Robert Dreicer, MD, MS, MACP, FASCO

Associate Director of Clinical Research, Medicine: Hematology and Oncology

University of Virginia School of Medicine

Charlottesville, VA

In prostate cancer, therapies and strategies have been developed, raising expectations of what constitutes a breakthrough, said Robert Dreicer, MD, MS, MACP, FASCO, an investigator involved in advanced prostate cancer research long enough to appreciate the significant advancements accomplished.

“Twenty or 30 years ago, if you improved radiographic progression-free survival [PFS] by a few months, we would have taken that, because we were making little progress,” said Dreicer, a professor of medicine and urology at the University of Virginia School of Medicine in Charlottesville. However, those strides come with a caveat. Although therapies can significantly improve survival in cases of metastatic castration-resistant or castration-sensitive disease, a cure remains elusive.

There is another problem, he said. Despite the availability of new therapies and strategies like androgen deprivation therapy (ADT) intensification, many of the latest therapies remain underutilized in the United States.

“It’s nice to make incremental progress, and the drugs that are being studied may increasingly move the needle,” he said. “But we also have a problem by not applying data that can already improve outcomes.” It is not a matter of access to the new drugs, he said. “It’s an educational challenge.”

Neeraj Agarwal, MD, FASCO

Professor of Medicine

University of Utah

Presidential Endowed Chair of Cancer Research

Director

Genitourinary Oncology Program

Center of Investigational Therapeutics

Huntsman Cancer Institute

Salt Lake City, Utah

There have been a lot of developments to track with the treatment of advanced prostate cancer. Over the past decade, many important studies helped define the impact of ADT intensification, using androgen receptor pathway inhibitors to further intensify ADT plus chemotherapy. Studies of next-generation androgen receptor (AR) inhibitors, such as abiraterone acetate (Zytiga), enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa), in advanced prostate cancers have shown positive results in certain patient subgroups. Combining PARP inhibitors with androgen receptor therapy has improved outcomes, and new types of therapies targeting prostate-specific membrane antigen (PSMA) have opened novel avenues for fighting cancer cells.

Such advancements have helped extend survival for subgroups, while new research focusing on biomarkers has created the potential to better identify which patients are most likely to experience recurrence and progression. This means the opportunity to extend patients’ lives has grown.

PARP Inhibition

In June, the FDA approved the PARP inhibitor talazoparib (Talzenna) plus enzalutamide for patients with metastatic castration-resistant prostate cancer (mCRPC) who have cancers harboring mutations in homologous recombination repair (HRR) genes.¹

The pivotal study behind the approval was the phase 3 TALAPRO-2 trial (NCT03395197). Though widely used in the mCRPC setting, enzalutamide typically is only effective for approǡimately 18 to 24 months, said Neeraj Agarwal, MD, FASCO, of the University of Utah’s Huntsman Cancer Institute, one of the study’s investigators. ܹ

"So the first question that comes to our mind is, ‘Why shouldn’t we improve the duration of response to enzalutamide?’” he said.

One strategy is to look at PARP, a DNA repair enzyme that is upregulated when patients take enzalutamide, essentially coming to the rescue of prostate cancer cells, Agarwal said.

“Over the last 10 years, we've seen preclinical data showinł a siłnificant interplay between Rs and PARP,” he said. “When you inhibit ARs, PARP gets upregulated. And if you inhibit PARP, AR gets downregulated.”

In July, Agarwal and colleagues published results of a planned primary analysis of TALAPRO-2. Among 402 patients with mCRPC who received talazoparib plus enzalutamide, median imaging-based PFS was not reached (95% CI, 27.5-not reached) compared with 21.9 months (95% CI, 16.6-25.1) in the 403 patients who received placebo plus enzalutamide (HR, 0.63; 95% CI, 16.6-25.1). In its approval, the FDA focused on the subgroup of patients who had the clearest benefit. ܹThe benefit was more pronounced in patients with HRR mutation, with a 55% reduction in risk of disease progression or death,” Agarwal said. “And [there] was a 34% reduction in risk of progression or death in HRR mutation–negative patients.”

PROpel Trial

In May, olaparib (Lynparza) was approved, in combination with abiraterone acetate and prednisone or prednisolone, for the treatment of adults with mCRPC harboring deleterious or suspected deleterious BRCA mutations.³ The approval was based on results from the PROpel trial (NCT03732820), in which 796 patients with mCRPC were randomized to receive first-line abiraterone plus prednisone (or prednisolone) along with either olaparib or placebo.⁴

The study found patients who received olaparib had superior outcomes to those in the placebo group. The primary end point, median investigator-assessed imaging-based PFS, was significantly longer in the olaparib group at 24.8 months compared with 16.6 months in the placebo group (HR, 0.66; 95% CI, 0.54-0.81; P <.001 TABLE).⁴

However, a subgroup analysis showed that the overall benefit was primarily driven by outcomes in patients with BRCA mutations. In this subgroup (n = 85), the olaparib combination led to siłnificant improvements in imaging-based PFS (HR, 0.24; 95% CI, 0.12-0.45) and overall survival (OS; HR, 0.30; 95% CI, 0.15-0.59) compared with placebo.^5,6

