For prostate cancer awareness month, Bamidele A. Adesunloye, MD, MS, and Evan Pisick, MD, discussed recent changes and new developments that have been added to the treatment landscape.
Transformative developments have impacted the field of prostate cancer and helped reshape the approach to treating and managing patients with this disease. With new therapeutic strategies recently approved, the potential to significantly impact patient outcomes is an exciting avenue for many oncologists.
“There's been a lot of changes in the landscape when it comes to prostate cancer therapy compared with about 20 years ago, especially with the combination of PARP inhibitor and androgen receptor–signaling inhibitors,” Bamidele A. Adesunloye, MD, MS, told Targeted OncologyTM in an interview.
In the past few months alone, the FDA has granted approval to multiple new combinations for patients with metastatic castration-resistant prostate cancer (mCRPC), including olaparib (Lynparza) in combination with abiraterone and prednisone or prednisolone for adult patients with mCRPC, and talazoparib (Talzenna) with enzalutamide (Xtandi) for patients with mCRPC that have homologous recombination repair (HRR) gene alterations in their disease.
The integration of PARP inhibitors and androgen receptor–signaling inhibitors represents a significant milestone in the ongoing fight to improve the quality of life for patients with prostate cancer.
The PROpel trial (NCT03732820), a phase 3 randomized, placebo-controlled, global, double-blind trial, enrolled patients with mCRPC and treated them with 300 mg of olaparib (two 150 mg tablets) 2 times a day plus abiraterone at 1000 mg doses once a day.
Those eligible for enrollment were patients with first-line mCRPC who had ongoing androgen deprivation with gonadotropin-releasing hormone analogue or bilateral orchiectomy. Patients were required to be a candidate for abiraterone therapy with documented evidence of progressive disease, have normal organ and bone marrow function, and have an ECOG performance status of 0 or 1.
Findings showed that the addition of olaparib resulted in a median radiographic progression-free survival (rPFS) of 24.8 months vs 16.6 months with standard of care (HR, 0.66; 95% CI, 0.54-0.81; P < .0001) per investigator review. The blinded independent central review confirmed these findings (HR, 0.61; 95% CI, 0.49-0.74; nominal P < .0001).1
Consistent with rPFS results, a trend toward overall survival (OS) benefit was seen in the intention-to-treat (ITT) population where patients received abiraterone with olaparib vs abiraterone with placebo (HR, 0.81; 95% CI, 0.67-1.00; P = .0544), with a median OS of 42.1 months vs 34.7 months, respectively.2
Additionally, the safety profile of the combination was similar to what has been previously observed in clinical trials and the established adverse events (AEs) of each agent alone.
“The primary analysis showed that the rPFS was significantly longer for patients who received abiraterone acetate a pairing with olaparib. In fact, the triplet was approved by the FDA recently for patients with mCRPC with deleterious or suspected deleterious BRCA mutations,” said Adesunloye, medical oncologist at City of Hope Atlanta.
According to data from the phase 3 study, the combination achieved statistically significant and clinically meaning progression free survival (PFS) improvement when used as a first-line therapy for this patient population.3
Findings showed that the primary end point of rPFS was met with a 55% reduced risk of progression of death in patients on the combination arm (n = 200), despite median rPFS not being reached (NR) in the talazoparib arm (95% CI, 21.9–NR) vs 13.8 months (95% CI, 11.0-16.7) in the placebo arm (HR, 0.45; 95% CI, 0.33-0.61, P < .0001).
The combination demonstrated a 37% lower risk of rPFS in the talazoparib plus enzalutamide arm compared with the placebo plus enzalutamide arm (HR, 0.63; 95% CI, 0.51-0.78; P < .0001).3,4 Among those in the HRR gene-altered subgroup, an rPFS benefit was also demonstrated when patients received talazoparib plus enzalutamide (HR, 0.44; 95% CI, 0.32-0.60, P < .0001). This benefit extended to the BRCA-mutated population (HR, 0.20; 95% CI, 0.11-0.36, P < .0001), and the non-BRCA population (HR, 0.68; 95% CI, 0.46-1.02; P = .060).
For safety, no new signals were seen with the combination. Grade 3/4 treatment emergent AEs were observed in 66.2% of patients given the combination vs 37.2% of patients treated with placebo and enzalutamide. Additionally, 67.2% of patients in the combination arm had a dose interruption of talazoparib due to an AE vs 19.6% in the placebo arm.
