New Class of Radiopharmaceutical Therapy Makes Headway in Prostate Cancer

Investigators have made great strides in the development of radiopharmaceuticals for prostate cancer diagnostics, culminating in recent FDA approvals for the first prostate-specific membrane antigen (PSMA)–targeted radioligands, gallium 68 (⁶⁸Ga)–PSMA-11 and piflufolastat F 18 (Pylarify), for the detection of disease recurrence and metastatic lesions.^1,2

Meanwhile, the use of PSMA-targeted radiopharmaceuticals for prostate cancer therapy is heading for the mainstream treatment landscape. Positive results from the phase 3 VISION trial (NCT03511664) involving lutetium 177 (¹⁷⁷Lu)–PSMA-617, a radiolabeled small molecule inhibitor of PSMA, were recently published and could be used to support FDA approval for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

A number of other PSMA-targeted radioligands are undergoing clinical evaluation, including several that incorporate monoclonal antibodies (mAbs) rather than small molecule inhibitors (TABLE). The 2 types of agents have distinct pharmacokinetic, safety, and efficacy profiles that could lend themselves to different patient populations.^5,6

To date, clinical development has been focused on conjugating PSMA-targeted drugs to beta-emitting radioisotopes, but alpha emitters could offer greater efficacy if the challenge of increased toxicity can be addressed.^5-8 Early clinical data for alpha emitters such as actinium 225 (²²⁵Ac)–labeled small molecule inhibitors and mAbs demonstrate promising results, including in tandem therapy with ¹⁷⁷Lu-PSMA-617.^6,8,9

Targeted Radioactive Chasers

Radiopharmaceuticals are systemically delivered radioactive isotopes or compounds that localize to tumors—via either physiologic mechanisms or incorporation of a specific targeting molecule—while sparing normal tissues. They can be used as tracers, facilitating tumor detection via diagnostic imaging using PET/CT or other imaging technologies that detect the radiation (often in the form of positrons) emitted by the radioisotopes. Alternatively, radiopharmaceuticals can be designed to enter cancer cells and induce cytotoxic DNA damage for therapeutic purposes.^6,10,11

In the diagnostic field, much of the recent attention has centered on radiopharmaceuticals targeting PSMA, a cell membrane protein expressed at particularly high levels on prostate cancer cells.^7,11 Administered intravenously, PSMA-targeted radiolabeled tracers accumulate at tumor sites with high levels of PSMA expression.¹¹

PSMA-targeted radiotracers have progressed rapidly through clinical trials.⁶ In December 2020, ⁶⁸Ga-PSMA-11 became the first PSMA-targeted radiopharmaceutical approved for PET imaging purposes in patients with prostate cancer. Specifically, ⁶⁸Ga-PSMA-11 can be used to help confirm suspected prostate cancer recurrence based on elevated prostate-specific antigen (PSA) levels or to detect metastatic lesions.¹

In May 2021, ⁶⁸Ga-PSMA-11 was joined by a second PET imaging agent, piflufolastat F 18, a small molecule targeting PSMA conjugated to a fluorine 18 isotope.² Piflufolastat F 18 was approved for the same indications that ⁶⁸Ga-PSMA-11 has.² However, the FDA approved ⁶⁸Ga-PSMA-11 for use at 2 academic sites—the University of California, Los Angeles and the University of California, San Francisco—whereas piflufolastat F 18 is expected to be more widely available throughout the United States.^2,12

If detected early, recurrent disease can be managed effectively with salvage therapy, and accurate detection of metastatic lesions can help spare patients unnecessary surgery. Current PET/CT tracers for prostate cancer imaging have limited ability to detect recurrent disease in a timely manner and identify occult metastases. Thus, the introduction of PSMA-targeted tracers is revolutionizing prostate cancer imaging and detection.⁷

Radiopharmaceuticals Therapies

The development of radiopharmaceutical therapies has also progressed rapidly in recent years. Although the current market for such therapeutics is estimated at approximately one-third the size of the imaging market, the uptake is expected to grow substantially over the next several years.¹³ The category, sometimes called radiotheranostics, broadly comprises beta- and alpha-emitting radiation therapy and brachytherapy.^3,13

The concept of leveraging radioisotopes for cancer therapy has been explored for more than 70 years, notably through the use of radioactive iodine for thyroid cancer.³ Two beta-emitting agents, strontium-89 chloride (Metastron) and samarium-153 (Quadramet), have been FDA approved since the 1990s for palliating painful bone metastases and are used in this setting for patients with prostate cancer.^3,14

In 2013, the FDA approved radium-223 dichloride (Xofigo), an alpha-emitting radiopharmaceutical, for the treatment of patients with castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastatic disease.