Dreicer cautioned that the approval was based on a very specific patient population with most patients progressing to the mCRPC setting without first receiving second-generation antiandrogen agents. Patients were permitted if they received docetaxel (Taxotere) as neoadjuvant/adjuvant treatment for localized prostate cancer and metastatic hormone-sensitive prostate cancer (mHSPC).⁴

“Based on the data presented, the FDA deemed that only people with BRCA positivity showed enough benefit to łet the approval,ܺ" Dreicer said. ܹThis isnܼ't to suggest that this isnܼ't an important development. But it is not yet a broadly applicable combination for most patients with mCRPC.”

The new approval represented an expanded indication for olaparib, which in 2020 was approved for adult patients with germline or somatic HRR gene–mutated mCRPC who had progressed following treatment with abiraterone or enzalutamide.⁷

Second-Generation Antiandrogens

Results from other important studies have been published in recent years, centered on ADT intensification using second-generation androgen receptor inhibitors.

STAMPEDE (NCT00268476), a long-term study platform examining the addition of a variety of agents to ADT in the first-line setting, has generated many publications. In 2017 results showed that adding abiraterone acetate and prednisolone to ADT led to a survival benefit in patients with newly diagnosed locally advanced or metastatic prostate cancer. At a median follow-up of 40 months, the 3-year OS rate was 83% in the combination group compared with 76% for ADT alone (HR, 0.63; 95% CI, 0.52-0.76; P <.001) However, the size of the benefit differed between patients with nonmetastatic cancers (HR, 0.75) and the metastatic group (HR, 0.61).

The STAMPEDE group published its most recent report in May, evaluating 2 trials: One added abiraterone/prednisone to ADT and one added abiraterone/ prednisone to enzalutamide and ADT. It looked at the long-term impact of addinł enzalutamide to abiraterone in patients with metastatic prostate cancer who were starting ADT.⁹ The study results showed that abiraterone improved survival over ADT alone, but adding enzalutamide did not improve outcomes and had a negative impact on safety.

Similarly to the 2017 STAMPEDE report, investigators for the LATITUDE trial (NCT01715285) showed in 2019 that, at a median follow-up of 51.8 months, patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (mCSPC) who received abiraterone acetate plus prednisone in addition to ADT had a significantly longer median OS (95% CI, 48.2-not reached) compared with those who received placebo plus ADT (35.6 months; 95% CI, 33.5%-40.0%; [HR, 0.66; 95% CI, 0.56-0.78; P <.0001]).¹⁰

The trial began as a randomized, double-blind study, but after the first interim analysis patients were allowed to cross over to receive abiraterone acetate and prednisone instead of placebo. The final analysis showed that 46% of patients in the abiraterone group and 57% of patients in the placebo group had died.

That same year, Agarwal and his colleagues in the TITAN study group (NCT02489318) published results demonstrating that the addition of apalutamide to ADT led to greater OS and imaging-based PFS in patients with mCSPC compared to placebo plus ADT.¹¹ Meanwhile, results from the ARCHES study (NCT02677896), published in 2019, demonstrated the potential of enzalutamide in mHSPC. Patients were assigned to either enzalutamide or placebo in addition to ADT. As in the TITAN study, the authors found the androgen receptor inhibitor combination outperformed ADT alone, extending imaging-based PFS.¹²

Androgen Receptor Inhibition in De Novo Cases

Similar studies but for patients with de novo mCSPC, showed that adding androgen receptor inhibitors to standard therapies improved results. The PEACE-1 (NCT0195746) phase 3 results showed adding abiraterone plus prednisone to the standard therapy of ADT and docetaǡel improved OS (HR, 0.82; 95% CI, 0.69-0.98; P = .030) and imaging-based PFS (HR, 0.54; 99.9% CI, 0.41-0.72; P <.0001), thought it led to a ܹ"modestܺ" increase in toxicity.¹³

The ARSENS trial (NCT02799602), added darolutamide to ADT and docetaxel in patients with mHSPC, finding improved outcomes among patients given darolutamide.¹⁴ In a subgroup analysis of patients with de novo mHSPC, the HR for death was 0.71 (95% CI, 0.59-0.85).¹⁵

New Vision for Prostate Cancer Therapy

Other significant research has examined new targets, including PSMA, which is seen as a relevant therapeutic target in advanced cases of prostate cancer, Dreicer said. ܹ

"Itܼs a very important target," he said. "I think there is a lot of excitement and enthusiasm, though, we need data to get really excited."