“In that study, the rPFS for patients who received talazoparib flourished. Meanwhile, for the patients that enzalutamide with placebo, the rPFS was about 13.8 months, so there was a significant rPFS benefit with talazoparib compared with placebo in this case. That led to the FDA approval of talazoparib and enzalutamide in patients with mCRPC with an HRR-gene mutation,” added Adesunloye.
Another therapy that has provided patients with a new option was granted FDA approval in March 2022. The FDA approved lutetium (177Lu) vipivotide tetraxetan (Pluvicto) for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive mCRPC5 based on findings from the phase 3 VISION (NCT03511664) study.
The recommended dose of the agent is 7.4 gigabecquerels (GBq; 200 mCi) given via intravenous infusion every 6 weeks for up to 6 doses, or until disease progression or unacceptable toxicity.
In the phase 3 VISION study, patients were randomized in a 2:1 fashion to receive 177Lu-PSMA-617 plus best standard-of-care (n = 551) or best standard-of-care (BSOC) alone (n = 280).
“One thing before you could give a patient this drug is that [the patient] had to have had a PSMA PET scan, and the lesion must be positive,” said Adesunloye. “We've seen a few patients on this drug and very robust responses, and PFS as well, on the drug. The practical use for Pluvicto from the VISION trial was that patients must have had at least 1 or 2 lines of systemic chemotherapy, and they must have had been treated with androgen receptor pathway inhibition.”
Findings from the VISION study showed that there was a statistically significant and clinically meaningful improvement in OS among patients treated with the experimental arm. The median OS in the 177Lu-PSMA-617 plus BSOC arm was 15.3 months vs 11.3 months in the BSOC arm, respectively (HR: 0.62; 95% CI, 0.52-0.74; P < .001).
Regarding safety, the most frequently observed AEs (≥20%) occurred at a higher incidence among patients receiving 177Lu-PSMA-617, and included fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation.
“Pluvicto is a radioactive PSMA ligand that we use for patients who have failed hormone therapy and chemotherapy. It was huge for us because it gave another option because right now, it's 1 of the last lines of therapy in the way it was approved. Patients had to have already had chemotherapy, and sometimes people do not get that until the end, and a lot of people had already failed hormone therapies. However, I know there are trials ongoing of introducing it much earlier in treatment.” said Evan Pisick, MD.
According to Pisick, chief of medical oncology, City of Hope Chicago, there have already been good results when using this treatment in earlier lines, with 1 patient who went into complete remission for a period of time. However, supply issues in 2022 and 2023 prevented many patients from receiving the agent.
Now, the shortages are resolved, but multiple factors still contribute to delays in getting patients access to treatment, such as radioligand availability, the need for PSMA-avid status on a PSMA PET scan, and the extended process of accessing 177Lu-PSMA-617.
“Our patients were still getting [treatment] if they had already been enrolled on it, but new patients couldn't get it. Now that they've opened plants in the United States, we can start enrolling new patients, and actually get it on schedule,” added Pisick.
In the evolving treatment landscape of mCRPC, promising advances like immunotherapy, and bipolar antigen therapy are on the horizon. These novel approaches hold significant potential, and experts like Pisick eagerly await their results in larger patient populations. However, questions still remain about who the ideal candidates are.
“Things like bipolar androgen therapy are still in their infancy. The question is, what will that become in the future? Who will be the patient for that? There's still a lot of early data for new immunotherapies because prostate cancer is 1 of the few cancers that we don't use a lot of immunotherapy in. There are new trials being looked at,” said Pisick.
More prostate-directed therapies, including high frequency ultrasound, are being utilized in patients with mCRPC, according to Pisick; especially in those who have already failed prior radiation therapy and have local recurrence, and for whom surgery may not be an option for.
As this landscape continues to grow with data, there is a growing possibility that community oncologists may consider these therapies for a wider range of patients. With these new products, along with those already approved, there is a need for comprehensive guidelines, such as those from the National Comprehensive Cancer Network (NCCN), to reflect the dynamic changes occurring in the field.
“The treatment landscape is changing. Over time, we may see community oncologists prescribing these drugs to all comers. Especially when we run out of options, we may start prescribing it to all comers as off-label. I think the guideline makers like the NCCN will have to come up with guidelines to tell us how to sequence drugs,” added Adesunloye.