with a median PFS of 10.63 months compared with 3.83 months for olaparib alone (HR: 0.640; 95% CI: 0.272-1.504; P = .3063). These data are still early, but I find it interesting that HRR‑proficient patients did not appear to benefit from the combination compared with olaparib alone. Based on this information, it may be better to focus on enhancing PARPi in patients who are HRR-deficient.
The combination of cediranib and olaparib resulted in some modest toxicities including fatigue and diarrhea, which is an adverse event of the angiogenesis inhibitor. Hypertension was an adverse event of cediranib, but apart from that, no new safety signals were observed.
Several studies are looking at combining radiation therapy with a PARPi. The ongoing phase II NADIR trial is looking at gonadotropin-releasing hormone (GnRH) and intensity‑modulated radiation therapy (IMRT) vs GnRH plus IMRT and niraparib in patients with high-risk prostate cancer (estimated N = 180).54 The primary endpoint is disease-free survival at 24 months and secondary endpoints include OS, time to progression, and safety.
Many combination strategies are being tested, including AR therapy, immunotherapy, and other agents. I strongly encourage healthcare professionals to discuss clinical trial enrollment with their patients so we can learn more about these combinations and further improve outcomes for our patients with prostate cancer.