Experts anticipate that a new generation of therapeutic radioisotopes in development will expand therapeutic efficacy of these agents, particularly for more prevalent tumor types.^3,15

The new crop of agents includes ¹⁷⁷Lu-dotatate (Lutathera), a radiolabeled somatostatin analogue that the FDA approved in January 2018 for the treatment of patients with somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors.¹⁶

However, ¹⁷⁷Lu-dotatate occupies a small niche market, whereas PSMA-targeted radioligand therapy (RLT), which is designed to treat patients with prostate cancer, the second-leading cause of cancer-related mortality in men in the United States,¹⁷ has brought much greater attention to the field of radiopharmaceutical therapy.¹⁵

PSMA-targeting small molecule inhibitors and mAbs are conjugated to different radioisotopes for therapeutic purposes, most commonly ¹⁷⁷Lu, which emits beta radiation. At the forefront of clinical development are the radiolabeled inhibitors ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA-I&T.

Research groups in Germany initially developed both therapies. Endocyte subsequently purchased the rights to ¹⁷⁷Lu-PSMA-617, and Novartis, which acquired Endocyte in 2018, is now developing the therapy.¹⁵ Meanwhile, POINT Biopharma acquired ¹⁷⁷Lu-PSMA-I&T.¹⁸

Findings from multiple studies in small cohorts of patients with mCRPC have demonstrated that treatment with ¹⁷⁷Lu-PSMA-617 or ¹⁷⁷Lu-PSMA-I&T resulted in significant declines in PSA levels.7 In terms of pharmacokinetics, ¹⁷⁷Lu-PSMA-617 is favored because of its lower kidney uptake, but no head-tohead comparisons of the 2 agents have been performed to date.⁷

Results from the first prospective trial (LuPSMA; Australian New Zealand Clinical Trials Registry number 12615000912583) of ¹⁷⁷Lu-PSMA-617 in 30 patients with mCRPC demonstrated a PSA response in more than half of the participants, with response defined according to Prostate Cancer Clinical Trial Working Group criteria as a PSA decline from baseline of 50% or greater. The most common treatment-related adverse events (TRAEs) were dry mouth, nausea, and fatigue. Grade 3/4 TRAEs included lymphocytopenia (37%) and anemia and thrombocytopenia (13% each); however, investigators described the overall rate of grade 3/4 hematologic toxicity as low and comparable to previously published retrospective data.¹⁹

In the phase 2 TheraP trial (NCT03392428), ¹⁷⁷Lu-PSMA-617 administered at 6 to 8.5 GBq every 6 weeks for up to 6 cycles was compared with cabazitaxel (Jevtana) given at 20 mg/m2 every 3 weeks for up to 10 cycles. Among 183 patients with mCRPC, the RLT resulted in a higher PSA response rate (66% vs 37%; difference, 29%; 95% CI, 16%-42%; P < .0001) and a lower rate of grade 3/4 AEs (33% vs 53%, respectively).²⁰

Investigators have published topline data from the international, randomized, phase 3 VISION trial comparing ¹⁷⁷Lu-PSMA-617 (7.4 GBq every 6 weeks for 4-6 cycles) plus standard of care (SOC; excluding cabazitaxel) vs SOC alone in patients with mCRPC. Outcomes from 581 patients were reported in the analysis set after a median follow-up of 20.3 months (95% CI, 19.8-21.0 months) in the ¹⁷⁷Lu-PSMA-617 arm and 19.8 months (95% CI, 18.3-20.8 months) in the control group. Treatment with the RLT significantly delayed progression, with the median imaging-based progression-free survival (PFS) of 8.7 months compared with 3.4 months for SOC (HR, 0.40; 99.2% CI, 0.29-0.57; P < .001).⁴

Among 831 patients who underwent randomization, the median overall survival (OS) was 15.3 months for patients treated with ¹⁷⁷Lu-PSMA-617 plus SOC vs 11.3 months for those treated with SOC alone (HR, 0.62; 95% CI, 0.52-0.74; P < .001). Fatigue, dry mouth, and nausea were the most common AEs in the ¹⁷⁷Lu-PSMA-617 arm; grade 3 and higher AEs, predominantly hematologic toxicities, also were more common with the RLT.⁴

In June 2021, the FDA awarded 177Lu-PSMA-617 a breakthrough therapy designation on the basis of these results. Ongoing studies are examining the agent in patients with chemotherapy-naïve mCRPC or hormone-sensitive prostate cancer.²¹

Meanwhile, ongoing clinical development of radiolabeled PSMA inhibitors focuses on further improving safety and efficacy. One strategy involves adding an albumin-binding domain to the RLT to enhance circulation time and increase tumor uptake. Cancer Targeted Technology is developing one such drug, ¹⁷⁷Lu-DOTA-N3-CTT1403.^11,22