Some of the first meaningful data regarding PSMA-targeting therapies was published in 2021, when results from the phase 3 VISION trial (NCT03511664) were published. The study investigated lutetium 177-PSMA-617, abbreviated as ¹⁷⁷Lu-PSMA-617.¹⁶ A total of 813 patients with mCRPC who had prior treatment of at least 1 androgen receptor pathway inhibitor and 1 or 2 taxane regimens, and who were PSMA-positive based on gallium-68–labeled PSMA-11 PET-CT scans, were randomized to receive standard of care alone or combined with ¹⁷⁷Lu-PSMA-617. At a median follow-up of 20.9 months, patients in the intervention arm had a median imaging-based PFS of 8.7 months vs 3.4 months in the standard-of-care group (HR for progression or death, 0.40; 99.2% CI, 0.29-0.57; P <.001) OS also improved in the intervention arm, and all of the secondary end points favored ¹⁷⁷Lu-PSMA-617. ܹ

"Itܼs a small molecule that targets prostate-specific membrane antigen," Dreicer explained, "and then it drops a radioactive material that kills the cell." He said the benefit regarding survival was "modest, but important."

Those data led to FDA approval of lutetium Lu 177 vipivotide tetraxetan (Pluvicto), to treat patients with PSMA-positive mCRPC who have been treated with an androgen receptor pathway inhibitor and taxane-based chemotherapy. The agency also approved a radioactive diagnostic agent to identify patients who meet the PSMA criteria.¹⁷

Agarwal said one exciting aspect of PSMA is that it can be targeted in multiple ways, including using chimeric antigen receptor (CAR) T cells and bispecific antibodies.

"There are other drug-delivery systems, but PSMA can be tarłeted in a specific fashion because it is very selectively expressed on prostate cancer [cells]," he said.

Agarwal said PSMA is also expressed in the salivary glands and the kidneys, creating the potential for adverse events (AEs) in those places. In general, he said, the close link between PSMA and prostate cancer makes it a strong target for future development.

Safety and Important Considerations

Agarwal conceded that AEs are an important part of the conversation with all of newer therapies. For instance, in TALAPRO-2, nearly half of patients (46%) in the talazoparib group experienced grade 3 to 4 anemia and 8% and thus discontinued the drug.² He noted, though, that 42% of patients had grade 1/2 anemia–often cancer related–before protocol treatment. Similar AEs were noted in the PROpel trial, in which olaparibܼ's expanded approval was based.⁴

In the PEACE-1 trial, patients with de novo mCSPC who received abiraterone in addition to ADT and docetaǡel had a 22% rate of grade 3 or higher hypertension, compared with 13% in patients who did not receive abiraterone. Other AEs, including neutropenia and fatigue, did not vary significantly between arms.¹³

Biomarkers

Investigators have worked to identify new molecular biomarkers of risk stratification and progression in prostate cancer. For instance, a study published in June suggested that immunohistochemical staining of a 3-biomarker panel (Appl1, Sortilin, and Syndecan-1) outperformed traditional stratification based on hematoxylin and eosin staining for predicting clinical and biochemical recurrence.¹⁸ i

Biomarker testing could help refine clinical decisions by giving a better understanding of which therapies my work best for individual patients. A review published last year identified a number of coding and noncoding genes, as well as the TMPRSS2-ERG gene fusion, that may have value in predicting treatment response. However, the review also concluded that there is a "wide molecular field that lies unexplored," suggesting the possibility of more breakthroughs in the coming years.¹⁹

From Bench to Bedside

Dreicer noted that prostate cancer treatment involves clinicians in various types of settings, from small community practices to large, specialized prostate cancer clinics. ܹ

"Community medical oncologists who practices near large urology group practices, may not see a lot of prostate cancer," he said. ܹ"Their colleagues in those advanced practice clinics take care of those patients." Conversely, medical oncologists not near an advanced prostate cancer clinic might see more cases of prostate cancer. ܹ

"Community oncologists have to keep up with a lot of information, changing almost every day, and in a large number of common cancers," he said.

No clinician can know everything, Dreicer said, but it is important that clinicians know about "profoundly impactful" developments like ADT intensification.

Agarwal advised a proactive mindset, utilizing tools like intensification before it is too late. When it comes to advanced prostate cancer, he said, ܹ"too late" often comes quickly.

"In prostate cancer, which is [seen in] an older, more frail population, about 40% of patients do not receive their next life-prolonging therapy because they lose their performance status so quickly or they succumb to their disease," he said.

Despite the availability of multiple lines of therapy, he said patients with prostate cancer actually receive a median of less than 2 lines. Sometimes clinicians feel they should start with enzalutamide saving olaparib or talazoparib for later, after enzalutamide alone stops working. That is the wrong approach, Agarwal said.

"Donܼ't leave any drug for later," he said. ܹIf [your patient is] eligible for the drug. I would say use it."

REFERENCES

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5. LYNPARZA® (olaparib) plus abiraterone approved in the US for the treatment of BRCA-mutated metastatic castration-resistant prostate cancer. News release. Astra-Zeneca. Accessed July 21, 2023. https://bit.ly/44Fni3l

6. FDA Approves Lynparza (olaparib) Plus Abiraterone and Prednisone or Prednisolone for Treatment of Adult Patients With BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer (mCRPC). Drugs.com. Accessed August 2, 2023. h ps://bit.ly/3KoKI58

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