PSMA Antibodies

Although the focus has been on small molecule PSMA inhibitors, several radiolabeled antibodies, which have different characteristics that can affect efficacy and safety, also are in development. Antibodies are larger and more challenging to synthesize, and they have a longer half-life in the circulation.^5,6

Antibody therapy tends to lead to more off-target toxicity in the bone marrow and liver, whereas small molecule inhibitors have more on-target toxicity in other tissues where PSMA is expressed, including the kidney, salivary glands, and small intestine. The major toxicities associated with ¹⁷⁷Lu-PSMA-617 are dry mouth and nausea, whereas hematologic toxicities are more common with PSMA antibody–based radiopharmaceuticals.^5,23

¹⁷⁷Lu conjugated to the PSMA-targeted mAb J591 has demonstrated efficacy in early-phase clinical trials in patients with prostate cancer, albeit with dose-limiting myelosuppression. In findings from a phase 1/2 study (NCT00538668), fractionated dosing permitted higher cumulative doses of 177Lu-J591 to be administered, with higher doses correlated with increases in both efficacy and toxicity. Myelosuppression was generally predictable, short-term, and self-limiting.^24,25

Telix Pharmaceuticals is developing TLX591 (¹⁷⁷Lu-DOTA-rosopatamab), which employs an enhanced version of the J591 antibody, rosopatamab, conjugated to ¹⁷⁷Lu. The therapy has been engineered to have a shorter plasma half-life, which is expected to reduce hematologic toxicity while maintaining antitumor efficacy.²⁵ TLX591 is scheduled to be evaluated as a second-line treatment for patients with mCRPC that expresses PSMA in the phase 3 PROSTACT trial (NCT04876651).²⁶

Alpha Emitters

Another strategy to increase the efficacy of RLT is to use alpha radiation–emitting isotopes, such as ²²⁵Ac. These have several potential advantages, including higher energy and lower cell penetration. The former increases the probability of inducing double-stranded breaks in the DNA of target cells, and the latter helps localize their cytotoxic activity to the tumor.^6,7,15

Radium 223, the only alpha-emitting radiopharmaceutical approved for prostate cancer, is a calcium mimetic that naturally accumulates in areas of high bone turnover. It is approved for the treatment of patients with symptomatic bone metastases but has no efficacy against extraskeletal metastases.^6,13

A number of clinical studies of ²²⁵Ac-PSMA-617, an alpha emitter that Novartis also is developing, have demonstrated significant antitumor efficacy but at the cost of increased toxicity. Dry mouth is a particularly common AE that can significantly reduce quality of life and is a leading cause of treatment discontinuation.^27-30

Several strategies to reduce the risk of toxicity are being tested. These include dynamic de-escalation, wherein a fixed dose of 8 MBq is used in the first cycle and then reduced in subsequent cycles in patients with a good response.

Another approach being explored is tandem RLT combining ¹⁷⁷Lu-PSMA-617 with ²²⁵Ac-PSMA-617, which could augment the efficacy of the former while mitigating the toxicity of the latter. In a retrospective study of ¹⁷⁷Lu-naïve patients with a poor prognosis (N = 15) who received treatment within a prospective patient registry (REALITY Study; NCT04833517), tandem therapy resulted in biochemical partial remission in 53.3% of patients, a median PFS of 9.1 months (defined by PSA progression), and a median OS of 14.8 months. The only grade 3/4 toxicities were 2 cases of grade 3 anemia.⁸

The use of PSMA-targeted mAbs as opposed to small molecule inhibitors also could help reduce AEs because mAbs have less on-target toxicity in nontumor tissues such as salivary glands. Initial findings from an ongoing phase 1 trial (NCT03276572) showed that treatment with 225Ac-J591 at 7 dose levels between 13.3 and 93.3 kBq/kg resulted in a PSA response in 35% of 22 patients and just 1 grade 3/4 TRAE.⁹

Telix Pharmaceuticals is developing TLX592, known as ²²⁵Ac-TLX592 and ⁶⁴Cu-DOTA-TLX592, a next-generation PSMA-targeted mAb optimized for use as a ²²⁵Ac-immunoconjugate. Because alpha radiation cannot be detected with PET, investigators are performing preliminary examination of the biological properties of TLX592 using a copper 64–conjugated version in the first-in-human CUPID trial (NCT04726033), which recently began enrolling patients. Copper 64 will be substituted with 225Ac when therapeutic dosing of participants begins.³¹

Finally, some investigators are using a third alpha-emitting radioisotope, thorium 227 (²²⁷Th), in RLT. BAY 2315497 is a ²²⁷Th-conjugated PSMA-targeted mAb.³² A phase 1 clinical trial of this drug is ongoing (NCT03724747).

References

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